CA2423469A1 - Methods and products related to pulmonary delivery of polysaccharides - Google Patents
Methods and products related to pulmonary delivery of polysaccharides Download PDFInfo
- Publication number
- CA2423469A1 CA2423469A1 CA002423469A CA2423469A CA2423469A1 CA 2423469 A1 CA2423469 A1 CA 2423469A1 CA 002423469 A CA002423469 A CA 002423469A CA 2423469 A CA2423469 A CA 2423469A CA 2423469 A1 CA2423469 A1 CA 2423469A1
- Authority
- CA
- Canada
- Prior art keywords
- polysaccharide
- heparin
- dry
- glycosaminoglycan
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 229920001282 polysaccharide Polymers 0.000 title claims abstract description 246
- 239000005017 polysaccharide Substances 0.000 title claims abstract description 246
- 238000000034 method Methods 0.000 title claims abstract description 133
- 150000004676 glycans Chemical class 0.000 title claims abstract description 59
- 230000002685 pulmonary effect Effects 0.000 title abstract description 30
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 43
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 307
- 239000002245 particle Substances 0.000 claims description 223
- 229920000669 heparin Polymers 0.000 claims description 202
- 229960002897 heparin Drugs 0.000 claims description 186
- 238000002360 preparation method Methods 0.000 claims description 95
- 229920002683 Glycosaminoglycan Polymers 0.000 claims description 83
- 239000000203 mixture Substances 0.000 claims description 71
- 239000000443 aerosol Substances 0.000 claims description 65
- 210000004072 lung Anatomy 0.000 claims description 60
- 239000008280 blood Substances 0.000 claims description 50
- 210000004369 blood Anatomy 0.000 claims description 46
- 230000000694 effects Effects 0.000 claims description 44
- 206010028980 Neoplasm Diseases 0.000 claims description 32
- 239000003814 drug Substances 0.000 claims description 29
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical group CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
- 210000002345 respiratory system Anatomy 0.000 claims description 26
- 201000011510 cancer Diseases 0.000 claims description 22
- 229920000642 polymer Polymers 0.000 claims description 22
- 238000001356 surgical procedure Methods 0.000 claims description 21
- 239000004094 surface-active agent Substances 0.000 claims description 20
- 238000009472 formulation Methods 0.000 claims description 19
- 208000035475 disorder Diseases 0.000 claims description 18
- 229940124597 therapeutic agent Drugs 0.000 claims description 17
- 208000006011 Stroke Diseases 0.000 claims description 16
- 210000004879 pulmonary tissue Anatomy 0.000 claims description 16
- 206010027476 Metastases Diseases 0.000 claims description 15
- 230000009401 metastasis Effects 0.000 claims description 15
- 210000001519 tissue Anatomy 0.000 claims description 15
- 229920002971 Heparan sulfate Polymers 0.000 claims description 14
- 239000003055 low molecular weight heparin Substances 0.000 claims description 14
- 229940127215 low-molecular weight heparin Drugs 0.000 claims description 13
- 102000004169 proteins and genes Human genes 0.000 claims description 13
- 108090000623 proteins and genes Proteins 0.000 claims description 13
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 10
- 208000007536 Thrombosis Diseases 0.000 claims description 9
- 230000033115 angiogenesis Effects 0.000 claims description 9
- 208000023504 respiratory system disease Diseases 0.000 claims description 9
- 230000002792 vascular Effects 0.000 claims description 9
- 230000001154 acute effect Effects 0.000 claims description 8
- 238000001514 detection method Methods 0.000 claims description 8
- 229920001542 oligosaccharide Polymers 0.000 claims description 8
- 150000002482 oligosaccharides Chemical class 0.000 claims description 8
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 7
- 201000001320 Atherosclerosis Diseases 0.000 claims description 7
- 206010014561 Emphysema Diseases 0.000 claims description 7
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 7
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 7
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 7
- 208000006673 asthma Diseases 0.000 claims description 6
- 229920001277 pectin Chemical class 0.000 claims description 6
- 239000001814 pectin Chemical class 0.000 claims description 6
- 235000010987 pectin Nutrition 0.000 claims description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 6
- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 5
- 206010053567 Coagulopathies Diseases 0.000 claims description 5
- 206010051055 Deep vein thrombosis Diseases 0.000 claims description 5
- 201000004681 Psoriasis Diseases 0.000 claims description 5
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 5
- 206010047249 Venous thrombosis Diseases 0.000 claims description 5
- 230000002491 angiogenic effect Effects 0.000 claims description 5
- 208000015294 blood coagulation disease Diseases 0.000 claims description 5
- 230000009852 coagulant defect Effects 0.000 claims description 5
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical class CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 4
- 206010002388 Angina unstable Diseases 0.000 claims description 4
- 229920001287 Chondroitin sulfate Polymers 0.000 claims description 4
- 206010020751 Hypersensitivity Diseases 0.000 claims description 4
- 206010063837 Reperfusion injury Diseases 0.000 claims description 4
- 208000007814 Unstable Angina Diseases 0.000 claims description 4
- 230000007815 allergy Effects 0.000 claims description 4
- 229940059329 chondroitin sulfate Drugs 0.000 claims description 4
- 229920002674 hyaluronan Chemical class 0.000 claims description 4
- 229960003160 hyaluronic acid Drugs 0.000 claims description 4
- 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229960000292 pectin Drugs 0.000 claims description 4
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 4
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical class FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- 208000026935 allergic disease Diseases 0.000 claims description 3
- 230000002785 anti-thrombosis Effects 0.000 claims description 3
- 206010003246 arthritis Diseases 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 102000039446 nucleic acids Human genes 0.000 claims description 3
- 108020004707 nucleic acids Proteins 0.000 claims description 3
- 150000007523 nucleic acids Chemical class 0.000 claims description 3
- 210000000056 organ Anatomy 0.000 claims description 3
- 230000000399 orthopedic effect Effects 0.000 claims description 3
- 230000036470 plasma concentration Effects 0.000 claims description 3
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims description 3
- 230000000250 revascularization Effects 0.000 claims description 3
- 229920000045 Dermatan sulfate Chemical class 0.000 claims description 2
- 230000010100 anticoagulation Effects 0.000 claims description 2
- AVJBPWGFOQAPRH-FWMKGIEWSA-L dermatan sulfate Chemical class CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@H](OS([O-])(=O)=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](C([O-])=O)O1 AVJBPWGFOQAPRH-FWMKGIEWSA-L 0.000 claims description 2
- 229940051593 dermatan sulfate Drugs 0.000 claims description 2
- 230000002107 myocardial effect Effects 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 235000012054 meals Nutrition 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 abstract description 45
- 230000009885 systemic effect Effects 0.000 abstract description 3
- 150000004804 polysaccharides Chemical class 0.000 description 187
- 229940090880 ardeparin Drugs 0.000 description 50
- -1 sorbitan fatty acid Chemical class 0.000 description 34
- 241000283973 Oryctolagus cuniculus Species 0.000 description 32
- 241000700159 Rattus Species 0.000 description 30
- 238000007920 subcutaneous administration Methods 0.000 description 26
- 238000003556 assay Methods 0.000 description 23
- 230000001858 anti-Xa Effects 0.000 description 18
- 210000002381 plasma Anatomy 0.000 description 18
- 239000007788 liquid Substances 0.000 description 17
- 239000012530 fluid Substances 0.000 description 16
- 239000000843 powder Substances 0.000 description 15
- 230000002401 inhibitory effect Effects 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 14
- 108010067372 Pancreatic elastase Proteins 0.000 description 12
- 102000016387 Pancreatic elastase Human genes 0.000 description 12
- 210000003437 trachea Anatomy 0.000 description 12
- 239000003146 anticoagulant agent Substances 0.000 description 11
- 229920002678 cellulose Polymers 0.000 description 11
- 238000003379 elimination reaction Methods 0.000 description 11
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 10
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 230000015271 coagulation Effects 0.000 description 10
- 238000005345 coagulation Methods 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 230000008030 elimination Effects 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 229960000187 tissue plasminogen activator Drugs 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 235000010980 cellulose Nutrition 0.000 description 9
- 210000004881 tumor cell Anatomy 0.000 description 9
- 230000004888 barrier function Effects 0.000 description 8
- 230000004071 biological effect Effects 0.000 description 8
- 210000004204 blood vessel Anatomy 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 230000017531 blood circulation Effects 0.000 description 7
- 239000001913 cellulose Substances 0.000 description 7
- 206010008118 cerebral infarction Diseases 0.000 description 7
- 230000006378 damage Effects 0.000 description 7
- 210000004379 membrane Anatomy 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 230000002265 prevention Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 201000006474 Brain Ischemia Diseases 0.000 description 6
- 206010008120 Cerebral ischaemia Diseases 0.000 description 6
- 229920002101 Chitin Polymers 0.000 description 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 229940127219 anticoagulant drug Drugs 0.000 description 6
- 239000000427 antigen Substances 0.000 description 6
- 108091007433 antigens Proteins 0.000 description 6
- 102000036639 antigens Human genes 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 230000004087 circulation Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000008263 liquid aerosol Substances 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 238000010254 subcutaneous injection Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 108010022901 Heparin Lyase Proteins 0.000 description 5
- 229920000954 Polyglycolide Polymers 0.000 description 5
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 229940127218 antiplatelet drug Drugs 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 230000008021 deposition Effects 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 230000008034 disappearance Effects 0.000 description 5
- 230000002255 enzymatic effect Effects 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 239000003527 fibrinolytic agent Substances 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 230000000302 ischemic effect Effects 0.000 description 5
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 5
- 230000000069 prophylactic effect Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000001694 spray drying Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 208000005189 Embolism Diseases 0.000 description 4
- 108010054147 Hemoglobins Proteins 0.000 description 4
- 102000001554 Hemoglobins Human genes 0.000 description 4
- 230000036770 blood supply Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 238000000227 grinding Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 150000002772 monosaccharides Chemical class 0.000 description 4
- 239000004633 polyglycolic acid Substances 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 229960000103 thrombolytic agent Drugs 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010014522 Embolism venous Diseases 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 3
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 3
- 239000005642 Oleic acid Substances 0.000 description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 3
- 229920002732 Polyanhydride Polymers 0.000 description 3
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 208000001435 Thromboembolism Diseases 0.000 description 3
- 241000001727 Tropicoporus linteus Species 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 210000001132 alveolar macrophage Anatomy 0.000 description 3
- 230000001746 atrial effect Effects 0.000 description 3
- 230000023555 blood coagulation Effects 0.000 description 3
- 208000029028 brain injury Diseases 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000306 component Substances 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 150000002016 disaccharides Chemical group 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 210000002889 endothelial cell Anatomy 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 210000002744 extracellular matrix Anatomy 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 230000009545 invasion Effects 0.000 description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 3
- 210000003141 lower extremity Anatomy 0.000 description 3
- 229920002521 macromolecule Polymers 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 3
- 229920000747 poly(lactic acid) Polymers 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000004626 polylactic acid Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 230000000241 respiratory effect Effects 0.000 description 3
- 230000035939 shock Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000001052 transient effect Effects 0.000 description 3
- 208000004043 venous thromboembolism Diseases 0.000 description 3
- DBTMGCOVALSLOR-DEVYUCJPSA-N (2s,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](CO)O[C@H](O)[C@@H]2O)O)O[C@H](CO)[C@H]1O DBTMGCOVALSLOR-DEVYUCJPSA-N 0.000 description 2
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 2
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 2
- 240000002900 Arthrospira platensis Species 0.000 description 2
- 235000016425 Arthrospira platensis Nutrition 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 2
- AFWTZXXDGQBIKW-UHFFFAOYSA-N C14 surfactin Natural products CCCCCCCCCCCC1CC(=O)NC(CCC(O)=O)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(=O)NC(CC(O)=O)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)O1 AFWTZXXDGQBIKW-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010014498 Embolic stroke Diseases 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 108010007979 Glycocholic Acid Proteins 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 108090000288 Glycoproteins Proteins 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920001543 Laminarin Polymers 0.000 description 2
- 239000005717 Laminarin Substances 0.000 description 2
- 108010085895 Laminin Proteins 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- MITFXPHMIHQXPI-UHFFFAOYSA-N Oraflex Chemical compound N=1C2=CC(C(C(O)=O)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 MITFXPHMIHQXPI-UHFFFAOYSA-N 0.000 description 2
- 206010057249 Phagocytosis Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000013566 Plasminogen Human genes 0.000 description 2
- 108010051456 Plasminogen Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 206010036790 Productive cough Diseases 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 239000004147 Sorbitan trioleate Substances 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229920006362 Teflon® Polymers 0.000 description 2
- 108010009583 Transforming Growth Factors Proteins 0.000 description 2
- 102000009618 Transforming Growth Factors Human genes 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- SMPZPKRDRQOOHT-UHFFFAOYSA-N acronycine Chemical compound CN1C2=CC=CC=C2C(=O)C2=C1C(C=CC(C)(C)O1)=C1C=C2OC SMPZPKRDRQOOHT-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 230000009692 acute damage Effects 0.000 description 2
- 206010000891 acute myocardial infarction Diseases 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 230000003024 amidolytic effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000002429 anti-coagulating effect Effects 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229960004676 antithrombotic agent Drugs 0.000 description 2
- 210000002469 basement membrane Anatomy 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000003727 cerebral blood flow Effects 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000000593 degrading effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- FRKBLBQTSTUKOV-UHFFFAOYSA-N diphosphatidyl glycerol Natural products OP(O)(=O)OCC(OP(O)(O)=O)COP(O)(O)=O FRKBLBQTSTUKOV-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 210000003038 endothelium Anatomy 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 108010083213 heparitinsulfate lyase Proteins 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 229940066294 lung surfactant Drugs 0.000 description 2
- 239000003580 lung surfactant Substances 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 108010082117 matrigel Proteins 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 230000008782 phagocytosis Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 229940031937 polysaccharide vaccine Drugs 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 229920002635 polyurethane Polymers 0.000 description 2
- 239000004814 polyurethane Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 2
- 229920001289 polyvinyl ether Polymers 0.000 description 2
- OLTAWOVKGWWERU-UHFFFAOYSA-N proxazole Chemical compound C=1C=CC=CC=1C(CC)C1=NOC(CCN(CC)CC)=N1 OLTAWOVKGWWERU-UHFFFAOYSA-N 0.000 description 2
- 229960001801 proxazole Drugs 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 108091006082 receptor inhibitors Proteins 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 102220328183 rs377651050 Human genes 0.000 description 2
- WVYADZUPLLSGPU-UHFFFAOYSA-N salsalate Chemical compound OC(=O)C1=CC=CC=C1OC(=O)C1=CC=CC=C1O WVYADZUPLLSGPU-UHFFFAOYSA-N 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 235000019337 sorbitan trioleate Nutrition 0.000 description 2
- 229960000391 sorbitan trioleate Drugs 0.000 description 2
- 208000024794 sputum Diseases 0.000 description 2
- 210000003802 sputum Anatomy 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- PVYJZLYGTZKPJE-UHFFFAOYSA-N streptonigrin Chemical compound C=1C=C2C(=O)C(OC)=C(N)C(=O)C2=NC=1C(C=1N)=NC(C(O)=O)=C(C)C=1C1=CC=C(OC)C(OC)=C1O PVYJZLYGTZKPJE-UHFFFAOYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- NJGWOFRZMQRKHT-UHFFFAOYSA-N surfactin Natural products CC(C)CCCCCCCCCC1CC(=O)NC(CCC(O)=O)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(=O)NC(CC(O)=O)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)O1 NJGWOFRZMQRKHT-UHFFFAOYSA-N 0.000 description 2
- NJGWOFRZMQRKHT-WGVNQGGSSA-N surfactin C Chemical compound CC(C)CCCCCCCCC[C@@H]1CC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O1 NJGWOFRZMQRKHT-WGVNQGGSSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 229960003676 tenidap Drugs 0.000 description 2
- LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 229920001664 tyloxapol Polymers 0.000 description 2
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 2
- 229960004224 tyloxapol Drugs 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 2
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 2
- 229960001600 xylazine Drugs 0.000 description 2
- YXBQLONCIPUQKO-UJPOAAIJSA-N (1r)-1-[(3ar,5r,6s,6ar)-6-[3-(dimethylamino)propoxy]-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]ethane-1,2-diol Chemical compound O1C(C)(C)O[C@@H]2[C@@H](OCCCN(C)C)[C@@H]([C@H](O)CO)O[C@@H]21 YXBQLONCIPUQKO-UJPOAAIJSA-N 0.000 description 1
- HZSBSRAVNBUZRA-RQDPQJJXSA-J (1r,2r)-cyclohexane-1,2-diamine;tetrachloroplatinum(2+) Chemical compound Cl[Pt+2](Cl)(Cl)Cl.N[C@@H]1CCCC[C@H]1N HZSBSRAVNBUZRA-RQDPQJJXSA-J 0.000 description 1
- MNHVIVWFCMBFCV-AVGNSLFASA-N (2S)-2-[[(2S)-2-[[(4S)-4-amino-4-carboxybutanoyl]amino]-6-diazo-5-oxohexanoyl]amino]-6-diazo-5-oxohexanoic acid Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CCC(=O)C=[N+]=[N-])C(=O)N[C@@H](CCC(=O)C=[N+]=[N-])C(O)=O MNHVIVWFCMBFCV-AVGNSLFASA-N 0.000 description 1
- RJMIEHBSYVWVIN-LLVKDONJSA-N (2r)-2-[4-(3-oxo-1h-isoindol-2-yl)phenyl]propanoic acid Chemical compound C1=CC([C@H](C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-LLVKDONJSA-N 0.000 description 1
- VYPKEODFNOEZGS-VIFPVBQESA-N (2r)-2-acetamido-3-(2-hydroxybenzoyl)sulfanylpropanoic acid Chemical compound CC(=O)N[C@H](C(O)=O)CSC(=O)C1=CC=CC=C1O VYPKEODFNOEZGS-VIFPVBQESA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- MDKGKXOCJGEUJW-VIFPVBQESA-N (2s)-2-[4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-VIFPVBQESA-N 0.000 description 1
- MWOGMBZGFFZBMK-LJZWMIMPSA-N (2s)-2-[[(2s)-2-[[2-[[(2s,3s)-2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MWOGMBZGFFZBMK-LJZWMIMPSA-N 0.000 description 1
- AUDFHJLSHQWFQQ-SFHVURJKSA-N (2s)-2-[[2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetyl]amino]-3-hydroxypropanoic acid Chemical compound CC1=C(CC(=O)N[C@@H](CO)C(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 AUDFHJLSHQWFQQ-SFHVURJKSA-N 0.000 description 1
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 description 1
- XYRIRLDHOQSNLW-UHFFFAOYSA-N (3-oxo-1h-2-benzofuran-1-yl) 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetate Chemical compound CC1=C(CC(=O)OC2C3=CC=CC=C3C(=O)O2)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 XYRIRLDHOQSNLW-UHFFFAOYSA-N 0.000 description 1
- BVNJBATUHVXZKP-QXMHVHEDSA-N (3z)-6-chloro-5-fluoro-3-[hydroxy(thiophen-2-yl)methylidene]-2-oxoindole-1-carboxamide Chemical compound C12=CC(F)=C(Cl)C=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 BVNJBATUHVXZKP-QXMHVHEDSA-N 0.000 description 1
- ZDHHGGFQZRPUSN-UHFFFAOYSA-N (4-chlorophenyl)-[3-(2h-tetrazol-5-ylmethyl)indol-1-yl]methanone Chemical compound C1=CC(Cl)=CC=C1C(=O)N1C2=CC=CC=C2C(CC2=NNN=N2)=C1 ZDHHGGFQZRPUSN-UHFFFAOYSA-N 0.000 description 1
- PPQZABOURJVKNI-UHFFFAOYSA-N (4-fluorophenyl)-[4-(4-fluorophenyl)-4-hydroxy-1-methylpiperidin-3-yl]methanone Chemical compound C1N(C)CCC(O)(C=2C=CC(F)=CC=2)C1C(=O)C1=CC=C(F)C=C1 PPQZABOURJVKNI-UHFFFAOYSA-N 0.000 description 1
- SWXOGPJRIDTIRL-DOUNNPEJSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s)-1-amino-3-(1h-indol-3-yl)-1-oxopropan-2-yl]-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pent Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 SWXOGPJRIDTIRL-DOUNNPEJSA-N 0.000 description 1
- JFTOCKFCHJCDDX-UVTDQMKNSA-N (4z)-4-benzylidene-5,6,7,8-tetrahydroisoquinoline-1,3-dione Chemical compound C1CCCC2=C1C(=O)NC(=O)\C2=C/C1=CC=CC=C1 JFTOCKFCHJCDDX-UVTDQMKNSA-N 0.000 description 1
- MWWSFMDVAYGXBV-FGBSZODSSA-N (7s,9s)-7-[(2r,4s,5r,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydron;chloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-FGBSZODSSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- OJRZEKJECRTBPJ-NGAMADIESA-N (z,5s)-5-acetamido-1-diazonio-6-hydroxy-6-oxohex-1-en-2-olate Chemical compound CC(=O)N[C@H](C(O)=O)CC\C([O-])=C\[N+]#N OJRZEKJECRTBPJ-NGAMADIESA-N 0.000 description 1
- FONKWHRXTPJODV-DNQXCXABSA-N 1,3-bis[2-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-3h-pyrrolo[3,2-e]indole-6-carbonyl]-1h-indol-5-yl]urea Chemical compound C1([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C4=CC(O)=C5NC=C(C5=C4[C@H](CCl)C3)C)=C2C=C(O)C2=C1C(C)=CN2 FONKWHRXTPJODV-DNQXCXABSA-N 0.000 description 1
- OUPZKGBUJRBPGC-HLTSFMKQSA-N 1,5-bis[[(2r)-oxiran-2-yl]methyl]-3-[[(2s)-oxiran-2-yl]methyl]-1,3,5-triazinane-2,4,6-trione Chemical compound O=C1N(C[C@H]2OC2)C(=O)N(C[C@H]2OC2)C(=O)N1C[C@H]1CO1 OUPZKGBUJRBPGC-HLTSFMKQSA-N 0.000 description 1
- UOAFGUOASVSLPK-UHFFFAOYSA-N 1-(2-chloroethyl)-3-(2,2-dimethylpropyl)-1-nitrosourea Chemical compound CC(C)(C)CNC(=O)N(N=O)CCCl UOAFGUOASVSLPK-UHFFFAOYSA-N 0.000 description 1
- ZHXUEUKVDMWSKV-UHFFFAOYSA-N 1-(3,5-ditert-butyl-4-hydroxyphenyl)hex-5-yn-1-one Chemical compound CC(C)(C)C1=CC(C(=O)CCCC#C)=CC(C(C)(C)C)=C1O ZHXUEUKVDMWSKV-UHFFFAOYSA-N 0.000 description 1
- JQJSFAJISYZPER-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-(2,3-dihydro-1h-inden-5-ylsulfonyl)urea Chemical compound C1=CC(Cl)=CC=C1NC(=O)NS(=O)(=O)C1=CC=C(CCC2)C2=C1 JQJSFAJISYZPER-UHFFFAOYSA-N 0.000 description 1
- ZKFNOUUKULVDOB-UHFFFAOYSA-N 1-amino-1-phenylmethyl phosphonic acid Chemical compound OP(=O)(O)C(N)C1=CC=CC=C1 ZKFNOUUKULVDOB-UHFFFAOYSA-N 0.000 description 1
- YETULFFXNIHQLK-UHFFFAOYSA-N 1-ethynyl-4-(2-fluorophenyl)benzene Chemical compound FC1=CC=CC=C1C1=CC=C(C#C)C=C1 YETULFFXNIHQLK-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- ULIDRMKBVYYVIQ-UHFFFAOYSA-N 1-phenyltetrazol-5-amine Chemical compound NC1=NN=NN1C1=CC=CC=C1 ULIDRMKBVYYVIQ-UHFFFAOYSA-N 0.000 description 1
- WHBHBVVOGNECLV-OBQKJFGGSA-N 11-deoxycortisol Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 WHBHBVVOGNECLV-OBQKJFGGSA-N 0.000 description 1
- OOMDVERDMZLRFX-UHFFFAOYSA-N 2,2-bis(aminomethyl)propane-1,3-diol;cyclobutane-1,1-dicarboxylic acid;platinum Chemical compound [Pt].NCC(CN)(CO)CO.OC(=O)C1(C(O)=O)CCC1 OOMDVERDMZLRFX-UHFFFAOYSA-N 0.000 description 1
- RPZANUYHRMRTTE-UHFFFAOYSA-N 2,3,4-trimethoxy-6-(methoxymethyl)-5-[3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxyoxane;1-[[3,4,5-tris(2-hydroxybutoxy)-6-[4,5,6-tris(2-hydroxybutoxy)-2-(2-hydroxybutoxymethyl)oxan-3-yl]oxyoxan-2-yl]methoxy]butan-2-ol Chemical compound COC1C(OC)C(OC)C(COC)OC1OC1C(OC)C(OC)C(OC)OC1COC.CCC(O)COC1C(OCC(O)CC)C(OCC(O)CC)C(COCC(O)CC)OC1OC1C(OCC(O)CC)C(OCC(O)CC)C(OCC(O)CC)OC1COCC(O)CC RPZANUYHRMRTTE-UHFFFAOYSA-N 0.000 description 1
- SRETXDDCKMOQNE-UHFFFAOYSA-N 2,3-bis(4-methoxyphenyl)-1h-indole Chemical compound C1=CC(OC)=CC=C1C1=C(C=2C=CC(OC)=CC=2)C2=CC=CC=C2N1 SRETXDDCKMOQNE-UHFFFAOYSA-N 0.000 description 1
- VKDGNNYJFSHYKD-UHFFFAOYSA-N 2,5-diamino-2-(difluoromethyl)pentanoic acid;hydron;chloride Chemical compound Cl.NCCCC(N)(C(F)F)C(O)=O VKDGNNYJFSHYKD-UHFFFAOYSA-N 0.000 description 1
- KLIVRBFRQSOGQI-UHFFFAOYSA-N 2-(11-oxo-6h-benzo[c][1]benzothiepin-3-yl)acetic acid Chemical compound S1CC2=CC=CC=C2C(=O)C2=CC=C(CC(=O)O)C=C12 KLIVRBFRQSOGQI-UHFFFAOYSA-N 0.000 description 1
- LRXFKKPEBXIPMW-UHFFFAOYSA-N 2-(9h-fluoren-2-yl)propanoic acid Chemical compound C1=CC=C2C3=CC=C(C(C(O)=O)C)C=C3CC2=C1 LRXFKKPEBXIPMW-UHFFFAOYSA-N 0.000 description 1
- NJWBUDCAWGTQAS-UHFFFAOYSA-N 2-(chrysen-6-ylmethylamino)-2-methylpropane-1,3-diol;methanesulfonic acid Chemical compound CS(O)(=O)=O.C1=CC=C2C(CNC(CO)(CO)C)=CC3=C(C=CC=C4)C4=CC=C3C2=C1 NJWBUDCAWGTQAS-UHFFFAOYSA-N 0.000 description 1
- QXLQZLBNPTZMRK-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-1-(2,4-dimethylphenyl)prop-2-en-1-one Chemical compound CN(C)CC(=C)C(=O)C1=CC=C(C)C=C1C QXLQZLBNPTZMRK-UHFFFAOYSA-N 0.000 description 1
- DCXHLPGLBYHNMU-UHFFFAOYSA-N 2-[1-(4-azidobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(N=[N+]=[N-])C=C1 DCXHLPGLBYHNMU-UHFFFAOYSA-N 0.000 description 1
- KPRFMAZESAKTEJ-UHFFFAOYSA-N 2-[1-amino-4-[2,5-dioxo-4-(1-phenylethyl)pyrrolidin-3-yl]-1-oxobutan-2-yl]-5-carbamoylheptanedioic acid;azane Chemical compound [NH4+].[NH4+].C=1C=CC=CC=1C(C)C1C(CCC(C(CCC(CC([O-])=O)C(N)=O)C([O-])=O)C(N)=O)C(=O)NC1=O KPRFMAZESAKTEJ-UHFFFAOYSA-N 0.000 description 1
- IDCAZKFFVIMCCS-UHFFFAOYSA-N 2-[3-(4-chlorophenyl)-4-imino-2-oxoimidazolidin-1-yl]acetonitrile Chemical compound C1=CC(Cl)=CC=C1N1C(=O)N(CC#N)CC1=N IDCAZKFFVIMCCS-UHFFFAOYSA-N 0.000 description 1
- ANMLJLFWUCQGKZ-UHFFFAOYSA-N 2-[3-(trifluoromethyl)anilino]-3-pyridinecarboxylic acid (3-oxo-1H-isobenzofuran-1-yl) ester Chemical compound FC(F)(F)C1=CC=CC(NC=2C(=CC=CN=2)C(=O)OC2C3=CC=CC=C3C(=O)O2)=C1 ANMLJLFWUCQGKZ-UHFFFAOYSA-N 0.000 description 1
- XILVEPYQJIOVNB-UHFFFAOYSA-N 2-[3-(trifluoromethyl)anilino]benzoic acid 2-(2-hydroxyethoxy)ethyl ester Chemical compound OCCOCCOC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 XILVEPYQJIOVNB-UHFFFAOYSA-N 0.000 description 1
- NLGUJWNOGYWZBI-UHFFFAOYSA-N 2-[3-chloro-4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound ClC1=CC(C(C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 NLGUJWNOGYWZBI-UHFFFAOYSA-N 0.000 description 1
- LNXXSBRGLBOASF-UHFFFAOYSA-N 2-[[2-(4-chlorophenyl)-4-methyl-1,3-oxazol-5-yl]methoxy]-2-methylpropanoic acid Chemical compound O1C(COC(C)(C)C(O)=O)=C(C)N=C1C1=CC=C(Cl)C=C1 LNXXSBRGLBOASF-UHFFFAOYSA-N 0.000 description 1
- QCXJFISCRQIYID-IAEPZHFASA-N 2-amino-1-n-[(3s,6s,7r,10s,16s)-3-[(2s)-butan-2-yl]-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-10-propan-2-yl-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]-4,6-dimethyl-3-oxo-9-n-[(3s,6s,7r,10s,16s)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propa Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N=C2C(C(=O)N[C@@H]3C(=O)N[C@H](C(N4CCC[C@H]4C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]3C)=O)[C@@H](C)CC)=C(N)C(=O)C(C)=C2O2)C2=C(C)C=C1 QCXJFISCRQIYID-IAEPZHFASA-N 0.000 description 1
- HZLCGUXUOFWCCN-UHFFFAOYSA-N 2-hydroxynonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(O)(C(O)=O)CC(O)=O HZLCGUXUOFWCCN-UHFFFAOYSA-N 0.000 description 1
- DSWLRNLRVBAVFC-UHFFFAOYSA-N 2-methylsulfinyl-1-pyridin-2-ylethanone Chemical compound CS(=O)CC(=O)C1=CC=CC=N1 DSWLRNLRVBAVFC-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- GRLUHXSUZYFZCW-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-n,n-dimethylpropan-1-amine;dihydrochloride Chemical compound Cl.Cl.C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 GRLUHXSUZYFZCW-UHFFFAOYSA-N 0.000 description 1
- GTJXPMSTODOYNP-BTKVJIOYSA-N 3-[(e)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 GTJXPMSTODOYNP-BTKVJIOYSA-N 0.000 description 1
- QNKJFXARIMSDBR-UHFFFAOYSA-N 3-[2-[bis(2-chloroethyl)amino]ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione Chemical compound O=C1N(CCN(CCCl)CCCl)C(=O)NC11CCCCC1 QNKJFXARIMSDBR-UHFFFAOYSA-N 0.000 description 1
- PLZMRGRLCWCLFW-UHFFFAOYSA-N 3-[5-(3-bromophenyl)tetrazol-2-yl]-1-piperidin-1-ylpropan-1-one Chemical compound BrC1=CC=CC(C2=NN(CCC(=O)N3CCCCC3)N=N2)=C1 PLZMRGRLCWCLFW-UHFFFAOYSA-N 0.000 description 1
- WUIABRMSWOKTOF-OYALTWQYSA-N 3-[[2-[2-[2-[[(2s,3r)-2-[[(2s,3s,4r)-4-[[(2s,3r)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)ox Chemical compound OS([O-])(=O)=O.N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-OYALTWQYSA-N 0.000 description 1
- YUORBURTMIUPMW-UHFFFAOYSA-N 3-methyl-5-[2-(4-phenyl-3,6-dihydro-2h-pyridin-1-yl)ethyl]-1,3-oxazolidin-2-one Chemical compound O1C(=O)N(C)CC1CCN1CC=C(C=2C=CC=CC=2)CC1 YUORBURTMIUPMW-UHFFFAOYSA-N 0.000 description 1
- WFFZGYRTVIPBFN-UHFFFAOYSA-N 3h-indene-1,2-dione Chemical class C1=CC=C2C(=O)C(=O)CC2=C1 WFFZGYRTVIPBFN-UHFFFAOYSA-N 0.000 description 1
- WOVTUUKKGNHVFZ-UHFFFAOYSA-N 4-(fluoren-9-ylidenemethyl)benzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1C=C1C2=CC=CC=C2C2=CC=CC=C21 WOVTUUKKGNHVFZ-UHFFFAOYSA-N 0.000 description 1
- CUQPTVCVZLUXJB-UHFFFAOYSA-N 4-[1-hydroxy-2-(propan-2-ylamino)ethyl]benzene-1,2-diol;sulfuric acid;dihydrate Chemical compound O.O.OS(O)(=O)=O.CC(C)NCC(O)C1=CC=C(O)C(O)=C1.CC(C)NCC(O)C1=CC=C(O)C(O)=C1 CUQPTVCVZLUXJB-UHFFFAOYSA-N 0.000 description 1
- LQVMQEYROPXMQH-UHFFFAOYSA-N 4-dibenzofuran-2-yl-4-oxobutanoic acid Chemical compound C1=CC=C2C3=CC(C(=O)CCC(=O)O)=CC=C3OC2=C1 LQVMQEYROPXMQH-UHFFFAOYSA-N 0.000 description 1
- LLLVZDVNHNWSDS-UHFFFAOYSA-N 4-methylidene-3,5-dioxabicyclo[5.2.2]undeca-1(9),7,10-triene-2,6-dione Chemical compound C1(C2=CC=C(C(=O)OC(=C)O1)C=C2)=O LLLVZDVNHNWSDS-UHFFFAOYSA-N 0.000 description 1
- CXSJGNHRBWJXEA-UHFFFAOYSA-N 5,12-dihydrophthalazino[3,2-b]phthalazine-7,14-dione Chemical compound C1C2=CC=CC=C2C(=O)N2N1C(=O)C1=CC=CC=C1C2 CXSJGNHRBWJXEA-UHFFFAOYSA-N 0.000 description 1
- PXLPCZJACKUXGP-UHFFFAOYSA-N 5-(3,4-dichlorophenyl)-6-ethylpyrimidine-2,4-diamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C(Cl)=C1 PXLPCZJACKUXGP-UHFFFAOYSA-N 0.000 description 1
- HEOZYYOUKGGSBJ-UHFFFAOYSA-N 5-(4-methoxybenzoyl)-2,3-dihydro-1h-pyrrolizine-1-carboxylic acid Chemical compound C1=CC(OC)=CC=C1C(=O)C1=CC=C2N1CCC2C(O)=O HEOZYYOUKGGSBJ-UHFFFAOYSA-N 0.000 description 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- DQOGWKZQQBYYMW-LQGIGNHCSA-N 5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline-2,4-diamine;(2s,3s,4s,5r,6s)-3,4,5,6-tetrahydroxyoxane-2-carboxylic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O.COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 DQOGWKZQQBYYMW-LQGIGNHCSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- KXBCLNRMQPRVTP-UHFFFAOYSA-N 6-amino-1,5-dihydroimidazo[4,5-c]pyridin-4-one Chemical compound O=C1NC(N)=CC2=C1N=CN2 KXBCLNRMQPRVTP-UHFFFAOYSA-N 0.000 description 1
- ZNTIXVYOBQDFFV-UHFFFAOYSA-N 6-amino-1,5-dihydroimidazo[4,5-c]pyridin-4-one;methanesulfonic acid Chemical compound CS(O)(=O)=O.O=C1NC(N)=CC2=C1N=CN2 ZNTIXVYOBQDFFV-UHFFFAOYSA-N 0.000 description 1
- OAIZNWQBWDHNIH-UHFFFAOYSA-N 6-chloro-4-phenyl-1-(2,2,2-trifluoroethyl)quinazolin-2-one Chemical compound N=1C(=O)N(CC(F)(F)F)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 OAIZNWQBWDHNIH-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- KABRXLINDSPGDF-UHFFFAOYSA-N 7-bromoisoquinoline Chemical compound C1=CN=CC2=CC(Br)=CC=C21 KABRXLINDSPGDF-UHFFFAOYSA-N 0.000 description 1
- XWXVKXXKKLBDDJ-UHFFFAOYSA-N 7-chloro-3,3a-dihydro-2h-[1,2]oxazolo[3,2-b][1,3]benzoxazin-9-one Chemical compound O1C2CCON2C(=O)C2=CC(Cl)=CC=C21 XWXVKXXKKLBDDJ-UHFFFAOYSA-N 0.000 description 1
- HCKFPALGXKOOBK-NRYMJLQJSA-N 7332-27-6 Chemical compound C1([C@]2(O[C@]3([C@@]4(C)C[C@H](O)[C@]5(F)[C@@]6(C)C=CC(=O)C=C6CC[C@H]5[C@@H]4C[C@H]3O2)C(=O)CO)C)=CC=CC=C1 HCKFPALGXKOOBK-NRYMJLQJSA-N 0.000 description 1
- LPDLEICKXUVJHW-QJILNLRNSA-N 78nz2pmp25 Chemical compound OS(O)(=O)=O.O([C@]12[C@H](OC(C)=O)[C@]3(CC)C=CCN4CC[C@@]5([C@H]34)[C@H]1N(C)C1=C5C=C(C(=C1)OC)[C@]1(C(=O)OC)C3=C(C4=CC=CC=C4N3)CCN3C[C@H](C1)C[C@@](C3)(O)CC)C(=O)N(CCCl)C2=O LPDLEICKXUVJHW-QJILNLRNSA-N 0.000 description 1
- ZOCUOMKMBMEYQV-GSLJADNHSA-N 9alpha-Fluoro-11beta,17alpha,21-trihydroxypregna-1,4-diene-3,20-dione 21-acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ZOCUOMKMBMEYQV-GSLJADNHSA-N 0.000 description 1
- 101150114464 ATRN gene Proteins 0.000 description 1
- 206010000060 Abdominal distension Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 206010001605 Alcohol poisoning Diseases 0.000 description 1
- FDQGNLOWMMVRQL-UHFFFAOYSA-N Allobarbital Chemical compound C=CCC1(CC=C)C(=O)NC(=O)NC1=O FDQGNLOWMMVRQL-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108700032558 Aspergillus restrictus MITF Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010003557 Asthma exercise induced Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 102100036597 Basement membrane-specific heparan sulfate proteoglycan core protein Human genes 0.000 description 1
- HNNIWKQLJSNAEQ-UHFFFAOYSA-N Benzydamine hydrochloride Chemical compound Cl.C12=CC=CC=C2C(OCCCN(C)C)=NN1CC1=CC=CC=C1 HNNIWKQLJSNAEQ-UHFFFAOYSA-N 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 244000056139 Brassica cretica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 108010004032 Bromelains Proteins 0.000 description 1
- CIUUIPMOFZIWIZ-UHFFFAOYSA-N Bropirimine Chemical compound NC1=NC(O)=C(Br)C(C=2C=CC=CC=2)=N1 CIUUIPMOFZIWIZ-UHFFFAOYSA-N 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 0 C(C1)C2*C1CC2 Chemical compound C(C1)C2*C1CC2 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N CC1CCCC1 Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- 101100042788 Caenorhabditis elegans him-1 gene Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000009458 Carcinoma in Situ Diseases 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- DQEFEBPAPFSJLV-UHFFFAOYSA-N Cellulose propionate Chemical compound CCC(=O)OCC1OC(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C1OC1C(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C(COC(=O)CC)O1 DQEFEBPAPFSJLV-UHFFFAOYSA-N 0.000 description 1
- 229920002284 Cellulose triacetate Polymers 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- KATBVKFXGKGUFE-UHFFFAOYSA-N Cintazone Chemical compound C12=CC=CC=C2N2C(=O)C(CCCCC)C(=O)N2C=C1C1=CC=CC=C1 KATBVKFXGKGUFE-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 244000089742 Citrus aurantifolia Species 0.000 description 1
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 1
- PPASFTRHCXASPY-UHFFFAOYSA-N Cl.Cl.NCCCNc1ccc2c3c(nn2CCNCCO)c4c(O)ccc(O)c4C(=O)c13 Chemical compound Cl.Cl.NCCCNc1ccc2c3c(nn2CCNCCO)c4c(O)ccc(O)c4C(=O)c13 PPASFTRHCXASPY-UHFFFAOYSA-N 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 229920002911 Colestipol Polymers 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010042086 Collagen Type IV Proteins 0.000 description 1
- 102000004266 Collagen Type IV Human genes 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- YXKFATPOEMHNMJ-KJEYTGHBSA-N Cormethasone acetate Chemical compound C1C(F)(F)C2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COC(C)=O)(O)[C@@]1(C)C[C@@H]2O YXKFATPOEMHNMJ-KJEYTGHBSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000192700 Cyanobacteria Species 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- SPKNARKFCOPTSY-UHFFFAOYSA-N D-asperlin Natural products CC1OC1C1C(OC(C)=O)C=CC(=O)O1 SPKNARKFCOPTSY-UHFFFAOYSA-N 0.000 description 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- WYQPLTPSGFELIB-JTQPXKBDSA-N Difluprednate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2CC[C@@](C(=O)COC(C)=O)(OC(=O)CCC)[C@@]2(C)C[C@@H]1O WYQPLTPSGFELIB-JTQPXKBDSA-N 0.000 description 1
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 1
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 1
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- NBEALWAVEGMZQY-UHFFFAOYSA-N Enpromate Chemical compound C=1C=CC=CC=1C(C#C)(C=1C=CC=CC=1)OC(=O)NC1CCCCC1 NBEALWAVEGMZQY-UHFFFAOYSA-N 0.000 description 1
- RHAXSHUQNIEUEY-UHFFFAOYSA-N Epirizole Chemical compound COC1=CC(C)=NN1C1=NC(C)=CC(OC)=N1 RHAXSHUQNIEUEY-UHFFFAOYSA-N 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 208000004657 Exercise-Induced Asthma Diseases 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 1
- 208000000616 Hemoptysis Diseases 0.000 description 1
- 108090000481 Heparin Cofactor II Proteins 0.000 description 1
- 102100030500 Heparin cofactor 2 Human genes 0.000 description 1
- 102000007625 Hirudins Human genes 0.000 description 1
- 108010007267 Hirudins Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- ACEWLPOYLGNNHV-UHFFFAOYSA-N Ibuprofen piconol Chemical compound C1=CC(CC(C)C)=CC=C1C(C)C(=O)OCC1=CC=CC=N1 ACEWLPOYLGNNHV-UHFFFAOYSA-N 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 108010054698 Interferon Alfa-n3 Proteins 0.000 description 1
- 108010078049 Interferon alpha-2 Proteins 0.000 description 1
- 208000005615 Interstitial Cystitis Diseases 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 208000003947 Knee Osteoarthritis Diseases 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 description 1
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 1
- 101100533565 Leptosphaeria maculans sirE gene Proteins 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 208000004852 Lung Injury Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 238000007807 Matrigel invasion assay Methods 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- HRHKSTOGXBBQCB-UHFFFAOYSA-N Mitomycin E Natural products O=C1C(N)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)C3N(C)C3CN12 HRHKSTOGXBBQCB-UHFFFAOYSA-N 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 101100072408 Mus musculus Il21r gene Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- USVMJSALORZVDV-SDBHATRESA-N N(6)-(Delta(2)-isopentenyl)adenosine Chemical compound C1=NC=2C(NCC=C(C)C)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O USVMJSALORZVDV-SDBHATRESA-N 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 102100033174 Neutrophil elastase Human genes 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- KYRVNWMVYQXFEU-UHFFFAOYSA-N Nocodazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CS1 KYRVNWMVYQXFEU-UHFFFAOYSA-N 0.000 description 1
- KGTDRFCXGRULNK-UHFFFAOYSA-N Nogalamycin Natural products COC1C(OC)(C)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C4C5(C)OC(C(C(C5O)N(C)C)O)OC4=C3C3=O)=C3C=C2C(C(=O)OC)C(C)(O)C1 KGTDRFCXGRULNK-UHFFFAOYSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 description 1
- 102000010752 Plasminogen Inactivators Human genes 0.000 description 1
- 108010077971 Plasminogen Inactivators Proteins 0.000 description 1
- 102100039418 Plasminogen activator inhibitor 1 Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001305 Poly(isodecyl(meth)acrylate) Polymers 0.000 description 1
- 229920002845 Poly(methacrylic acid) Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- XESARGFCSKSFID-UHFFFAOYSA-N Pyrazofurin Natural products OC1=C(C(=O)N)NN=C1C1C(O)C(O)C(CO)O1 XESARGFCSKSFID-UHFFFAOYSA-N 0.000 description 1
- 235000014443 Pyrus communis Nutrition 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041235 Snoring Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 235000011941 Tilia x europaea Nutrition 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- 206010069363 Traumatic lung injury Diseases 0.000 description 1
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 1
- 206010064390 Tumour invasion Diseases 0.000 description 1
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 1
- VGQOVCHZGQWAOI-UHFFFAOYSA-N UNPD55612 Natural products N1C(O)C2CC(C=CC(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-UHFFFAOYSA-N 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 108010031318 Vitronectin Proteins 0.000 description 1
- 102100035140 Vitronectin Human genes 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- ZMQRJWIYMXZORG-GZIFKOAOSA-N [(1e,3r,4r,6r,7z,9z,11e)-3,6,13-trihydroxy-3-methyl-1-[(2s)-6-oxo-2,3-dihydropyran-2-yl]trideca-1,7,9,11-tetraen-4-yl] dihydrogen phosphate Chemical compound OC/C=C/C=C\C=C/[C@H](O)C[C@@H](OP(O)(O)=O)[C@@](O)(C)\C=C\[C@@H]1CC=CC(=O)O1 ZMQRJWIYMXZORG-GZIFKOAOSA-N 0.000 description 1
- VUPBDWQPEOWRQP-RTUCOMKBSA-N [(2R,3S,4S,5R,6R)-2-[(2R,3S,4S,5S,6S)-2-[(1S,2S)-3-[[(2R,3S)-5-[[(2S,3R)-1-[[2-[4-[4-[[4-amino-6-[3-(4-aminobutylamino)propylamino]-6-oxohexyl]carbamoyl]-1,3-thiazol-2-yl]-1,3-thiazol-2-yl]-1-[(2S,3R,4R,5S,6S)-5-amino-3,4-dihydroxy-6-methyloxan-2-yl]oxy-2-hydroxyethyl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-hydroxy-5-oxopentan-2-yl]amino]-2-[[6-amino-2-[(1S)-3-amino-1-[[(2S)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-1-(1H-imidazol-5-yl)-3-oxopropoxy]-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl] carbamate Chemical compound C[C@@H](O)[C@H](NC(=O)C[C@H](O)[C@@H](C)NC(=O)[C@@H](NC(=O)c1nc(nc(N)c1C)[C@H](CC(N)=O)NC[C@H](N)C(N)=O)[C@H](O[C@@H]1O[C@@H](CO)[C@@H](O)[C@H](O)[C@@H]1O[C@H]1O[C@H](CO)[C@@H](O)[C@H](OC(N)=O)[C@@H]1O)c1cnc[nH]1)C(=O)NC(O[C@@H]1O[C@@H](C)[C@@H](N)[C@@H](O)[C@H]1O)C(O)c1nc(cs1)-c1nc(cs1)C(=O)NCCCC(N)CC(=O)NCCCNCCCCN VUPBDWQPEOWRQP-RTUCOMKBSA-N 0.000 description 1
- ZBNRGEMZNWHCGA-PDKVEDEMSA-N [(2r)-2-[(2r,3r,4s)-3,4-bis[[(z)-octadec-9-enoyl]oxy]oxolan-2-yl]-2-hydroxyethyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC ZBNRGEMZNWHCGA-PDKVEDEMSA-N 0.000 description 1
- NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 description 1
- SPKNARKFCOPTSY-XWPZMVOTSA-N [(2r,3s)-2-[(2s,3r)-3-methyloxiran-2-yl]-6-oxo-2,3-dihydropyran-3-yl] acetate Chemical compound C[C@H]1O[C@@H]1[C@H]1[C@@H](OC(C)=O)C=CC(=O)O1 SPKNARKFCOPTSY-XWPZMVOTSA-N 0.000 description 1
- ZHHIHQFAUZZMTG-BSVJBJGJSA-N [(2r,3s,4s,5r,6r)-2-[(2r,3s,4s,5s,6s)-2-[(1r,2s)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[[(2r,3s,4s)-3-hydroxy-5-[[(2s,3r)-3-hydroxy-1-oxo-1-[2-[4-[4-[3-[[(1s)-1-phenylethyl] Chemical compound OS(O)(=O)=O.N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C ZHHIHQFAUZZMTG-BSVJBJGJSA-N 0.000 description 1
- MVLBCBPGBUAVJQ-CENSZEJFSA-N [(6s,8s,9r,10s,11s,13s,14s,16r,17r)-17-(chloromethylsulfanylcarbonyl)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] propanoate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCCl)(OC(=O)CC)[C@@]2(C)C[C@@H]1O MVLBCBPGBUAVJQ-CENSZEJFSA-N 0.000 description 1
- IVCRCPJOLWECJU-XQVQQVTHSA-N [(7r,8r,9s,10r,13s,14s,17s)-7,13-dimethyl-3-oxo-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1C[C@]2(C)[C@@H](OC(C)=O)CC[C@H]2[C@@H]2[C@H](C)CC3=CC(=O)CC[C@@H]3[C@H]21 IVCRCPJOLWECJU-XQVQQVTHSA-N 0.000 description 1
- KMLCRELJHYKIIL-UHFFFAOYSA-N [1-(azanidylmethyl)cyclohexyl]methylazanide;platinum(2+);sulfuric acid Chemical compound [Pt+2].OS(O)(=O)=O.[NH-]CC1(C[NH-])CCCCC1 KMLCRELJHYKIIL-UHFFFAOYSA-N 0.000 description 1
- FBRAWBYQGRLCEK-UHFFFAOYSA-N [17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3,11-dioxo-7,8,12,14,15,16-hexahydro-6h-cyclopenta[a]phenanthren-17-yl] butanoate Chemical compound C1CC2=CC(=O)C=CC2(C)C2(F)C1C1CC(C)C(C(=O)CCl)(OC(=O)CCC)C1(C)CC2=O FBRAWBYQGRLCEK-UHFFFAOYSA-N 0.000 description 1
- ODEDPKNSRBCSDO-UHFFFAOYSA-N [2-(hexadecylsulfanylmethyl)-3-methoxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCSCC(COC)COP([O-])(=O)OCC[N+](C)(C)C ODEDPKNSRBCSDO-UHFFFAOYSA-N 0.000 description 1
- NAFFDQVVNWTDJD-UHFFFAOYSA-L [4-(azanidylmethyl)oxan-4-yl]methylazanide;cyclobutane-1,1-dicarboxylate;platinum(4+) Chemical compound [Pt+4].[NH-]CC1(C[NH-])CCOCC1.[O-]C(=O)C1(C([O-])=O)CCC1 NAFFDQVVNWTDJD-UHFFFAOYSA-L 0.000 description 1
- JURAJLFHWXNPHG-UHFFFAOYSA-N [acetyl(methylcarbamoyl)amino] n-methylcarbamate Chemical compound CNC(=O)ON(C(C)=O)C(=O)NC JURAJLFHWXNPHG-UHFFFAOYSA-N 0.000 description 1
- 238000012084 abdominal surgery Methods 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 229960002054 acenocoumarol Drugs 0.000 description 1
- VABCILAOYCMVPS-UHFFFAOYSA-N acenocoumarol Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=C([N+]([O-])=O)C=C1 VABCILAOYCMVPS-UHFFFAOYSA-N 0.000 description 1
- RUGAHXUZHWYHNG-NLGNTGLNSA-N acetic acid;(4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5, Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 RUGAHXUZHWYHNG-NLGNTGLNSA-N 0.000 description 1
- IGCAUIJHGNYDKE-UHFFFAOYSA-N acetic acid;1,4-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione Chemical compound CC([O-])=O.CC([O-])=O.O=C1C2=CC=CC=C2C(=O)C2=C1C(NCC[NH2+]CCO)=CC=C2NCC[NH2+]CCO IGCAUIJHGNYDKE-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- QAWIHIJWNYOLBE-OKKQSCSOSA-N acivicin Chemical compound OC(=O)[C@@H](N)[C@@H]1CC(Cl)=NO1 QAWIHIJWNYOLBE-OKKQSCSOSA-N 0.000 description 1
- 229950008427 acivicin Drugs 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 229950000616 acronine Drugs 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229950004955 adozelesin Drugs 0.000 description 1
- BYRVKDUQDLJUBX-JJCDCTGGSA-N adozelesin Chemical compound C1=CC=C2OC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)NC=C5C)=CC2=C1 BYRVKDUQDLJUBX-JJCDCTGGSA-N 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940040563 agaric acid Drugs 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 229960005142 alclofenac Drugs 0.000 description 1
- ARHWPKZXBHOEEE-UHFFFAOYSA-N alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 1
- 229960004229 alclometasone dipropionate Drugs 0.000 description 1
- DJHCCTTVDRAMEH-DUUJBDRPSA-N alclometasone dipropionate Chemical compound C([C@H]1Cl)C2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O DJHCCTTVDRAMEH-DUUJBDRPSA-N 0.000 description 1
- LSWBQIAZNGURQV-WTBIUSKOSA-N algestone acetonide Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)C)[C@@]1(C)CC2 LSWBQIAZNGURQV-WTBIUSKOSA-N 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229920013820 alkyl cellulose Polymers 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 102000004139 alpha-Amylases Human genes 0.000 description 1
- 108090000637 alpha-Amylases Proteins 0.000 description 1
- 229940024171 alpha-amylase Drugs 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229950004821 ambomycin Drugs 0.000 description 1
- NSZFBGIRFCHKOE-LFZVSNMSSA-N amcinafal Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(CC)(CC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O NSZFBGIRFCHKOE-LFZVSNMSSA-N 0.000 description 1
- 229950004850 amcinafal Drugs 0.000 description 1
- 229950003408 amcinafide Drugs 0.000 description 1
- QZNJPJDUBTYMRS-UHFFFAOYSA-M amfenac sodium hydrate Chemical compound O.[Na+].NC1=C(CC([O-])=O)C=CC=C1C(=O)C1=CC=CC=C1 QZNJPJDUBTYMRS-UHFFFAOYSA-M 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229950010999 amiprilose Drugs 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229950004699 anirolac Drugs 0.000 description 1
- HDNJXZZJFPCFHG-UHFFFAOYSA-N anitrazafen Chemical compound C1=CC(OC)=CC=C1C1=NN=C(C)N=C1C1=CC=C(OC)C=C1 HDNJXZZJFPCFHG-UHFFFAOYSA-N 0.000 description 1
- 229950002412 anitrazafen Drugs 0.000 description 1
- VGQOVCHZGQWAOI-HYUHUPJXSA-N anthramycin Chemical compound N1[C@@H](O)[C@@H]2CC(\C=C\C(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-HYUHUPJXSA-N 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000004019 antithrombin Substances 0.000 description 1
- 208000007474 aortic aneurysm Diseases 0.000 description 1
- 101150059062 apln gene Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 238000010420 art technique Methods 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 239000010425 asbestos Substances 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 238000004630 atomic force microscopy Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 229960001671 azapropazone Drugs 0.000 description 1
- WOIIIUDZSOLAIW-NSHDSACASA-N azapropazone Chemical compound C1=C(C)C=C2N3C(=O)[C@H](CC=C)C(=O)N3C(N(C)C)=NC2=C1 WOIIIUDZSOLAIW-NSHDSACASA-N 0.000 description 1
- HRXVDDOKERXBEY-UHFFFAOYSA-N azatepa Chemical compound C1CN1P(=O)(N1CC1)N(CC)C1=NN=CS1 HRXVDDOKERXBEY-UHFFFAOYSA-N 0.000 description 1
- 229950004295 azotomycin Drugs 0.000 description 1
- 229960000560 balsalazide disodium Drugs 0.000 description 1
- XFILPEOLDIKJHX-QYZOEREBSA-N batimastat Chemical compound C([C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)[C@H](CSC=1SC=CC=1)C(=O)NO)C1=CC=CC=C1 XFILPEOLDIKJHX-QYZOEREBSA-N 0.000 description 1
- 229950001858 batimastat Drugs 0.000 description 1
- 229960005149 bendazac Drugs 0.000 description 1
- BYFMCKSPFYVMOU-UHFFFAOYSA-N bendazac Chemical compound C12=CC=CC=C2C(OCC(=O)O)=NN1CC1=CC=CC=C1 BYFMCKSPFYVMOU-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960005430 benoxaprofen Drugs 0.000 description 1
- 229950005567 benzodepa Drugs 0.000 description 1
- 229960001689 benzydamine hydrochloride Drugs 0.000 description 1
- MMIMIFULGMZVPO-UHFFFAOYSA-N benzyl 3-bromo-2,6-dinitro-5-phenylmethoxybenzoate Chemical compound [O-][N+](=O)C1=C(C(=O)OCC=2C=CC=CC=2)C([N+](=O)[O-])=C(Br)C=C1OCC1=CC=CC=C1 MMIMIFULGMZVPO-UHFFFAOYSA-N 0.000 description 1
- VFIUCBTYGKMLCM-UHFFFAOYSA-N benzyl n-[bis(aziridin-1-yl)phosphoryl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)NP(=O)(N1CC1)N1CC1 VFIUCBTYGKMLCM-UHFFFAOYSA-N 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 201000009036 biliary tract cancer Diseases 0.000 description 1
- 208000020790 biliary tract neoplasm Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- QRZAKQDHEVVFRX-UHFFFAOYSA-N biphenyl-4-ylacetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1C1=CC=CC=C1 QRZAKQDHEVVFRX-UHFFFAOYSA-N 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- UIDLJTHRRPMIQP-UHFFFAOYSA-L bis[2-[4-(2-methylpropyl)phenyl]propanoyloxy]aluminum;hydrate Chemical compound O.C1=CC(CC(C)C)=CC=C1C(C)C(=O)O[Al]OC(=O)C(C)C1=CC=C(CC(C)C)C=C1 UIDLJTHRRPMIQP-UHFFFAOYSA-L 0.000 description 1
- OIPMQULDKWSNGX-UHFFFAOYSA-N bis[[ethoxy(oxo)phosphaniumyl]oxy]alumanyloxy-ethoxy-oxophosphanium Chemical compound [Al+3].CCO[P+]([O-])=O.CCO[P+]([O-])=O.CCO[P+]([O-])=O OIPMQULDKWSNGX-UHFFFAOYSA-N 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- 229950006844 bizelesin Drugs 0.000 description 1
- 229960004395 bleomycin sulfate Drugs 0.000 description 1
- 239000012503 blood component Substances 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 210000001601 blood-air barrier Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- PZOHOALJQOFNTB-UHFFFAOYSA-M brequinar sodium Chemical compound [Na+].N1=C2C=CC(F)=CC2=C(C([O-])=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PZOHOALJQOFNTB-UHFFFAOYSA-M 0.000 description 1
- 235000019835 bromelain Nutrition 0.000 description 1
- 210000003123 bronchiole Anatomy 0.000 description 1
- 229950011622 broperamole Drugs 0.000 description 1
- 229950009494 bropirimine Drugs 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 108700002839 cactinomycin Proteins 0.000 description 1
- 229950009908 cactinomycin Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- IVFYLRMMHVYGJH-PVPPCFLZSA-N calusterone Chemical compound C1C[C@]2(C)[C@](O)(C)CC[C@H]2[C@@H]2[C@@H](C)CC3=CC(=O)CC[C@]3(C)[C@H]21 IVFYLRMMHVYGJH-PVPPCFLZSA-N 0.000 description 1
- 229950009823 calusterone Drugs 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- 229950009338 caracemide Drugs 0.000 description 1
- 229950005155 carbetimer Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 206010061592 cardiac fibrillation Diseases 0.000 description 1
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 1
- 229960003184 carprofen Drugs 0.000 description 1
- 229950001725 carubicin Drugs 0.000 description 1
- BBZDXMBRAFTCAA-AREMUKBSSA-N carzelesin Chemical compound C1=2NC=C(C)C=2C([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)C3=CC4=CC=C(C=C4O3)N(CC)CC)=C2C=C1OC(=O)NC1=CC=CC=C1 BBZDXMBRAFTCAA-AREMUKBSSA-N 0.000 description 1
- 229950007509 carzelesin Drugs 0.000 description 1
- 229950010667 cedefingol Drugs 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 229920006218 cellulose propionate Polymers 0.000 description 1
- 229940107792 certoparin Drugs 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- CKMOQBVBEGCJGW-UHFFFAOYSA-L chembl1200760 Chemical compound [Na+].[Na+].C1=C(C([O-])=O)C(O)=CC=C1N=NC1=CC=C(C(=O)NCCC([O-])=O)C=C1 CKMOQBVBEGCJGW-UHFFFAOYSA-L 0.000 description 1
- OWSKEUBOCMEJMI-KPXOXKRLSA-N chembl2105946 Chemical compound [N-]=[N+]=CC(=O)CC[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@H](CCC(=O)C=[N+]=[N-])C(O)=O OWSKEUBOCMEJMI-KPXOXKRLSA-N 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 150000001840 cholesterol esters Chemical class 0.000 description 1
- 101150087654 chrnd gene Proteins 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 229950002545 cicloprofen Drugs 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 230000005796 circulatory shock Effects 0.000 description 1
- 229950011359 cirolemycin Drugs 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 229950005384 cliprofen Drugs 0.000 description 1
- 229960005465 clobetasone butyrate Drugs 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- SJCRQMUYEQHNTC-UHFFFAOYSA-N clopirac Chemical compound CC1=CC(CC(O)=O)=C(C)N1C1=CC=C(Cl)C=C1 SJCRQMUYEQHNTC-UHFFFAOYSA-N 0.000 description 1
- 229950009185 clopirac Drugs 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- GMRWGQCZJGVHKL-UHFFFAOYSA-N colestipol Chemical compound ClCC1CO1.NCCNCCNCCNCCN GMRWGQCZJGVHKL-UHFFFAOYSA-N 0.000 description 1
- 229960002604 colestipol Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 229950002276 cortodoxone Drugs 0.000 description 1
- 229940072645 coumadin Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- ZHPBLHYKDKSZCQ-UHFFFAOYSA-N cyclooctylmethanol Chemical compound OCC1CCCCCCC1 ZHPBLHYKDKSZCQ-UHFFFAOYSA-N 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- YCWXIQRLONXJLF-PFFGJIDWSA-N d06307 Chemical compound OS(O)(=O)=O.C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC.C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC YCWXIQRLONXJLF-PFFGJIDWSA-N 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229960004969 dalteparin Drugs 0.000 description 1
- 229960003109 daunorubicin hydrochloride Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 229960001145 deflazacort Drugs 0.000 description 1
- FBHSPRKOSMHSIF-GRMWVWQJSA-N deflazacort Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)=N[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O FBHSPRKOSMHSIF-GRMWVWQJSA-N 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229960003662 desonide Drugs 0.000 description 1
- WBGKWQHBNHJJPZ-LECWWXJVSA-N desonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O WBGKWQHBNHJJPZ-LECWWXJVSA-N 0.000 description 1
- CIWBQSYVNNPZIQ-PKWREOPISA-N dexamethasone dipropionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CIWBQSYVNNPZIQ-PKWREOPISA-N 0.000 description 1
- 229950000250 dexamethasone dipropionate Drugs 0.000 description 1
- VPOCYEOOFRNHNL-RQDPQJJXSA-J dexormaplatin Chemical compound Cl[Pt](Cl)(Cl)Cl.N[C@@H]1CCCC[C@H]1N VPOCYEOOFRNHNL-RQDPQJJXSA-J 0.000 description 1
- 229950001640 dexormaplatin Drugs 0.000 description 1
- 229950010621 dezaguanine Drugs 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- WVYXNIXAMZOZFK-UHFFFAOYSA-N diaziquone Chemical compound O=C1C(NC(=O)OCC)=C(N2CC2)C(=O)C(NC(=O)OCC)=C1N1CC1 WVYXNIXAMZOZFK-UHFFFAOYSA-N 0.000 description 1
- 229950002389 diaziquone Drugs 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229960004515 diclofenac potassium Drugs 0.000 description 1
- KXZOIWWTXOCYKR-UHFFFAOYSA-M diclofenac potassium Chemical compound [K+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KXZOIWWTXOCYKR-UHFFFAOYSA-M 0.000 description 1
- 229960001193 diclofenac sodium Drugs 0.000 description 1
- DOBMPNYZJYQDGZ-UHFFFAOYSA-N dicoumarol Chemical compound C1=CC=CC2=C1OC(=O)C(CC=1C(OC3=CC=CC=C3C=1O)=O)=C2O DOBMPNYZJYQDGZ-UHFFFAOYSA-N 0.000 description 1
- 229960001912 dicoumarol Drugs 0.000 description 1
- HIZKPJUTKKJDGA-UHFFFAOYSA-N dicumarol Natural products O=C1OC2=CC=CC=C2C(=O)C1CC1C(=O)C2=CC=CC=C2OC1=O HIZKPJUTKKJDGA-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 229960002124 diflorasone diacetate Drugs 0.000 description 1
- BOBLHFUVNSFZPJ-JOYXJVLSSA-N diflorasone diacetate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H](C)[C@@](C(=O)COC(C)=O)(OC(C)=O)[C@@]2(C)C[C@@H]1O BOBLHFUVNSFZPJ-JOYXJVLSSA-N 0.000 description 1
- 229960000616 diflunisal Drugs 0.000 description 1
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 1
- 229960004875 difluprednate Drugs 0.000 description 1
- 229950007956 diftalone Drugs 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- CZLKTMHQYXYHOO-QTNFYWBSSA-L disodium;(2s)-2-[(2-phosphonatoacetyl)amino]butanedioic acid Chemical compound [Na+].[Na+].OC(=O)C[C@@H](C(O)=O)NC(=O)CP([O-])([O-])=O CZLKTMHQYXYHOO-QTNFYWBSSA-L 0.000 description 1
- SVJSWELRJWVPQD-KJWOGLQMSA-L disodium;(2s)-2-[[4-[2-[(6r)-2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl]amino]pentanedioate Chemical compound [Na+].[Na+].C([C@@H]1CC=2C(=O)N=C(NC=2NC1)N)CC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 SVJSWELRJWVPQD-KJWOGLQMSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 1
- GZBONOYGBJSTHF-QLRNAMTQSA-N drocinonide Chemical compound C([C@@H]1CC2)C(=O)CC[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O GZBONOYGBJSTHF-QLRNAMTQSA-N 0.000 description 1
- 229950006082 drocinonide Drugs 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 description 1
- 229950004683 drostanolone propionate Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229950005133 duazomycin Drugs 0.000 description 1
- 229930192837 duazomycin Natural products 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 1
- 229950006700 edatrexate Drugs 0.000 description 1
- 229960002046 eflornithine hydrochloride Drugs 0.000 description 1
- MGQRRMONVLMKJL-KWJIQSIXSA-N elsamitrucin Chemical compound O1[C@H](C)[C@H](O)[C@H](OC)[C@@H](N)[C@H]1O[C@@H]1[C@](O)(C)[C@@H](O)[C@@H](C)O[C@H]1OC1=CC=CC2=C(O)C(C(O3)=O)=C4C5=C3C=CC(C)=C5C(=O)OC4=C12 MGQRRMONVLMKJL-KWJIQSIXSA-N 0.000 description 1
- 229950002339 elsamitrucin Drugs 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 229950002798 enlimomab Drugs 0.000 description 1
- 229950010625 enloplatin Drugs 0.000 description 1
- 229950001022 enpromate Drugs 0.000 description 1
- 238000007824 enzymatic assay Methods 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 229950003801 epirizole Drugs 0.000 description 1
- 229960003265 epirubicin hydrochloride Drugs 0.000 description 1
- 229950001426 erbulozole Drugs 0.000 description 1
- KLEPCGBEXOCIGS-QPPBQGQZSA-N erbulozole Chemical compound C1=CC(NC(=O)OCC)=CC=C1SC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C=CC(OC)=CC=2)OC1 KLEPCGBEXOCIGS-QPPBQGQZSA-N 0.000 description 1
- HCZKYJDFEPMADG-UHFFFAOYSA-N erythro-nordihydroguaiaretic acid Natural products C=1C=C(O)C(O)=CC=1CC(C)C(C)CC1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-UHFFFAOYSA-N 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- ITSGNOIFAJAQHJ-BMFNZSJVSA-N esorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)C[C@H](C)O1 ITSGNOIFAJAQHJ-BMFNZSJVSA-N 0.000 description 1
- 229950002017 esorubicin Drugs 0.000 description 1
- 229960001766 estramustine phosphate sodium Drugs 0.000 description 1
- IIUMCNJTGSMNRO-VVSKJQCTSA-L estramustine sodium phosphate Chemical compound [Na+].[Na+].ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 IIUMCNJTGSMNRO-VVSKJQCTSA-L 0.000 description 1
- 229950009769 etabonate Drugs 0.000 description 1
- WCDWBPCFGJXFJZ-UHFFFAOYSA-N etanidazole Chemical compound OCCNC(=O)CN1C=CN=C1[N+]([O-])=O WCDWBPCFGJXFJZ-UHFFFAOYSA-N 0.000 description 1
- 229950006566 etanidazole Drugs 0.000 description 1
- 229960002822 ethyl biscoumacetate Drugs 0.000 description 1
- SEGSDVUVOWIWFX-UHFFFAOYSA-N ethyl biscoumacetate Chemical compound C1=CC=C2C(=O)C(C(C=3C(C4=CC=CC=C4OC=3O)=O)C(=O)OCC)=C(O)OC2=C1 SEGSDVUVOWIWFX-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- HZQPPNNARUQMJA-IMIWJGOWSA-N ethyl n-[4-[[(2r,4r)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methylsulfanyl]phenyl]carbamate;hydrochloride Chemical compound Cl.C1=CC(NC(=O)OCC)=CC=C1SC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 HZQPPNNARUQMJA-IMIWJGOWSA-N 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 229960001493 etofenamate Drugs 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 208000024695 exercise-induced bronchoconstriction Diseases 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 229960000192 felbinac Drugs 0.000 description 1
- 229950003579 fenamole Drugs 0.000 description 1
- 229960001395 fenbufen Drugs 0.000 description 1
- ZPAKPRAICRBAOD-UHFFFAOYSA-N fenbufen Chemical compound C1=CC(C(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 ZPAKPRAICRBAOD-UHFFFAOYSA-N 0.000 description 1
- IDKAXRLETRCXKS-UHFFFAOYSA-N fenclofenac Chemical compound OC(=O)CC1=CC=CC=C1OC1=CC=C(Cl)C=C1Cl IDKAXRLETRCXKS-UHFFFAOYSA-N 0.000 description 1
- 229950006236 fenclofenac Drugs 0.000 description 1
- HAWWPSYXSLJRBO-UHFFFAOYSA-N fendosal Chemical compound C1=C(O)C(C(=O)O)=CC(N2C(=CC=3C4=CC=CC=C4CCC=32)C=2C=CC=CC=2)=C1 HAWWPSYXSLJRBO-UHFFFAOYSA-N 0.000 description 1
- 229950005416 fendosal Drugs 0.000 description 1
- 229950002296 fenpipalone Drugs 0.000 description 1
- 230000002600 fibrillogenic effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229950004322 flazalone Drugs 0.000 description 1
- BYZCJOHDXLROEC-RBWIMXSLSA-N fluazacort Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)=N[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O BYZCJOHDXLROEC-RBWIMXSLSA-N 0.000 description 1
- 229950002335 fluazacort Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 229960004369 flufenamic acid Drugs 0.000 description 1
- OPYFPDBMMYUPME-UHFFFAOYSA-N flumizole Chemical compound C1=CC(OC)=CC=C1C1=C(C=2C=CC(OC)=CC=2)NC(C(F)(F)F)=N1 OPYFPDBMMYUPME-UHFFFAOYSA-N 0.000 description 1
- 229950005288 flumizole Drugs 0.000 description 1
- WEGNFRKBIKYVLC-XTLNBZDDSA-N flunisolide acetate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O WEGNFRKBIKYVLC-XTLNBZDDSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229950007253 fluquazone Drugs 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 229950003750 fluretofen Drugs 0.000 description 1
- 229960000289 fluticasone propionate Drugs 0.000 description 1
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 1
- 229960003765 fluvastatin Drugs 0.000 description 1
- 210000001650 focal adhesion Anatomy 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- UXTSQCOOUJTIAC-UHFFFAOYSA-N fosquidone Chemical compound C=1N2CC3=CC=CC=C3C(C)C2=C(C(C2=CC=C3)=O)C=1C(=O)C2=C3OP(O)(=O)OCC1=CC=CC=C1 UXTSQCOOUJTIAC-UHFFFAOYSA-N 0.000 description 1
- 229950005611 fosquidone Drugs 0.000 description 1
- 229950010404 fostriecin Drugs 0.000 description 1
- 229940087051 fragmin Drugs 0.000 description 1
- 229950006099 furobufen Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 229960003627 gemfibrozil Drugs 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 150000002327 glycerophospholipids Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 108010006406 heparinase II Proteins 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 1
- 229940006607 hirudin Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- SOCGJDYHNGLZEC-UHFFFAOYSA-N hydron;n-methyl-n-[4-[(7-methyl-3h-imidazo[4,5-f]quinolin-9-yl)amino]phenyl]acetamide;chloride Chemical compound Cl.C1=CC(N(C(C)=O)C)=CC=C1NC1=CC(C)=NC2=CC=C(NC=N3)C3=C12 SOCGJDYHNGLZEC-UHFFFAOYSA-N 0.000 description 1
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 208000018875 hypoxemia Diseases 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229950005954 ibuprofen piconol Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229950006905 ilmofosine Drugs 0.000 description 1
- 229950011445 ilonidap Drugs 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 229960004187 indoprofen Drugs 0.000 description 1
- 229950008443 indoxole Drugs 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940095443 innohep Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229960003507 interferon alfa-2b Drugs 0.000 description 1
- 229940109242 interferon alfa-n3 Drugs 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229950004204 intrazole Drugs 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229950010897 iproplatin Drugs 0.000 description 1
- 229960000779 irinotecan hydrochloride Drugs 0.000 description 1
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 229960003317 isoflupredone acetate Drugs 0.000 description 1
- QFGMXJOBTNZHEL-UHFFFAOYSA-N isoxepac Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(CC(=O)O)=CC=C21 QFGMXJOBTNZHEL-UHFFFAOYSA-N 0.000 description 1
- 229950011455 isoxepac Drugs 0.000 description 1
- YYUAYBYLJSNDCX-UHFFFAOYSA-N isoxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC=1C=C(C)ON=1 YYUAYBYLJSNDCX-UHFFFAOYSA-N 0.000 description 1
- 229950002252 isoxicam Drugs 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- FPKOGTAFKSLZLD-FQEVSTJZSA-N lamifiban Chemical compound C1=CC(C(=N)N)=CC=C1C(=O)N[C@H](C(=O)N1CCC(CC1)OCC(O)=O)CC1=CC=C(O)C=C1 FPKOGTAFKSLZLD-FQEVSTJZSA-N 0.000 description 1
- 229950003178 lamifiban Drugs 0.000 description 1
- 108010021336 lanreotide Proteins 0.000 description 1
- 229960001739 lanreotide acetate Drugs 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- KDQAABAKXDWYSZ-SDCRJXSCSA-N leurosidine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-SDCRJXSCSA-N 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 230000006372 lipid accumulation Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- OXROWJKCGCOJDO-JLHYYAGUSA-N lornoxicam Chemical compound O=C1C=2SC(Cl)=CC=2S(=O)(=O)N(C)\C1=C(\O)NC1=CC=CC=N1 OXROWJKCGCOJDO-JLHYYAGUSA-N 0.000 description 1
- 229960002202 lornoxicam Drugs 0.000 description 1
- 208000018769 loss of vision Diseases 0.000 description 1
- 231100000864 loss of vision Toxicity 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 231100000515 lung injury Toxicity 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- GQVWFGYYMWLERN-UHFFFAOYSA-J magnesium;2-carboxyphenolate;2-hydroxyethyl(trimethyl)azanium;sulfate;tetrahydrate Chemical compound O.O.O.O.[Mg+2].[O-]S([O-])(=O)=O.C[N+](C)(C)CCO.C[N+](C)(C)CCO.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O GQVWFGYYMWLERN-UHFFFAOYSA-J 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960003951 masoprocol Drugs 0.000 description 1
- HCZKYJDFEPMADG-TXEJJXNPSA-N masoprocol Chemical compound C([C@H](C)[C@H](C)CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-TXEJJXNPSA-N 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- JBVNBBXAMBZTMQ-CEGNMAFCSA-N megestrol Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 JBVNBBXAMBZTMQ-CEGNMAFCSA-N 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- 229960003846 melengestrol acetate Drugs 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- LWYJUZBXGAFFLP-OCNCTQISSA-N menogaril Chemical compound O1[C@@]2(C)[C@H](O)[C@@H](N(C)C)[C@H](O)[C@@H]1OC1=C3C(=O)C(C=C4C[C@@](C)(O)C[C@H](C4=C4O)OC)=C4C(=O)C3=C(O)C=C12 LWYJUZBXGAFFLP-OCNCTQISSA-N 0.000 description 1
- 229950002676 menogaril Drugs 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 1
- 229960004963 mesalazine Drugs 0.000 description 1
- OJGJQQNLRVNIKE-UHFFFAOYSA-N meseclazone Chemical compound O1C2=CC=C(Cl)C=C2C(=O)N2C1CC(C)O2 OJGJQQNLRVNIKE-UHFFFAOYSA-N 0.000 description 1
- 229950000701 meseclazone Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 125000005395 methacrylic acid group Chemical class 0.000 description 1
- KPQJSSLKKBKWEW-RKDOVGOJSA-N methanesulfonic acid;5-nitro-2-[(2r)-1-[2-[[(2r)-2-(5-nitro-1,3-dioxobenzo[de]isoquinolin-2-yl)propyl]amino]ethylamino]propan-2-yl]benzo[de]isoquinoline-1,3-dione Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.[O-][N+](=O)C1=CC(C(N([C@@H](CNCCNC[C@@H](C)N2C(C=3C=C(C=C4C=CC=C(C=34)C2=O)[N+]([O-])=O)=O)C)C2=O)=O)=C3C2=CC=CC3=C1 KPQJSSLKKBKWEW-RKDOVGOJSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- BKBBTCORRZMASO-ZOWNYOTGSA-M methotrexate monosodium Chemical compound [Na+].C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C([O-])=O)C=C1 BKBBTCORRZMASO-ZOWNYOTGSA-M 0.000 description 1
- 229960003058 methotrexate sodium Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- HRHKSTOGXBBQCB-VFWICMBZSA-N methylmitomycin Chemical compound O=C1C(N)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N(C)[C@H]3CN12 HRHKSTOGXBBQCB-VFWICMBZSA-N 0.000 description 1
- CDMLLMOLWUKNEK-AOHDELFNSA-M methylprednisolone suleptanate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCCCCCC(=O)N(C)CCS([O-])(=O)=O)CC[C@H]21 CDMLLMOLWUKNEK-AOHDELFNSA-M 0.000 description 1
- 229950010796 methylprednisolone suleptanate Drugs 0.000 description 1
- VQJHOPSWBGJHQS-UHFFFAOYSA-N metoprine, methodichlorophen Chemical compound CC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C(Cl)=C1 VQJHOPSWBGJHQS-UHFFFAOYSA-N 0.000 description 1
- QTFKTBRIGWJQQL-UHFFFAOYSA-N meturedepa Chemical compound C1C(C)(C)N1P(=O)(NC(=O)OCC)N1CC1(C)C QTFKTBRIGWJQQL-UHFFFAOYSA-N 0.000 description 1
- 229950009847 meturedepa Drugs 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- DRCJGCOYHLTVNR-ZUIZSQJWSA-N mitindomide Chemical compound C1=C[C@@H]2[C@@H]3[C@H]4C(=O)NC(=O)[C@H]4[C@@H]3[C@H]1[C@@H]1C(=O)NC(=O)[C@H]21 DRCJGCOYHLTVNR-ZUIZSQJWSA-N 0.000 description 1
- 229950001314 mitindomide Drugs 0.000 description 1
- 229950002137 mitocarcin Drugs 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 229950000911 mitogillin Drugs 0.000 description 1
- 108010026677 mitomalcin Proteins 0.000 description 1
- 229950007612 mitomalcin Drugs 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229950005715 mitosper Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960003251 morniflumate Drugs 0.000 description 1
- LDXSPUSKBDTEKA-UHFFFAOYSA-N morniflumate Chemical compound FC(F)(F)C1=CC=CC(NC=2C(=CC=CN=2)C(=O)OCCN2CCOCC2)=C1 LDXSPUSKBDTEKA-UHFFFAOYSA-N 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- NKDJNEGDJVXHKM-UHFFFAOYSA-N n,2-dimethyl-4,5,6,7-tetrahydroindazol-3-amine Chemical compound C1CCCC2=NN(C)C(NC)=C21 NKDJNEGDJVXHKM-UHFFFAOYSA-N 0.000 description 1
- HWCORKBTTGTRDY-UHFFFAOYSA-N n-(4-chlorophenyl)-1,3-dioxo-4h-isoquinoline-4-carboxamide Chemical compound C1=CC(Cl)=CC=C1NC(=O)C1C2=CC=CC=C2C(=O)NC1=O HWCORKBTTGTRDY-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- CRJGESKKUOMBCT-PMACEKPBSA-N n-[(2s,3s)-1,3-dihydroxyoctadecan-2-yl]acetamide Chemical compound CCCCCCCCCCCCCCC[C@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-PMACEKPBSA-N 0.000 description 1
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 1
- WRINSSLBPNLASA-FOCLMDBBSA-N n-methyl-n-[(e)-(n-methylanilino)diazenyl]aniline Chemical compound C=1C=CC=CC=1N(C)\N=N\N(C)C1=CC=CC=C1 WRINSSLBPNLASA-FOCLMDBBSA-N 0.000 description 1
- 229960004270 nabumetone Drugs 0.000 description 1
- 229960000899 nadroparin Drugs 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229960003940 naproxen sodium Drugs 0.000 description 1
- CDBRNDSHEYLDJV-FVGYRXGTSA-M naproxen sodium Chemical compound [Na+].C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CDBRNDSHEYLDJV-FVGYRXGTSA-M 0.000 description 1
- LTRANDSQVZFZDG-SNVBAGLBSA-N naproxol Chemical compound C1=C([C@H](C)CO)C=CC2=CC(OC)=CC=C21 LTRANDSQVZFZDG-SNVBAGLBSA-N 0.000 description 1
- 229950006890 naproxol Drugs 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000014399 negative regulation of angiogenesis Effects 0.000 description 1
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 231100000878 neurological injury Toxicity 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229950006046 nimazone Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229950006344 nocodazole Drugs 0.000 description 1
- KGTDRFCXGRULNK-JYOBTZKQSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](OC)(C)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C4[C@@]5(C)O[C@H]([C@H]([C@@H]([C@H]5O)N(C)C)O)OC4=C3C3=O)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 KGTDRFCXGRULNK-JYOBTZKQSA-N 0.000 description 1
- 229950009266 nogalamycin Drugs 0.000 description 1
- 229960004364 olsalazine sodium Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960004534 orgotein Drugs 0.000 description 1
- 108010070915 orgotein Proteins 0.000 description 1
- 229950008017 ormaplatin Drugs 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229940127084 other anti-cancer agent Drugs 0.000 description 1
- 229960002739 oxaprozin Drugs 0.000 description 1
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229950000370 oxisuran Drugs 0.000 description 1
- 229960000649 oxyphenbutazone Drugs 0.000 description 1
- HFHZKZSRXITVMK-UHFFFAOYSA-N oxyphenbutazone Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 HFHZKZSRXITVMK-UHFFFAOYSA-N 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 229960001744 pegaspargase Drugs 0.000 description 1
- 108010001564 pegaspargase Proteins 0.000 description 1
- 229950006960 peliomycin Drugs 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- VPAWVRUHMJVRHU-VGDKGRGNSA-N perfosfamide Chemical compound OO[C@@H]1CCO[P@@](=O)(N(CCCl)CCCl)N1 VPAWVRUHMJVRHU-VGDKGRGNSA-N 0.000 description 1
- 229950009351 perfosfamide Drugs 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 108010049224 perlecan Proteins 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DQDAYGNAKTZFIW-UHFFFAOYSA-N phenprocoumon Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC)C1=CC=CC=C1 DQDAYGNAKTZFIW-UHFFFAOYSA-N 0.000 description 1
- 229960004923 phenprocoumon Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 description 1
- 229950001100 piposulfan Drugs 0.000 description 1
- XESARGFCSKSFID-FLLFQEBCSA-N pirazofurin Chemical compound OC1=C(C(=O)N)NN=C1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 XESARGFCSKSFID-FLLFQEBCSA-N 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229960000851 pirprofen Drugs 0.000 description 1
- PIDSZXPFGCURGN-UHFFFAOYSA-N pirprofen Chemical compound ClC1=CC(C(C(O)=O)C)=CC=C1N1CC=CC1 PIDSZXPFGCURGN-UHFFFAOYSA-N 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 239000002797 plasminogen activator inhibitor Substances 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- JKPDEYAOCSQBSZ-OEUJLIAZSA-N plomestane Chemical compound O=C1CC[C@]2(CC#C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKPDEYAOCSQBSZ-OEUJLIAZSA-N 0.000 description 1
- 229950004541 plomestane Drugs 0.000 description 1
- 229920001483 poly(ethyl methacrylate) polymer Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 1
- 229920000212 poly(isobutyl acrylate) Polymers 0.000 description 1
- 229920000205 poly(isobutyl methacrylate) Polymers 0.000 description 1
- 229920001306 poly(lactide-co-caprolactone) Polymers 0.000 description 1
- 229920000184 poly(octadecyl acrylate) Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000197 polyisopropyl acrylate Polymers 0.000 description 1
- 229920000182 polyphenyl methacrylate Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920001290 polyvinyl ester Polymers 0.000 description 1
- 229920001291 polyvinyl halide Polymers 0.000 description 1
- 229950004406 porfiromycin Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 229960001586 procarbazine hydrochloride Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- LFULEKSKNZEWOE-UHFFFAOYSA-N propanil Chemical compound CCC(=O)NC1=CC=C(Cl)C(Cl)=C1 LFULEKSKNZEWOE-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 229960002466 proquazone Drugs 0.000 description 1
- JTIGKVIOEQASGT-UHFFFAOYSA-N proquazone Chemical compound N=1C(=O)N(C(C)C)C2=CC(C)=CC=C2C=1C1=CC=CC=C1 JTIGKVIOEQASGT-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- MKSVFGKWZLUTTO-FZFAUISWSA-N puromycin dihydrochloride Chemical compound Cl.Cl.C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO MKSVFGKWZLUTTO-FZFAUISWSA-N 0.000 description 1
- 238000011555 rabbit model Methods 0.000 description 1
- 239000000718 radiation-protective agent Substances 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229940107685 reopro Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000036387 respiratory rate Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960005496 reviparin Drugs 0.000 description 1
- 229960004356 riboprine Drugs 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 229910052895 riebeckite Inorganic materials 0.000 description 1
- 229960001487 rimexolone Drugs 0.000 description 1
- QTTRZHGPGKRAFB-OOKHYKNYSA-N rimexolone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CC)(C)[C@@]1(C)C[C@@H]2O QTTRZHGPGKRAFB-OOKHYKNYSA-N 0.000 description 1
- QXKJWHWUDVQATH-UHFFFAOYSA-N rogletimide Chemical compound C=1C=NC=CC=1C1(CC)CCC(=O)NC1=O QXKJWHWUDVQATH-UHFFFAOYSA-N 0.000 description 1
- 229950005230 rogletimide Drugs 0.000 description 1
- 229950001166 romazarit Drugs 0.000 description 1
- 229950000125 salcolex Drugs 0.000 description 1
- 229950009768 salnacedin Drugs 0.000 description 1
- 229960000953 salsalate Drugs 0.000 description 1
- GIZKAXHWLRYMLE-UHFFFAOYSA-M sanguinarium chloride Chemical compound [Cl-].C1=C2OCOC2=CC2=C3[N+](C)=CC4=C(OCO5)C5=CC=C4C3=CC=C21 GIZKAXHWLRYMLE-UHFFFAOYSA-M 0.000 description 1
- 229950011197 sanguinarium chloride Drugs 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
- 229950002093 seclazone Drugs 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229950006250 sermetacin Drugs 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229920000260 silastic Polymers 0.000 description 1
- 229950009089 simtrazene Drugs 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 230000008591 skin barrier function Effects 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- HVBBVDWXAWJQSV-UHFFFAOYSA-N sodium;(3-benzoylphenyl)-(difluoromethylsulfonyl)azanide Chemical compound [Na+].FC(F)S(=O)(=O)[N-]C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 HVBBVDWXAWJQSV-UHFFFAOYSA-N 0.000 description 1
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
- TVGNJNYKOTWAJQ-UHFFFAOYSA-M sodium;4-butyl-5-oxo-1,2-diphenylpyrazol-3-olate;propane-1,2,3-triol Chemical compound [Na+].OCC(O)CO.C=1C=CC=CC=1N1C(=O)C(CCCC)=C([O-])N1C1=CC=CC=C1 TVGNJNYKOTWAJQ-UHFFFAOYSA-M 0.000 description 1
- AVERBMQHYOZACV-UHFFFAOYSA-M sodium;7-chloro-4-[(3,4-dichlorophenyl)carbamoyl]-1,1-dioxo-2,3-dihydro-1$l^{6}-benzothiepin-5-olate;hydrate Chemical compound O.[Na+].C1CS(=O)(=O)C2=CC=C(Cl)C=C2C([O-])=C1C(=O)NC1=CC=C(Cl)C(Cl)=C1 AVERBMQHYOZACV-UHFFFAOYSA-M 0.000 description 1
- MIXCUJKCXRNYFM-UHFFFAOYSA-M sodium;diiodomethanesulfonate;n-propyl-n-[2-(2,4,6-trichlorophenoxy)ethyl]imidazole-1-carboxamide Chemical compound [Na+].[O-]S(=O)(=O)C(I)I.C1=CN=CN1C(=O)N(CCC)CCOC1=C(Cl)C=C(Cl)C=C1Cl MIXCUJKCXRNYFM-UHFFFAOYSA-M 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 229950009641 sparsomycin Drugs 0.000 description 1
- XKLZIVIOZDNKEQ-CLQLPEFOSA-N sparsomycin Chemical compound CSC[S@](=O)C[C@H](CO)NC(=O)\C=C\C1=C(C)NC(=O)NC1=O XKLZIVIOZDNKEQ-CLQLPEFOSA-N 0.000 description 1
- XKLZIVIOZDNKEQ-UHFFFAOYSA-N sparsomycin Natural products CSCS(=O)CC(CO)NC(=O)C=CC1=C(C)NC(=O)NC1=O XKLZIVIOZDNKEQ-UHFFFAOYSA-N 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 229950006050 spiromustine Drugs 0.000 description 1
- 229950004330 spiroplatin Drugs 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 210000002330 subarachnoid space Anatomy 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 229950007841 sulofenur Drugs 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 229960004492 suprofen Drugs 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 108700003774 talisomycin Proteins 0.000 description 1
- 229950002687 talisomycin Drugs 0.000 description 1
- 229950005100 talmetacin Drugs 0.000 description 1
- 229960005262 talniflumate Drugs 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229950003441 tebufelone Drugs 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- RNVNXVVEDMSRJE-UHFFFAOYSA-N teloxantrone hydrochloride Chemical compound Cl.Cl.OCCNCCN1NC2=C3C(=O)C=CC(=O)C3=C(O)C3=C2C1=CC=C3NCCNC RNVNXVVEDMSRJE-UHFFFAOYSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 229950008703 teroxirone Drugs 0.000 description 1
- 229950007324 tesicam Drugs 0.000 description 1
- 229950000997 tesimide Drugs 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- TUGDLVFMIQZYPA-UHFFFAOYSA-N tetracopper;tetrazinc Chemical compound [Cu+2].[Cu+2].[Cu+2].[Cu+2].[Zn+2].[Zn+2].[Zn+2].[Zn+2] TUGDLVFMIQZYPA-UHFFFAOYSA-N 0.000 description 1
- 150000004044 tetrasaccharides Chemical class 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical class C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 description 1
- 229950011457 tiamiprine Drugs 0.000 description 1
- 229960003723 tiazofurine Drugs 0.000 description 1
- FVRDYQYEVDDKCR-DBRKOABJSA-N tiazofurine Chemical compound NC(=O)C1=CSC([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=N1 FVRDYQYEVDDKCR-DBRKOABJSA-N 0.000 description 1
- SYRHIZPPCHMRIT-UHFFFAOYSA-N tin(4+) Chemical compound [Sn+4] SYRHIZPPCHMRIT-UHFFFAOYSA-N 0.000 description 1
- 229960005062 tinzaparin Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229950002345 tiopinac Drugs 0.000 description 1
- 229950002376 tirapazamine Drugs 0.000 description 1
- QVMPZNRFXAKISM-UHFFFAOYSA-N tirapazamine Chemical compound C1=CC=C2[N+]([O-])=NC(=N)N(O)C2=C1 QVMPZNRFXAKISM-UHFFFAOYSA-N 0.000 description 1
- COKMIXFXJJXBQG-NRFANRHFSA-N tirofiban Chemical compound C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 COKMIXFXJJXBQG-NRFANRHFSA-N 0.000 description 1
- 229960003425 tirofiban Drugs 0.000 description 1
- BISFDZNIUZIKJD-XDANTLIUSA-N tixocortol pivalate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CSC(=O)C(C)(C)C)(O)[C@@]1(C)C[C@@H]2O BISFDZNIUZIKJD-XDANTLIUSA-N 0.000 description 1
- 229960003114 tixocortol pivalate Drugs 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- 229960002044 tolmetin sodium Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960002190 topotecan hydrochloride Drugs 0.000 description 1
- 229960004167 toremifene citrate Drugs 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- VSVSLEMVVAYTQW-VSXGLTOVSA-N triclonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(Cl)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CCl)[C@@]2(C)C[C@@H]1Cl VSVSLEMVVAYTQW-VSXGLTOVSA-N 0.000 description 1
- 229950008073 triclonide Drugs 0.000 description 1
- 229960000538 trimetrexate glucuronate Drugs 0.000 description 1
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 1
- 229960004824 triptorelin Drugs 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 230000005951 type IV hypersensitivity Effects 0.000 description 1
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 1
- 108010052768 tyrosyl-isoleucyl-glycyl-seryl-arginine Proteins 0.000 description 1
- 229950008396 ulobetasol propionate Drugs 0.000 description 1
- BDSYKGHYMJNPAB-LICBFIPMSA-N ulobetasol propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]2(C)C[C@@H]1O BDSYKGHYMJNPAB-LICBFIPMSA-N 0.000 description 1
- SPDZFJLQFWSJGA-UHFFFAOYSA-N uredepa Chemical compound C1CN1P(=O)(NC(=O)OCC)N1CC1 SPDZFJLQFWSJGA-UHFFFAOYSA-N 0.000 description 1
- 229950006929 uredepa Drugs 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 239000012646 vaccine adjuvant Substances 0.000 description 1
- 229940124931 vaccine adjuvant Drugs 0.000 description 1
- 229960002730 vapreotide Drugs 0.000 description 1
- 108700029852 vapreotide Proteins 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 1
- 229960003895 verteporfin Drugs 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960005212 vindesine sulfate Drugs 0.000 description 1
- BCXOZISMDZTYHW-IFQBWSDRSA-N vinepidine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@H](C2)CC)N2CCC2=C1NC1=CC=CC=C21 BCXOZISMDZTYHW-IFQBWSDRSA-N 0.000 description 1
- 229960002166 vinorelbine tartrate Drugs 0.000 description 1
- GBABOYUKABKIAF-IWWDSPBFSA-N vinorelbinetartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IWWDSPBFSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- DVPVGSLIUJPOCJ-XXRQFBABSA-N x1j761618a Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(=O)CN(C)C)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(=O)CN(C)C)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 DVPVGSLIUJPOCJ-XXRQFBABSA-N 0.000 description 1
- 229950003017 zeniplatin Drugs 0.000 description 1
- 229950007802 zidometacin Drugs 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The invention relates to methods for delivering polysaccharides by a pulmonary route to achieve local and systemic therapeutic effects. The polysaccharides may be formulated or unformulated and in some instances have an extremely fast absorption rate.
Description
METHODS AND PRODUCTS RELATED TO PULMONARY DELIVERY OF
POLYSACCHARIDES
I'IEI'D OF TI-IE INVENTION
The present invention relates to methods and products associated with pulmonary delivery orpolysaccharides. In particular methods and products for delivering both unformulated and formulated polysaccharides are described.
BACKGROUND OF THE INVENTION
Recent advances in medicine have produced several alternative modes of drug delivery. Drugs which were previously only available in injectable forms, are now available in less invasive forms such as oral tablets or capsules, sustained release devices, and transdermal patches. Many of these advances, however, have occurred with protein based or small molecule drugs. Delivery of polysaccharides for therapeutic or 1 S prophylactic purposes is still associated with some problems.
Oral delivery of drugs is often preferred. The rapid metabolism of polysaccharides in the gastrointestinal tract, however, has prohibited their oral administration. Pulmonary delivery of drugs has also been proposed to be a preferred route of drug administration because of the large surface area of blood vessels in alveoli.
The thin barrier between the rich capillary bed and the air coupled with the very high blood flow rate makes alveoli of lungs one of the most desirable drug delivery sites.
Pulmonary delivery of protein based drugs has been quite successful.
Lnvestigators, however, have been trying for over 30 years to administer polysaccharides such as heparin by pulmonary delivery, with much less success. For instance, delivering heparin by conventional liquid aerosol spray or instillation only received limited success due to its poor penetration to the deep lung and resultant poor pharmacolcinetics perFormance.
An exceedingly high dose ol~ heparin is rcquii°ed to generate mcaninghul pharmacological elFects when inhaled as liquid heparin.
Natural polysaccharides such as heparin are polydisperse mixtures containing a large number of chains having different molecular weights (M Ws~ and as such the pharmacokinetics of these compounds are complicated. The anticoagulant response o(' heparin, (or instance, increases disproportionately in intensity and duration as the dose increases. t~s a result, anticoagulant e(~Uect ol~ heparin often has to be closclyr monitored _7_ t0 1111111m1Ze the OCCLIrreIlCe Of pOtelltlally dallgel'OL1S he11101'I'h age, Whlcl7 1S the 111OSt G0111m017 al7d 111x101' Slde etfeCt Of hepal'117. S111Ge hepal'lll 1S llOt a 5117g1e cllellllcal l lltlty and its disposition is determined by a number of pathophysiologic factors, its pharnlacolcinetic parameters vary substantially among differen t individuals and thus require dose adjustment for each specific individual. The frequency of side effects is associated with the routes of administration. The risk is higher in intermittent ( 1 ~l.?"%t>) and continuous (6.8°l°) infusion than the subcutaneous I°oute (~I.1 %).
SUMMARY OF THE iNVE~ITION
The invention relates to improved methods and products for delivering polysaccharides for prophylactic and therapeutic purposes. The inven tion is based in some aspects on the surprising discovery that pulmonary administration of polysaccharides in a dry aerosol form, in a formulated or unformulated form, results in an extremely rapid and efficient delivery of dle polysaccharide locally and systemically.
Many attempts have been made in the past to deliver polysaccharides such as heparin by inhalation. In general these attempts have been unsuccessful. It is well established that when heparin is delivered in a liquid aerosol, the amount of heparin that is absorbed in the blood is extremely low. It was discovered according to the invention that polysaccharides could be administered by pulmonary delivery in a dry aerosol with 2Q excellent results, including rapid absorption and good bioavailability, resulting in significant therapeutic benefits.
Thus, in some aspects, the invention is a method for delivering a polysaccharide to a subject in an unformulated dry powder. For instance, a method for producing a therapeutic effect by administering to a pulmonary tissue of a subject an unformulated dry polysaccharide particle ill an effective amount for producing a therapeutic effect, wherein the unformulated dry polysaccharide particle has a mean geometric diameter of I-SOQ microns, is provided.
In other aspects the invention is a method for delivcrin~~ at least 5% anti preferably at least 10°,~0 of a polysaccharide to the lower respiratory tract by administering to a pulmonary tissue of a subject an unforn7ulated dry polysaccl7aridc particle, wherein the unformulated dry polysaccharide particle has a mean ~~EOnletric diameter of 1-500 microns, and wherein at least 5°~'° or 10% of the polysaccharide administered is delivered to the lower respiratory tract.
In yet anather aspect the invention is a method for systen7ically delivering a polysaccharide to a subject by administering to a pulmonary tissue of the suhject an unformulated dry polysaccharide particle, wherein the un formulated dry polysaccharide particle has a mean geometric diameter of 1-500 n7icrans.
The palysaccharide usefill in the methods is any type of polysaccharide which has a prophylactic or therapeutic utility. In one embodiment the polysaccharide is a glycosaminoglycan, such as, for example, a heparin, a heparin sulfate, a low molecular weight heparin, a biotechnology derived heparin, a chemically modified heparin, a heparin mimetic {e.g., a monosaccharide, oligosaccharide or polysaccharide that has at least one heparin-like function such as AT-DI binding), or an unfi'actionated heparin preparation.
Generally the unformulafed dry polysaccharide particle has a mean geometric diameter of 1-500 microns, or any range of integers therebetween. In some embodiments the unformulated dry polysaccharide particle has a mean geometric diameter of 1-50, 1-200, 53-106, 1-5, 1- 20, 20-53, 53-75, or 75 -106 microns. In other embodiments the unforlnulated dry polysaccharide particle has a mean aerodynamic diameter of 1-5, 5-35, I-35, 35-70, 35-75, or 1-50 microns. In yet other embodiments the unformulated dry polysaccharide has a tap density of 0.01 - 0.4 g/cm~ or greater than 0.4 glcm3.
The prophylactic or therapeutic utility of the polysaccharide being delivered varies depending an the type of polysaccharide as well as the subject being treated.
Some polysaccharides, for instance, arc useful as vaccine antigens. These are generally used for prophylactic purposes, but, ill some oases call be used therapeutically as well.
Other polysaccharides have very diverse utilities, such as, the glycosaminoglycans, and in particular heparin-like-glycosaminoglycans. Glyeosaminoglycans have been established to be useful for treating and preventing coagulation disorders, thrombotic disorders, cardiovascular disease, vascular conditions, atherosclerosis, respiratory disorders, cancer, and an~iogenic disorders.
ThLIS, Ill SC)Ille elnbodlnlentS the SLlbleCt haS 01' is at I'1Sk C)I' a CC)aglllatl011 dISOI'C1C1' alld the thel'apeUtlC effect Ot the glyCOSa1171I1Og1yCd11 1S a11t1-COagLllatloll 01' alltlthro111bOS1S. Ill othel' e117boC11111e11tS the gIyCOSan71170g1yCa11 1S
LIS('l~Lll 1'C11' tl'CEltlll~
cardiovascular disease, such as For instance, acute myocardial inFarction, unstable angina, ischemic stroke, and atria( fibrillation, and vascular conditions, such as For instance, deep venous thrombosis, stroke, and pulmonary cnlbolisnl. In other embodiments the subject is preparing to undergo, is undergoing or is recovering l~ronl a surgical procedure or the subject is Undergoing a tissue or organ transplant.
Surgical procedures include but are not limited to cardiac-pulmonary by-pass surgery, corollary revascularization surgery, orthopedic surgery, and prosthesis replacement surgery.
The subject in other embodiments leas or is at risk oFatherosclerosis, a respiratory disorder, a cancer or metastasis, an inflammatory disorder, an allergy, andlor an angiogenic disorder. Respiratory disorders include but are not limited to asthma, emphysema, adult respiratory distress syndrome CARDS), and lung, kidney, heart gut, brain, skeletal muscle ischemial-reperfusion injury. Angiogenic disorders include but are not limited to neovaseular disorders of the eye, osteoporosis, psoriasis.
and arthritis.
In other embodiments the polysaccharide is a chondroitin sulfate, dermatan sulfate, hyaluronic acid, pectin or pectin derivative, oligosaccharide or pentasaccharide that binds to AT-III, laminarin, PI-$8, sulfated chitin, or other animal-derived, plant-derived, microorganism-derived, natural, synthetic, or modified polysaccharide. Pectin s and pectin derivatives are useful for anti-tumor applications.
In same embodiments when the polysaccharide is a glycosaminoglycan being administered for anticoagulant purposes, it is administered in an amount eI=f~ective to produce a minimum therapeutic level of approximately 0.X5 IUlml anti-Factor Xa activity.
The LmFormulated dry polysaccharide may be self administered by the subject or it may be administered by another, such as a health care professional. her instance, tile unformUlated dry polysaccharide may be administered through a tracheal tube.
In other aspects, fhe invention is a composition consisting oCunFormUlated dry glycosaminoglycan leaving a mean geometric diameter of I-500 microns. In some embodiments the unFormulated dry polysaccharide particle has a mean geometric diameter of 1-50, I- 200, S3-l OG, 1-5, 1- 2p, '?0-53, 53-75, or 75 flOG
microns. In other etIlbOd1111e11tS the L111foI'nlLllated dl'y polySaCCha1'Ide pal'tlCle 11W El Illeall ael'odyllaInIC
diameter of I-S, 5-35, 1-35, a5-70, 35-75, or 1-50 microns.
The glyc0saminoglycan in some embodiments may be a heparin, a heparin sulfate, a low molecular weight heparin, a biotechnology derived heparin, a chemically modified or synthesized heparin, heparin mimeties and an unfraclianated heparin preparation.
OptlOllally the cO111pOSlt1o11 play add1tl011al1y IIIGILIde a f01'lllLllated CII'y glycosaminoglycan preparation. 'rile glycosaminoglycan of the formulated dry glycosaminoglycan preparation may also be a heparin, a heparin sulfate, a low molecular weight heparin, a biotechnology derived heparin, a chemically modified Nepal°in, a heparin mimetic, and an unfractionated heparin preparation.
In same embodiments the glycosaminoglycan of the formulated dry preparation is the same as the glycosaminoglycan of the unformulated dry preparation and in other embodiments the glycosaminoglycan of the formulated dry preparation is different than the glycosaminoglycan of the unformulated dry preparation.
Optionally, the formulated dry glycosaminoglycan preparation includes a 7 5 polymer to effect slow release of the glycosaminoglycan. Thus the glycosaminoglycan of the unfonnulated preparation will be released rapidly and the glycosaminoglycan of the formulated preparation will be released slowly over time. In some embodiments the polymer is selected from the group consisting of poly lactic acid (PT.rA), polyglycolic acid (PGA), poly (D,I~, -lactic-co-glycolic acid) (Pf,GA), polyamides, polycarbonates, poly(ethylerLe oxide), polyvinyl compounds, poly vinyl ethers, polymers of acrylic and methacrylic acids, celluloses, and other polysaccharides. In other embodiments the formulated dry glycosaminoglycan preparation includes a surfactant, such as DPPC.
polyoxethylene-9-; auryl ether; palmitic acid; oleic acid; sorbitan tri0leate (Span 85);
glycocholate; surfactin; poloxomer; sorbitan fatty acid; sorbitan trioleate;
tyloxapol; and phopholipids.
A method for delivering a glycosaminoglycan to a subject by administering to a pulmonary tissue of a subject the above-described compositions is also disclosed according to the invention.
In other aspects the invention relates to methods of delivering either or both ~0 f01'IllLllated alld Llllf0l"mLllated pOlySilCGha1'ldeS by pLlllllollal'y adI111111SI1'at1011. ThLIS the invention in one aspect is a method of rapidly delivering a polysaccharide to a subject by adn11111SteI'lllg a Ch'y ael'0501 G011talllltlg a polySaCGhal'lde t0 a pLlllll0llal'y tISSLIG 01_ El -G-subject in an effective amount to produce a peak plasma concentration o1' laolysaccharide within three and preferably two hours.
In other aspects tl7e invention is a method oI~ rapidly delivering a polysaccharide t0 a SLIbIeCt by ad1771171S1e1'117g a dl'y ael'oS01 COlltalt1117g a pOlySaCCl7a1'lde t0 a pL11117017a1'~~
tissue of a subject in an effective amount to produce a peak thcrapeu tic activity ol~
polysaccharide within three or preferably two hour°s, In some embodiments the dry aerosol containing a polysaccharide is administered in an eFPective amount to produce the peals concentration or activity of polysaccharide within one and one half hours, In other embodiments the dry aerosol containing a polysaccharide is administered in an effective amount to produce the peals concentration or activity of polysaccharide within one hour or preferably within a half hour.
The polysaccharide in some embodiments is a glycosaminoglycan, Glycosaminoglycans include but are not limited to low-molecular-weight heparin, heparin, heparin sulfate, biotechnology derived heparin, chemically modified heparin, heparin mimetic, and unfractionated heparin preparation.
In some embodiments the dry aerosol contains an unformulated dry polysaccharide and in other embodiments it contains a fornnllated dry polysaccharide preparation or some combination thereof. Optionally the dry aerosol contains a dry polysaccharide formulated in a surfactant, such as DPPC. Tl7e SurFactant may optionally be coated on the particle surface or incorporated into the formulation.
In other embodiments additional molecules may optionally be administered.
These include, for instance, proteins, peptides, nucleic acids (e.g., IZNA, DNA, PNA, multiplexes of them (e.g.: triplex), and, small organic molecules).
The invention in another aspect relates to a method oC rapidly delivering a polysaccharide to a subject by administering a dry aerosol containing a polysaccharide to a pulmonary tissue of a subject in an effective amount to deliver at least 5°~0 of the polysaccharide to the blood within one hour. In some embodiments at least 5°,~0 oi~thi polysaccharide is detectable in the blood within one hour. In other embodiments at least 10°l0, 20%, 30°~'a, X10°.~°, 50%, 60%, 70°~'0, 8d°~o, or 90°.~0 oC the polysaccharide is delivered to or detectable in the blood within one hour.
In other aspects the invention is a method far producing a rapid therapeutic cIAIect by administering a dry aerosol containing a polysaccharide to n pulmonar>>
tissue of' a _ '7 _ subject in an effective amount for producing a therapeutic effect within 1 hour of administration. In some embodiments the dry aerosol is administered in an effective a1710L111t tOl' prOdLlClllg a thel'apeLltlG GfleGt Wlthlll 15 117111LIteS Of ad1171171S11'at1011. 111 yC;t Other eIllbOdImeIltS the dl'y ael'OSOI 1S ad1n1111Ste1'ed 111 all el'feCtlVC
a177OU17t 101' pl'OdL1C117t, a thel'apeLltlC CffeCt Wlt17111 1 Q InlnLlteS Of adIn1171StratIOl7.
The 111Ve11tIO11 117 anOtheI' aspect 1S a COIIIpOSlt1011 G0111p1'lslllg a dl'y ael'OSO1 formulation of particles containing a heparin-like glycosaminoglycan, wherein the particles have a mean geometric diameter of greater than 30 microns. In some embodiments the particles are spherical and in other embodiments the particles are non-1 Q spherical. In yet other embodiments the particles are porous and in other embodiments the particles are non-porous.
A composition of a dry aerosol formulation of particles containing a heparin-like glycosaminoglycan, wherein the particles have a mean aerodynamic diameter of greater than 5 microns is provided according to another aspect of the invention.
15 In another aspect the invention relates to a composition of a dry aerosol formulation of particles containing a heparin-like glycosaminoglycan, wherein the particles have a tap density of greater than O.4 glcm3.
Kits are provided according to yet other aspects of the invention. The kit is a lit for administering a dry aerosol containing a polysaccharide to the respiratory tract of a 20 subject and includes an inhalation apparatus, a polysaccharide dry aerosol particle preparation and a detection system. The polysaccharide dry aerosol particle is formulated to release at least 5°J° ofthe polysaccharide within three or preferably two hours.
In one embodiment afthe kit, the polysaccharide is a glycosan7inoglycan, such 25 as, a low-molecular-weight heparin, heparin, heparin sulfate, biotechnology derived heparin, chemically modified heparin, heparin mimetic and unfraGtionatEd heparin preparation.
The dry aerosol polysaccharide play be a formulated or unformulated polysaccharide particle preparation. The dry polysaccharide particle play have a mean 3Q geometric diameter of 1-500 microns, or any range of integers therebetween.
In same embodiments the particle has a mean geometric diameter of I-50, 1- 2pp, >~-106, I-~. 1-~~, ~~-S~, J~3-7~, OI' 75 ---I a~ 1I11C1'OtlS. Ill Othel' eIllbOd1111eI1tS the L1171'OI'111Lllated cll'V
-g_ polysaccharide particle has a mean aerodynamic diameter of I-5, 5-35. 1-35, 35-70, 35-75, or 1-SO microns.
According to other aspects of the invention a composition including both a formulated dry polysaccharide preparation and an unformulated dry polysaccharide preparation is provided. The polysaccharide may optianally be a glycosanlinoglycan.
Glycosaminoglycans include but are not limited to a heparin, a heparin sulFate, a low molecular weight heparin, a biotechnology del°ived heparin, a chemically modified heparin, a heparin mimetic, and an unfractionated heparin preparation.
In some embodiments, the polysaccharide of the formulated dry preparation is the same as the polysaccharide of the unformulated dry preparation and in other embodiments the palysaccharide of the formulated dry preparation is dil~Ferent than the polysaccharide of the unformulated dry preparation.
Optionally, the formulated dry polysaccharide preparafion includes a polymer to effect 510W I'eleaSe Of the pOlySaGGhal'Ide. ThLl9 the pOlySaGGharlde Of the Lln'~OI'InLllated preparation will be released rapidly and the polysaccharide of the formulated preparation will be released slowly over time. h some embodiments the polymer may be PLA, PGA, or PI'GA. In other embodiments fihe formulated dry polysaccharide preparation includes a surfactant, such as DPPC.
In some embodiments the ratio of unformulated pl°eparation to formulated preparation is 90:10, 70:30, 50:50, x0:70, or 10:90.
In other aspects the invention is a method for delivering a polysaccharide to a subject by administering to a pulmonary tissue of the subject the above described composition, e.g., a dry aerosol formulation comprising an unformulated dry glycosaminoglycan preparation and a formulated dry glycosaminoglycan preparation to deliver the polysaccharide fo the subject.
each of the limitations of the invention Gall encompass various embodiments oC~
the invention. It is, therefore, anticipated that each of the limitations ol~
the: invention IIIVOIVIIlg ally Olle elelllellt Or COnIbIIlat1011S OfelemelltS Gall be I11C1LlCled 111 eaCll aSpeCt OC' the invention.
13RICF D~SCRIPTIO~ ~ OI~ TI-IE DRAWINGS
Ia figure 1 is a set of graphs depicting the pharmacol:inetics of~ L1PI-1 particles af~tr:r inhalation: a) pharmacol:inetics of LJI°H as unformulated dry powder ( 1-~0() ym)C 1?
mg/1<g) or t'orlnulated nonporous small particles (I-3 LLlll) with DPPC as escipient (60'l°
UFI-I 40% DPPC) X10 mglkg) in rats. b) lavage study oFun t'ormulated UFI-I in rats at 1?
mglkg. The amount oI' UFI-I in lavage fluid and plasma were determined by whole blood clotting assay method. The total amount oFUFI-I sound in lavagc Iluid at ildicated tiu~c:
points was compared to the total amount of arcleparin in rat circulation at the c01'reSpolldlllg tune poIlltS. I ~ Inl plasma VOlLlllle as LlSed t"01' CoIlVe1"tlllg CollCEllt1"atlol7 t0 total amount of U~FH in circulation.
Figure 2 is a set of graphs depicting the pharmacolcinetics of 100°/'o unt'ormLllated ardeparin particles in rabbits: a) the pharmacokinetics of anti-Xa activity of un~ormLllated ardeparin of different particle size ranges in rabbits at 600 IUllcg. b) the pharmacol:inetics of unl'ormulated ardeparin is compared to s.c.
administration at 600 IUlkg. c) comparison of pharmacolcinetics between 600 and 300 IUII<g doses for unformulated ardeparin particle of 1-20 Iun size in rabbits. d) comparison of pharmacolcinetics between 600 and 300 tUllcg doses for unformulated ardeparin particles of 1-53 ltm size. e) comparison ofpharmacokinetics between s.c. administered ardeparin and dry unCormulated ardeparin of difFerent size ranges at 300 IUllcg. t]
results of lavage study after inhalation o~dry unformulated ardeparin of I-53 Lun size. The total amount of ardeparin in the lavage fluid and plasma was determined by anti-Xa assay, g) lavage study results of dry unformulated ardeparin o~ 1-53 dun size. The total amount of ?0 ardeparin in the lavage fluid and plasma was determined by anti-Xa assay.
Figul°e 3 is a set of graphs depicting a) comparison of pharmacolcinetics ol~
formulated ardeparin (~10°,~'o ardeparin 60°~'o DPPC, 3-7 llm geometric diameter) and unformulated ardeparin (100°~'° ardeparin, 1-20 ltm geometric diameter) at 600 IUlkg. h) pharmacokinetics of ardeparin after instillation in rabbits at 300 and 600 IUlkg.
Figure 4 is a graph depicting the el-fect of depth ol~ delivery site on the pharmacokinetics of formulated ardcparin particles (3- 7 1.1m, ~IOv'o ardeparin 60°'t>
DPPC). 'l"he delivery tube was placed either 1-2 cm or ~I-5 cm above bifurcation point" 6 ml oFair was used to aerosolize the powder for the lower tube position and 3 ml oI'air was used for the higher tube position.
Figure 5 is a graph depicting the pharmacokinetics of arcleparin aFtcr i.v.
bolus injection at 300 and 600 IU~/l:g doses.
Figure 6 is a graph depicting the protection of acute injury induced by human sputum leucocyte elastase (HSLE) in lung tissue by pulmonary inhalation of heparin particles. rormulated UFI-I (60°~'o UFI-I ~0% DPPC, 1-3 11m) at 1'~
mgh:g or un(ornlulate;d ardeparin particles ( 1-20 lam) at 600 IU/1<g were administered by inhalation to rats 1 hour S p1'101' to instillation oF0.25 ml oFl-ISLE (250 ltg). Rats were sacrilicecl ?4 hours later, the lungs were harvested and lavaged. The hemoglobin level in the lavage fluid was assayed.
Control group received no heparin was included for comparison.
FIgLlre 7 1S a plCtLlre deplGtlng the SGalllllllg electl'011 1111GI'OSCOpe tSEM) plCtLl1'eS
of heparin particles. The size, porosity, and the texture of the heparin of both Formulated and unformulated heparin particles were compared. The images were lateen with .IEOL
JSM-6320 FV Scanning Electron Microscape at 1 KV. a) The SEM oC unl:ormulated UFH particles showing a single pal-ticle. b) The SEM oCunformulated UFI-I
showing multiple particles. G) The SEM of Formulated UFH particles (60°lo UFH
X10°Jo DPPC).
DETAILED DESCRIPTION
In general, intrapulmonary delivery of polysaccharides has met with very little success. The prior art techniques For intrapulmanary delivery have involved administration in the form of a liquid aerosol or intratracheal liquid instillation. Whether given as liquid aerosol or intratracheal liquid instillation, the bioavailability o'F
polysaccharides such as heparin or LMWH delivered by an intrapulmonary route is consistently less than 10% of that achieved by s.c. subcutaneous) or i.v.
(intravenous) administration. When delivered as liquid heparin aerosol, the majority oFheparin is trapped in the upper airways and only less than 10°r~o oFthe delivered dose reaches the deep lung. Thus extremely high doses must be administered to achieve any therapeutic ?5 result. IF heparin is administered at the same doses as that which is ordinarily used For S.G. Or 1.V. adn11111Strat1011, IlO detectable hepal'lll 1S tOLllld 111 the blOOd C11'ClllatlOn altel' pulmonary delivery. An 8-10 times higher dose oFheparin is required For intrapulmonary heparin fo pravide a similar heparin concentration in the blood circulation as that which is achieved with s.c. administration. Additionally tile fate oi~
abS01'pt1011 01'hepal'lll Fr0111 the ILIIlg atteI' 111trapLllnlOllal'y dellVei'y OL' llqllld hCpal'l11 1S
IIILICh S10W°eI' than that OI' S.C. adn11111St1'atl0n. ti~~;i~ (the tulle ~Vllell pear aCtU?lty 1S I'('~1C11Gd~
1S typlCall)' ObSeI'Ved ~ 11OLI1'S aFtel' llltl'apL11n1O11a1'y dCllVCt'y.
SllbStalltlal a11101111tS OI' heparin have been observed to be remaining in the lung many hours after inhalation.
hurther, there has been no close dose-response relationship observed alter intrapulmonary delivery oFheparin. Consider"able variations in the pharmacokinetics of lntrapLllmollary heparin have been reported, SLlggeStlllg that 11115 I'oLlte ol'dellVel'y Inlay be dangerous because of the risk of heparin associated side eFfects.
There are several problems associated with pulmonary delivery ol~
polysaccharides. firstly, the presence of multiple membrane structures which separate the upper respiratory tract From the capillal°y circulation can lead to poor absorption.
These lipid membrane structures are impermeable to hydraphilic macromolecules such as heparin and low molecular heparin which are highly negatively charged polymers.
Delivery routes such as s.c. administration allow the polysaccharide to directly contact capillary vessels and thus be immediately absorbed. lPulmonary delivery methods also result in a large proportion of the drug being trapped in the trachea ar upper respiratory tract.
It was unexpectedly discovered according to the invention that intrapulmonary administration of polysaccharides using a dry aerosol particle preparation resulted in excellent absorption and bioavailability, producing significant therapeutic results in nivo.
Even snore surprising, it was discovered that the dry aerosol particles did not even need to be fornlulated to produce these results. It has been well documented in the prior art 2p that when proteins are administered as dry powder, the particles undergo two difFerent fates. The particles either become trapped in the upper respiratory tract or are delivered to the lower respiratory tract or in some cases the deep lung. In the upper respiratory tract, ciliated epithelia contribute to a process referred to as the "mucosiliary escalator""
in which particles are swept from the airways toward the mauth. In the deep lungs, alveolar macrophages phagocytosize the particles soon alter their deposition.
Small particles (diameter' <5 11M) get phagocytosed to a higher degree than larger particles.
The human lungs can remove or rapidly degrade deposited aerosols over periods ranging Iron minutes to hours. As the diameter oFthe particle increases, there is increasingly less phagocytosis by macrophages. However, increasing the particle size also minimizes the probability oFparficles (possessing Standard mass density) entering the airways and acini due to excessive deposition in the oropharyngeal or nasal regions (upper respiratory tracfi). Thus, the large particles (diameter > 5 1.~M) are known to get deposited excessively in the upper airways.
As a result of these teachings it is generally believed in the art fihat i1'a protein has to be delivered as a dry powder via pulmonary delivery, the protein must be Formulated in a certain way to achieve maximal therapeutic beneCt. l~or example, iFa protein is Formulated into dry particles which are made to be aerodynamically light, it can be delivered Formulated wifih a surfactanfi via pulmonary delivery (U'S Patent 1\lumber 5,855,913). It was discovered surprisingly according to the invention that delivery of polysaccharides can be accomplished wifihout adhering to these teachings.
Polysaccharides behave in a way thafi is totally different -Fram that predicted for an unformulated protein or other macromolecule. The data described in the Itxamples show that polysaccharides can be delivered via pulmonary inhalation, and that this process is independen t o~fihe size of the particle (within a broad range), texture, porosity, density, shape, and fine presence or absence of additives.
The polysaccharides can be signiFicantly absorbed as dry aerosol particles of defined sizes with or withoufi exipients. Thus, a "dry aerosol containing a polysaccharide" encompasses both unfarmulated dry aerosol polysaccharide particles or preparations and formulated dry aerosol polysaccharide particles or preparations. An '°unformulated dry aerosol polysaccharide particle or preparation" as used herein rej~ers ?0 to a composition which is composed of a polysaccharide in the form of dry particles having a mean geometric diameter of 1 - 500 microns and which does not include a carrier or other excipient to enhance delivery or result in slow release. The unformulated dry aerosol polysaccharide particle may include non-essential agents which are nofi expected to influence the delivery or absorpfiion of the polysaccharide.
Materials which are known to inE7uence polysaccharide release or absorption are polymeric materials and surfactants. Thus, both offihese materials may be found in the formulated particles buff not in the unFormulated particles. The unFarmulated particles, however, may include compounds other than polymers (except For polysaccharides) and surFaetanis, as long as fihe particle includes at least one therapeutically acfiive polysaccharide.
These include.
For instance, buff are not limited to, proteins. nucleic acids, small organic or inorganic molecules, carriers that do not have slow release properties. lareservatives, etc.
The unformulated {as well as the formulated} polysaccharide particles play include a single polysaccharide or multiple polysaccharides. Thus, the particles May include only one polysaccharide, more than one polysaccharide but only one polysaccharide which has a therapeutic activity, or more than one polysaccharide having a therapeutic activity.
A sot of particles having a "mean geometric diameter of I - 500 microns" is a set of particles having at least 50°I° of the particles falling within the size Tango of 1-500 microns or any range of integer numbers falling within 1-500 mice°ons.
The mean geometric diameter can be determined by one of skill in the art using routine methods.
For instance, moan geometric diameter can be established by scanning electron microscopy {SEM) or atomic force microscopy {AFM), which can be use to determine particle size, porosity and surface texture, as well as a coulter multisizer II{Goulter Electronics, Futon, Beds, England). In some embodiments the particles have a geometric size distribution of I-250, 1-100, I-50, 5-200, 10- 500, 10-250, 10-1p0, 100-200, 100-150, 53-106, I-5, 1- 20, 20-53, 53-75, or 75-I06 microns.
Unfonnulated dry aerosol particles can be propal°ed by any means known in the art for generating particles. One method for preparing the particles involves obtaining a dry pure preparation of the polysaccharide and grinding it to produce particles, optionally coupled with a step for selecting particles of a particular size range.
Cxamples of this typo of method al°e provided in the examples below. For instance, the polysaccharide can be ground into particles using a coffee grinder and then separated by size by using sieves of different mash sizes. Other methods include single or double emulsion solvent-evaporation procedures and spray drying. Particles of speci6o sizes can be generated by cryogrinding. This is accomplished by cooling the particles to a very low temperature, such as -190° C, e.g., using liquid nitrogen, and then grinding the particles. Additionally, polysaccharide Inay be dissolved in a suitable solvent {e.g., water and a volatile organic solvent like methylene chloride) and than nebulized (i.e., passing it through a small orifice at high pressure}. The solvent is then rapidly removed at a high ten lperature and the particles collected. An olectrospray injector can be used for this purpose.
In addition to the moan geometric diameter the particles may have a specific range of aerodynamic diameters. In one embodiment the particles have a mean ael'ody11a1111C dIa111etel' ol' 1-50 I111C1'o115. A x'meall aCl'odyt1al111C
C11a111CtC1'~~ 1'CI'el'S t0 tIIC
diameter that a particle appears to possess on the basis of its in-Flight speed, where it is assumed to be spherical and to possess a mass density of lglcnl~, The geometric diameter oFa spherical particle possessing unit mass density (Iglcnl~) is equivalent to its aerodynamic diameter. The aerodynamic diameter (cl;,~.,.) relates to a particle's geonletric dlallletel' ~C~~ aild nlaSS denSlty (f7) with the ~LIIICtIOn: t7~;,~~-=C7~(J
~1~. In SOIlIe en1170C11171eIltS
the particles have a meats aerodynamic diameter of 1-5, 1-35, 1-75, 35-75, ar microns.
The polysaccharide particles with sizes ranging from 1-500 l.Lm, porous or non-porous, spherical or non-spherical, light or heavy were associated with significant ) 0 absorption profiles. Although the prior art has taught that these Features are critical For promoting delivery of the particles to the deep lung, the data of the instant invention demonstrates that these properties are not critical for delivery to the deep lung. 'Thus the dry un formulated particles may have any physical properties, such as porosity or shape.
The porosity and shape of the particle influence the aerodynamic properties of the 15 particle. In some embodiments the particles may be aerodynamically light, but in other embodiments they may be heavy. The aerodynamic weight of the particle can be measured in terms of tap density. A particle that is aerodynamically light has a tap density of less than 0.~1 g/cm3 and preferably has a tap density in the range of x.01 glens'' 0.~1 g/cm3. A particle that is aerodynamically heavy has a tap density of greater than 20 0.~ gJcnl3. Tap density refers to the mass density of the particle, which is calculated as the mass of the particle divided by the minimum sphere volume within which it can be enclosed. A measurement of tap density may be obtained using equipment such as a GeoPyc~hM (Micronletrics Instrument Gorp., Georgia).
The unformulated polysaccharide particles showed unique pharmacolcinetics 25 featuring an extremely rapid absorption rate and a comparable elimination rate to that of s.c. administration. The addition of exipients such as DPPC to the particles did not appear to alter the pharmacolcinetic prafiles signil°icantly. Thus, the invention also encompasses the use aFformulated dry aerosol polysaccharide particles. A
~Clormulated dry aerosol polysaccharide particle or preparation" as used herein refers to a conlposilion 30 which is composed oFa polysacchal-ide in the Form oFdry particles having a mean geometric diameter oI' 1 - 5pQ microns and which ivrther includes a carrier or other excipieni to enhance cielivcry or achieve slow release oFthe polysaccharide:.
Similar to the unformulated polysaccharide particles, the porosity and shape were not critical.
Particles that were porous or non-porous, spherical al' non-spherical, light or heavy were aSSOGlated Wlth SlgnIIICaIlt abs01'pt1011 pl'OtlleS. Ill Olle eIl7bOdllllellt the 101'171LlIateCl particles are those having the properties described in US Patent Nos.
5,855,913 and 5,985,309. These formulated dry particles are aerodynamically light and have a mean geometric diameter o~ 5-30 microns, a tap density of less than O.~I g/enl~ and an aerodynamic diameter of 1-5 microns. In other embodiments the formulated dry particles are those having different properties than those described in US
Patent Nos.
5,855,913 and 5,985,309. For instance, it is possible that the formulated particles of the invention have a mean geometric diameter of 1-5 or 30-500 microns, a tap density of greater than 0.4 glcm~ and/or an aerodynamic diameter of 5-75 microns.
The formulated particles include at least one carrier or excipient. In one embodiment the excipient is a surfactant. A "surfactant" as used herein refers to a compound having a hydrophilic and lipophilic moiety, which promotes absorption of a drug by interacting with an interface between two innniscible phases.
SurFactants are useful in the dry particles for several, reasons, e.g., reduction of particle agglomeration, reduGtlOll O~ InaGPOphage phagOGytOSIS, etC. Whell COLlpled wlth ILIIlg SLII'faGtallt, a I11O1'e efficient absorption of polysaccharides can be achieved because surfactants, such as DPPC, will greatly facilitate diffusion of polysaccharides, such as heparin across the membrane surface of the alveoli by disguising the hydrophilic, charged groups of the heparin polymer. Surfactants are well known in the art and include but are not limited to phosphoglycerides, e.g., phosphatidylcholines, L-alpha-phosphatidylGholine dipalmitayl (DPPC) and diphosphatidyl glycerol (DPPG); hexadecanol; fatty acids;
polyethylene glycol (PEG); polyaxyethylene-9-; auryl ether; palmitiG acid; oleic acid;
sorbitan trioleate (Span 85); glycocholate; surfactin; poloxomer; sorbitan fatty acid ester; sorbitan trioleate; tyloxapol; phospholipids. 'I"he surCactan t may be incorporated within the particle or it may be coated on the surface oFthe particle.
Controlled release of polysaccharide can also be achieved with appropriate exipient materials that are biacompatible and biodegradable. These polymeric materials which ef=fect slow release of the polysaccharide may be any suitable polymeric material for generating particles, including, but not limited to, nonbioerodable/non-biodegradable and bioerodable/biociegradable polymers. Such polymers have been described in ~,~r~at detail in the prior art. They include, but are not limited to: polyalides, polycarbonatcs, polyallcylenes, polyallcylene glyeols, polyall:ylene oxides, polyall:ylenc tcrcpihalates.
polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides.
polyvinylpyrrolidone, polyglycolides, polysiloxancs, polyurethanes and copolymers thereof, alkyl cellulose, hydraxyall<yl celluloses, cellulose ethers, cellulose esters, vitro celluloses, polymers of acrylic and methacrylie esters, methyl cellulose, ethyl cellulose, hydroxyprapyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, poly (methyl methacrylafe), poly(ethylmethacrylate), poly{butylmethacrylate), poly(isobutylmethacrylate), poly(hexllethacrylate), poly(isodecylmethacrylate), poly(lauryl lethacrylate), poly (phenyl methacrylate), poly{methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), polyethylene, polypropylene poly{ethylene glycol), polyethylene oxide), poly{ethylene terephthalate), polyvinyl alcohols), polyvinyl acetate, poly vinyl chloride polystyrene, polyvinylpryrrolidone, hyaluronic acid, and chondroitin sulfate.
>jxamples of preferred non-biodegradable polymers include ethylene vinyl acetate, poly(meth) acrylic acid, polyalides, copolymers and mixtures thereof.
Cxamples of preferred biodegradable polymers include synthetic polymers such as polymers of lactic acid and glycolic acid, polyanhydrides, poly{ortho)esters, polyurethanes, poly{butic acid), poly(valeric acid), poly(caprolactone), poly(hydroxybutyrate), poly(lactide-co-glycolide) and poly(lactide-co-caprolactone), and natural polymers such as alginate and other polysaccharides including dextran and cellulose, collagen, chemical derivatives thereof {substitutions, additions ol~ chemical ?5 groups, for example, alkyl, allcylene, hydraxylations, oxidations, and other modifications routinely lade by those skilled in the art), albumin and other hydrophilic proteins, zero and other prolamines and hydrophobic proteins, copolymers and mixtures thcreoi~. In general, these materials degrade either by enzymatic hydrolysis or exposure to waver in lalla0, by SLII'faCe 01' bLlllf erOS1011_ The lol'eg0111g Illatel'lalS may be used alone, aS 1711}'SICaI
InlXtLlreS {blelldS), 01' aS CD-polymers. The ITloSt pl'Ct~EI'I'CCl pOlymel'S
al'e pOlyeStEI'S.
polyanhydrides, polystyrenes and blends lhcreof~.
I11 SOlne 111Sta11CeS, the lllVent1017 ellCOInpaSSeS a GOnlblllat1011 Of f01'171Lllated alld LIIIfOr111Lllated pOlySdCCharIdeS. rFhe Colnblllatl011 111ay C011ta111 ally I'atlo OI' pl'OpOrt1011 OI' FO1'mLllated:Llllt0l'llllllated pI'epal'at1017. 10l' 111StallCe, the COlllblllatlOll 171 ay IIICILIdC; a 1'rltlo of 10:90, 20:80, 30:70, ~10:G0; 50:50; 60:10, 70:30, 80:20, or 90:10. When the ratio is 0:50, the aGtLlal anlOLlllt OF p0lySaCGha1'lde IIl the f'01'111L11atEd pOrtloll 0I' the G0171bI11atlOn may be less than the actual amount of polysaccharide in the unFOrmulated portion because the formulation includes excipients which account for some of the mass of the formulated particles. The relative amounts may also be calculated as a relative ratio of fOrmulated:ullformulafed particles. The relative ratios of formulated:unformulated particles include, but are not limited to, 10:90, 20:80, 30:70, X10:60, 50:5p.
60:0, 70:30, 80:20, and 90:10. When the relative ratio of the combination preparation is 50:50, the preparation includes an equivalent actual amount of polysaccharide in the preparation.
The type of polysaccharide in the two components of the combination preparation may be the same or different. Thus? the polysaccharide that is in the formulated preparation may be the salve type of polysaccharide that is in the unformulated preparation, i.e., both may contain I,MWH. Alternatively, the type of polysaccharide may be different. For example, the unf0rmulated polysaccharide preparation may be LMWH and the formulated polysaccharide preparation may be UFH.
The dry aerosol particles of the invention are administered by inhalation to pulmonary tissue. The term "pulmonary tissue" as used herein reFers to any tissue of the respiratory tract and includes both the upper and lower respiratory tract, except where otherwise indicated. The particles may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichl0roflu0romethane, dichlor0tetrafluoroethane, carbon di0hide Or other suitable gas. In the case of a pressurized aerosol, the dosage unit' may be determined by providing a valve to deliver a metered amount. Capsules and cartridges For use in an inhaler or insufllator may be formulated containing a powder mix of the polysaccharide and a suitable powder base such as lactose or starch, iFthe particle is a formulated particle. In addition t0 the formulated or unformulated particles administered, other materials such as 100°'~o DffC
or other surfactant particles can be mixed in the dry aerosol particles to Iaromote tl7e delivery and dispersion oFthe dry Formulated or unFormulatcd particles.
'I"here arc separate and distinct from the formulated or un formulated particles, but are optionally included to enhance same aspect of the delivery process.
The dry aerosol particles when administer are rapidly absorbed and can produce a rapid local or systemic therapeutic result. A local therapeutic efFect refers to a biologic effect that occurs to the lung tissue. For instance, when the poly saccharide is a heparin, it may be desirable to produce a local effect for the treatment of a respiratory disease. A
systemic effect refers to a biologic effect that occurs outside of the lung tissue, e.g., in the blood. It has been discovered that the peak activity of the delivered polysaccharide can be achieved within 3 hours and preferably within two hours. In some embodiments the peals activity can be achieved even mare quickly, e.g., within one half hour or even within ten minutes. The surprisingly fast absorption of heparin, in particular, after inhalation as a dry aerosolized particle is believed to be extremely valuable in management of clinical conditions where a fast convenient non-invasive administration is desired. Heparin particles, especially 100°~'o heparin (UFH and LMWH) particles, can be used in acute coronary syndrome such as unstable angina to prevent the development of MI or death. Presently, acute coronary syndrome is being Treated either with i.v. UF~I
or s.c. administered LMWHs. Inhaled heparin particles will allow a rapid anticoagulationlantithrombosis state in the blood which cannof be achieved with s.c.
administration of LMWHs. Both i.v. UFH and s.c. LMWHs are being used for this purpose. The rapid absorption of heparin after inhalation call be combined with subsequent s.c. administration of LMWHs to improve the efficiency of antithromboticlanticoagulation treatment. Alternatively, heparin particles formulated for longer biological half life can be used as an alternative for s.c.
administration of LMWHs. Similar regimens can also be adopted for use of heparin in cerebral vascular diseases such as stroke, which require immediate early intervention. These and other therapeufic uses are described in more detail above.
In one embodiment, the polysaccharide is delivered in an amount such that 5%
of the polysaccharide is delivered to the lower respiratory tract or the deep lung. Although not being bound by a mechanism, it is believed that the methods for pulmonary delivery of polysaccharides have been successFul because the methods result in efficient and rapid delivery to the lower respiratory tract or deep lung alveolar surface. Deep lung has the I'1c11eSt Caplllal'y IletWOrk IOLltld 111 all al'gall 111 the hL1111a11 body, alld the 1'('.5plt'atoI'y membrane separate capillary lumen From alvealar air space is very thin {__<G
lam) and extremely permissible. In addition, the liquid layer lining the alveolar surface is rich in lung surfactants. In other embodiments at least 10°~'0, 20°~'0, 30°~'°, ~0°~'°, 50%, or ~0°/~ is delivered to the lower respiratory tract or to the deep lung. Delivery to either or both of these tissues results in efficient absorption of the polysaccharide and high bioavailability.
The amount of polysaccharide delivered to the lower respiratory tract or deep lung can be determined using routine methods. For instance, in a test system, ravage of animal lungs at indicated time intervals after inhalation can be used to determine the amount of heparin delivered to the lower respiratory tract. This data can be correlated to that amount which would occur in humans or animals being treated.
Alter°natively, a label, such as a radioactive or fluorescent label can be attached to the polysaccharide and used to determine the distribution of inhaled polysaccharide. The amount of polysaccharide delivered to the lower respiratory tract or deep lung also can be determined as the amount of therapeutic effect resulting from the presence of the polysaccharide in the lower respiratory tract or deep lung or in the region where the biological activity is occurring, e.g., the blood, or the blood plasma concentration of the polysaccharide. The type of parameter used to assess the effectivity of the delivery will vary depending on a variety of factors including the type of subject, the type of equipment available, and the disorder being treated or prevented. The peals plasma ?0 concentration ofa polysaccharide can be determined by measuring the level of polysaccharide present in the blood over time and determining when the peals level of concentration is reached. The amount of a therapeutic effect or a peals plasma acfivity can be identified using routine assays. The type of these effects will depend on the therapeutic parameter being assessed. For instance, if the polysaccharide is administered in order to prevent coagulation the amount of inhibition of factor Xa activity can be assessed. It is known that a minimum therapeu tic level of heparin-like glycosaminoglycan For producing therapeutic anticoagulant eFFect is approximately 0_35 IU/ml anti-Factor Xa activity. HLGAGs are also useful for inhibiting enzymatic activity, Sllch aS human leLICOGyte elaStaSe. 111 general, the ICAO Of I-1LGAGS OIl hlllllall ICLIIvOC ftC
elastase ranges from 1 nginll to 50 microgranl/ml. Alternatively, the .~1;
values of I-1LGAGs ranges from 10 nm to 10 IIM. In other instances, when the polysaccharide is a pOlySaCChal'lde ISOlated frOlll phellIIILIS llllteLIS, the blOlOglCal aCtlvltv w111C11 Call 1)C
aSSESSed 111C1udeS bOfill Gell-Inedlated 11T1n1Llnlfiy alld hLlln01'al In1111Lllllty. ThLIS, tile 1CVG1 OFGelI-lnedlated 1m111Lllllty oI' alltlbOdy pl'OdLlCfil011 111ay be 111caSLll'ed IIl ol'dcl' tp Ghal'aGfiel'lle the thel'apeUtlG ef'TeCt OTpealC blolOgIGa1 aGfilVlty Of these C0117pOLlIIdS. ()tll('.1' assays are well known to those oFordinary skill in fine arfi for each oFthe dil~Fel'ent polysaccharides.
Thus, the invention relates to intrapulmonary administrafiion of polysaccharides.
A "polysaccharide" is a polymer composed of monosaccharides linked to one another.
In many polysaccharides the basic building block of the polysaccharide is acfiually a disaccharide unit, which can be repeating or non-repeating. Thus, a unit when used with respecfi to a polysaccharide refers to a basic building bloG1< o1' a polysaccharide and can include a monomeric building block (monosaccharide) or a dimeriG building block (disaccharide). Polysaccharides include buff are not limited to heparin-like glycasaminoglycans, chondroitian sulfate, hyaluronic acid and derivatives or analogs thereof, chitin in derivatives and analogs thereof, e.g., 6-0-sulfafied carbo~ymefihyl chitin, 7 5 immunogenic polysaccharides isolated Pram phellinus linteus, PI-88 (a mixture of highly sulfated oligosaccharide derived from the sulfafiion of phosphomannum which is purif7ed from the high molecular weighfi core produced by fermentation of the yeast /~ichic~
lzolstii) and its derivafiives and analogs, polysaccharide antigens for vaccines, and calcium spirulan (Ca-SP, isolated from blue-green algae, spirulina platensis) and derivatives and analogs thereof.
The mefihods taught herein are sometimes described with reference to heparin-like glycosaminoglycans (I~LGAGs) but the properties taught herein can be extended to other polysaccharides, and unless a claim specifies ofiherwise the claims encompass any polysaccharides having a therapeutic utility. As used herein the terms "HhGAG"
and ?5 "glycosaminoglycans" are used interchangeably to refer to a family of molecules having heparin like structures and properties. These molecules include but are slot limited to low molecular weigh fi heparin (LMWI-I), heparin, biotechnologically prepared heparin, chEmlGally 1110C11~ed heparln, SyllfihetlC h epar111, heparlll 1111111et1GS
alld hepal'lll SLllfatC:.
The fierm "biotechnological heparin" encompasses heparin fihat is prepared from natural sources of' polysaccharides which have bEen chemically modified and is described ill Razi et al., l3ioche. .I. 1995 ,ILII 15;309 (Pfi 2): ~1G5-7?. Chemically modif7ed heparin is described in Yates et al., Carbohydrate Res ( 1996) Nov ~0;?9~1_ 15-27, and is known to those of skill in the art. Synthetic heparin is well lenown to those of shill iv the art and is described in Petitou, M. et al., Bioorg Med Chem Lett. (1999) Apr 19;9(8):1 1G1-G and Vlodavsky et al., Int. J. Cancer, 1999, 83:~2~1-X131. I-Ieparan SulFate rcl~ers to a glycasaminoglycan containing a disaccharide repeat unit similar to heparin, but which has more N-acetyl groups and fewer N- and O-sulFate groups. I-Ieparin mimetics are monosaccharides (e.g., suci°alfate), oligosaccharides, or polysaccharides having at least one biological activity of heparin (i.e., anticoagulation, inhibition of cancer, treatment of lung disorders, etc.). Preferably these molecules are highly sulfated. Heparin mimetics may be naturally occurring, synthetic or chemically modified. (Barchi, ,1J., Curr. Pharm.
Des., ?000, Mar, G(~):485-501).
LMWH as used herein refers to a heparin preparation having a molecular weight of about 3,000 daltons to about 8,000 daltons.
Several LMWH preparations are commercially available, but, LMWHs can also be prepared from heparin, using e.g., HLGAG degrading enzymes. HLGAG degrading 1 S enzymes include but axe not limited to heparinase-I, heparinase- II , heparinase-III, D-glucuronidase and L-iduronidase. The three heparinases from Flcrvobcrcic~rium lze~ar~inzrr~~ are enzymatic tools that have been used for the generation of LMWI-I (5,p00-8,000 Da) and ultra-low molecular weight heparin (3,000 Da). I-Ieparinase I
cleaves highly sulfated regions of HLGAGs at 2-O sulfated uronic acids, whereas heparinase I I
has a broader substrate specificity and cleaves glycosidic linkages containing both 2-O
sulfated and nonsulfated uronic acids ( Ernst, S., Langer, R., Gooney, C. L. &
Sasiselcharan, R. (7 995) Cr~il Rev Bioclzem Mot Biol 30, 387-~~~). Heparinase III, as opposed to heparinase I, cleaves primarily undersulfated regions of I-TLGAGs, viz"
glycosidie linkages containing a nansulfated uronic acid (Ernst, S., Langer, R., Caancy, C. L. & Sasiselcharan, R. (1995) C'r°ii Rev Biochem ~llol Biol 30, 387-~l~l~), Commercially available LMWI-I include, but are not limited to, enoYaparin (brand name Loveno~; clexane by Rhone-Poulenc Rorer), dalteparin (Fragmin, Pharmacia and Upjohn), certoparin (Sandobarin, Novartis), ardeparin (Normillo, Wyeth L~c~dcrlc), nadroparin (P"raxiparine, Sanofi-Winfhrop), pharnaparin (hlu~um, Wassermann), reviparin (Clivarin, Knoll AG), and tinzaparin (Innohep. Leo Laboratories.
Logiparin.
Novo Nordisk).
_ ?? _ The compositions may be administered therapeutically to a subject. As used hel'e111, a SLlbleCt IS a Ver'tebr'ate SLICK aS a hL1111a11, nOl1-hL1111an pl'1111ate, COw, hOl'Se, plg sheep, goat, dog, cat, or rodent.
I-ILGAGs have many therapeutic utilities. Tlle I-ILGAG compositions o(~
the invention can be used For the treatment of any type of condition in which I-ILGAG
therapy has been identified as a useful therapy. Thus, the invention is useFul in a variety of ll7 VZIZ'O, ila vivo and ex vivo methods in which HLGAG therapies are useFul. For instance, it is known that HLGAG compositions are useFul for preventin g and treating coagulation, angiogenesis, thrombotic disorders, cardiovascular' disease, vascular conditions, atherosclerosis, respiratory disorders, circulatory shock and related disorders, Alzheimer"s disease, as well as inhibiting cancer cell growth and metastasis.
Each of these disorders is well-known in the art and is described, for instance, in H~lrri,s~ol~ ',s Prilmiples of Iliierlzal Medicine (McGraw Hill, Inc., New York), which is incorporated by reference. The use of HLGAG compositions in various therapeutic methods is described and summarized in 1-Iuang, J. and Shirnamura, A., Coagulation Disorders, 12, 1251-1281 (1998).
Thus, the HLGAG preparations are useful for treating or preventing disorders associated with coagulation. A "disease associated with coagulation" as used herein refers to a condition characterized by local inflammation resulting from an interruption in the blood supply to a tissue due to a blockage of the blood vessel responsible For supplying blood to the tissue such as is seen for myocardial or cerebral infarction.
Coagulation disorders include, but are not limited to, cardiovascular disease and vascular conditions such as cerebral ischemia.
The methods of the invention are useful for treating cardiovascular disease.
Cardiovascular diseases include, but are not limited to, acute myocardial infarction, unstable angina, and atrial fibrillation. Myocardial infarction is a disease state which accurs with an abrupt decrease in coronary blood flow that follows a thrambotic occlusion of a coronary artery previously narrowed by atherosclcrosis. Such injury may be produced or facilitated by Factors such as cigarette smoking, hypertension, and lipid accumulation. Acute angina is due to transient myocardial ischemia. This disorder is LISLlally aSSOClated Wlth a heaV111eSS, preSSLlre, StlLleezlllg, 51110theI'111g, OI' ChOklllg FeC;llllg _ 7 j _ below the sternum. Episodes are usually caused by exertion or emotion, but can occur at rest.
Atrial Fibrillation is a common form of arrhythmia generally arising as a result of emotional stress or following surgery, exercise, or acute alcoholic intoxication.
Persistent forms of atrial fibrillation generally occur' in patients with cardiovascular' disease. Atrial fibrillation is characterized by disorganized atrial activity without discrete P waves on the surface ECG.
The compounds oFthe invention can be used for the treatment of cardiovascular disorders alone or in combination with other therapeutic agents for reducing the risk of a cardiovascular disease or For treating the cardiovascular disease. Other therapeutic agents include, but are not limited to, anti-inflammatory agents, anti-thrombotic agents, anti-platelet agents, fibrinolytic agents, lipid reducing agents, direct thrombin inhibitors, and glycoprotein IIbIILIa receptor inhibitor's.
Anti-inflammatory agents include Alclofenac; Alclometasone Dipropionate;
Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium;
Amiprilose Hydrachloride; Analcinra; Anirolac ; Anitrazafen; Apazone;
Balsalazide Disodium; Bendazac; Benoxaprofen ; Benzydamine Hydrochloride; Bromelain s;
Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen;
Clobetasal Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate;
Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoxinletasone; Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate;
Diflumidone Sodium; Diflunisal ; Difluprednate; Diftalone; Dimethyl Sulfoxide;
Drocinonide; Endryson e; Enlimomab ; Enolicam Sodium ; Epirizole ; Ctodolac;
Etofenamate ; Felbinac; Fenamole; Fenbufen; Fenclofenac; T'enclorac; Fendosal;
Fenpipalone; rentiazac; Flazalone; Fluazacort; Flufenamic Acid; Flumizole;
Flunisolide Acetate; F1LII11xrn ; FlLlIllXln lVleglLlllllne ; FIuOCOrt111 BLltyl;
FluoC0lnethOlQlle Acetate;
Fluquazone; FlurbiproFen ; FluretoFen; Fluticasone Propionate; Furaprofcn;
furobufen;
I-Ialcinonide; Halobetasol Propionate; I-Ialopredone Acetate; Ibufcnac ;
Ibuprofen;
Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap; Indomethacin; Indamcthacin Sodium; Indoprofen ; Indoxole ; Intrazole; IsoFlupredone Acetate; Isoxepac;
Isoxicam;
KetoproFen; Lafemizole hydrochloride ; Lornoxicam ; I;oteprednol Etabonate;
IVIeG101'el1a111ate ~~.OdlLlln; IVIeCIOfeIlaI111G AC:Id; lVleClorlSOlle DlbLltyl'ate; NlelenallllC AC1C1 Mesalamine; Meseclazone; Methylprednisolone Suleptanate; Morniflumate;
Nabumetone; Naproxen ; Naproxen Sodium ; Naproxol ; Nimazone; Olsalazine Sodium;
Orgotein ; Olpanoxin; OXaprozin; Oxyphenbutazone; Paranyline I-Iydrochlot"ide;
Pen town Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pirfenidonc ;
Piroxicam;
PlrOX1Ga111 ~11111aI11atG; PlrOX1Gd111 OlaI11111e; PIrprOfen; PI-ednazate;
Prlfelone; frodollc Acid; Proquazone; Proxazole; Proxazole Citrate ; Rimexolone; Romazarit ;
Salcolex ;
Salnacedin; Salsalate ; Salycilates; Sanguinarium Chloride ; Seclazone ;
Sermetacin;
Sudoxicanl; Sulindac; Suprofen; Talmetacin; Talniflumate ; 1'alosalate ;
Tebufelone ;
Tenidap; Tenidap Sodium; Tenoxicam; Tesicam; Tesimide; Tetrydamine; TiopinaC;
Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide;
TI°iFlumidate; Zidometacin;
Glucocorticoids; ZomepiraG Sodium.
Lipid reducing agents include gemfibrozil, Gholystyramine, colestipol, niCOtiniG
acid, probu Gol lovastatin, Fluvastatin, simvastatin, atorvastatin, pravastatin, cirivastatin.
Glycoprotein IIbIIIIa receptor Inhibitors are both antibodies and non-antibodies, and include but are not limited to ReoPro (abcixamab), lamifiban, tirofiban.
Anti-thrombotic agents and anti-platelet agents are described in more detail below.
The HLGAG preparations are also useful for treating vascular Conditions.
Vascular conditions include, but are not limited to, disorders such as deep venous thrombosis, cerebral ischemia, including stroke, and pulmonary embolism. A
cerebl"al ischemic attack or cerebral ischemia is a form of ischemic condition in which the blood supply to the brain is blocked. This interruption in the blood supply to the brain may result from a variety of causes, including an intrinsic blockage or occlusion of the blood vessel itself, a remotely originated source of occlusion, decreased perfusion pressure or increased blood viscosity resulting in inadequate Cerebral blood Flow, or a ruptured blood vessel in the subarachnoid space or intraCerebral tissue.
'the methods of the invention are useful for treating cerebral ischemia.
Cerebral ischemia may result in either transient or pertllanent deficits and the seriousness of the neurological damage in a patient who has experienced cerebral ischemia depends on the intensity and duration of the ischemic event. A transient ischemic attack is one in which the blood Flow to the brain is interrupted only briefly and causes temporary neurological deficits, which often are clear in less than 2~1 hours. Symptoms of TIA
include nunlbne:ss or weakness of face or limbs, loss of the ability to speak clearly and/or to understand the speech of others, a loss of vision or dinnless of vision, and a feeling of dizziness.
Permanent cerebral ischemic attach, also called stroke, are caused by a longer lnterl'L1pt1011 Ill blood l7ow t0 the bl'alll reSUltlllg fl'Olll elthel' a thl'OnlbOEl11bO11S111. A
Stroke GaLISES a LOSS Of 11eL1rOIIS typically reSUltlllg 111 a IleLll'OIOgIG
dellClt that May improve but that does not entirely resolve. Thromboembolic stroke is due to the occlusion of an extracranial or intracranial blood vessel by a thrombus or embolus.
Because it is often difficult to discern whether a stroke is caused by a thrombosis or an embolism, the term "thromboembolism" is used to cover strokes caused by either of These mechanisms.
The rapid absorption of HLGAGs, such as UFII or LMWH, after inhalation as dry particles can be very valuable ill the treatment of venous thromboembolism.
Intravenous administration of UFI-I has been used widely for treatment of venous fhromboembolism in combination with oral Warfarin. Due to the improved efficacy and reduced risks, however, LMWI-Is have been increasingly used as all alternative to intravenous UFH in treatment of venous thromboembolism. It has been established that efficacy of heparin therapy depends on achieving critical therapeutic levels (0.35- 0.7 Ulml anti-factor Xa activity) within the first 2~ hours of treatment.
Intrapulmonary delivery of heparin particles to achieve rapid therapeutic levels of heparin in the early stage of thromboembolism, could also be combined with either s.c.
administration of LMWHs or formulated heparin particles for prolonged antithrombotic/an ticoagulant effect.
The methods of the invention in some embodiments are directed to the treatment of acute thrombaembolic stroke using HLGAGs. An acute stroke is a medical syndrome involving neurological injury resulting from an ischemic event, which is an interruption in the blood supply to the brain.
An Effective amount of a I-ILGAG preparation alone or in combination with another therapeutic for the treatment of stroke is that amount suf'ticient to reduce in rilo brain injury resulting from the strolcE. A reduction of brain injury is any prevention of 3p injury to the brain which otherwise would have occurred in a subject experiencing a thromboembolic stroke absent the treatment of the invention. Several physiological parameters may be used to assess rEduction of brain injury, including smaller infarct sirE, improved regional cerebral blood flow, and decreased intracranial pressure, For example, as compared to pretreatment patient parameters, untreated stroke patients or stroke patients treated with thrombolytic agents alone.
The pharmaceutical I-ILGAG preparation may be used alone or in combination with a therapeutic agent f'or treating a disease associated with coagulation.
Bxamples of therapeutics useFul in the treatment o~diseases associated with coagulation include anticoagulation agents, antiplatelet agents, and thrombolytic agents.
Anticoagulation agents prevent the coagulation o~ blood components and thus prevent clot formation. Anticoagulants include, but are not limited to, war farm, coumadin, dicumarol, phenprocoumon, acenocoumarol, ethyl biscoumacetate, and indandione derivatives.
Antiplatelet agents inhibit platelet aggregation and are often used to prevent thramboembolic Stroke in patients who have experienced a transient isehemic attack or stroke. Antiplatelet agents include, but are not limited to, aspirin, thienopyridine derivatives such as ticlopodine and clopidogrel, dipyridamole and sul~inpyrazone. as well as IRGD mimetics and also antithrombin agents such as, but not limifed to, hirudin.
Thrombolytie agents lyse clots which cause the thrombaembolic stroke.
Thrombolytic agents have been used in the treatment of acute venous thromboembolism and pulmonary emboli and axe well known in the art (e.g. see l-Iennekens et al, J~lj~r ~'oll 2Q C"at~diol; v. 25 (7 supp), p. 185-225 (1995); Holmes, et al, JAf~~ G'oll Carcliol; v.?5 (7 supply, p. lOS-17S(1995)). Thrombolytic agents include, but are not limited to, plasminogen, a~-antiplasmin, streptolcinase, antistreplase, tissue plasminogen activator (tPA), and urokinase. '°tPA" as used herein includes native tPA and recombinant tPA, as well as modified forms of tPA that retain the enzymatic or I'ibrinolytic activities of native tPA, The enzymatic activity of tPA can be measured by assessing the ability of the molecule to convert plasminogen to plasmin. The ~'ibrinolytic activity of tPA may be determined by any in uilro clot lysis activity known in the art, such as the purified clot lysis assay described by Carlson, et. al.,~lnrrl. Biorhem. 168, ~l?8-135 (1988) and its modified form described by Bennett, W. p'. Et al., 1991, Sz~pra, the entire contents ol~
which are hereby incorporated by reference.
Pulmonary embolism as used herein refers to a disorder associated with the entrapment of a blood clot in the lumen of' a pulmonary artery, causing severe respiratory _7'7_ dysfunction. Pulmonary emboli often originate in the veins of the lower extremities where clots form in the drop leg veins and then travel to lungs via the venous circulation.
Thus, pulmonary embolism oFten arises as a complication of deep venous thrombosis in the lower extremity veins. Symptoms of pulmonary embolism include acute onset of shol-tness of breath, chest pain (worse with breathing), and rapid hear t rate and respiratory rate. Some individuals may experience haemoptysis.
The products and methods of the invention are also useful for treating or preventing atherosclerosis. Heparin has bean shown to be beneficial in prevention of atherosclerosis in various experimental models. Duo to the fast and morn direct access to the endothelium of the vascular system, inhaled heparin is useful in prevention of atherosclerosis. Atherosclerosis is one form of al-teriosclerosis that is believed to be the cause of mast coronary artery disease, aortic aneurysm and atrial disease of the lower extremities, as well as contributing to cerebrovascular disease.
Due to its fast absorption and variable elimination rate, HLGAG particles with or without exipients can be used as an alternative for the intravenous heparin far surgical and dialysis procedures. For example, HLGAG particles can be inhaled prior to surgery by volunteer inhalation or passively inhaled via trachea tube during the anesthesia prior to or during the surgery. Surgical patients, especially those over the age of 40 years have an increased risk of developing deep venous thrombosis. Thus, the use of HLGAG
particles for preventing the development of thrombosis associated with surgical procedures is contemplated. In addition to general surgical procedures such as cardiac-pulmonary by-pass surgery, coronary revascularization surgery, orthopedic surgery.
prosthesis replacemen t surgery, and abdominal surgery, the methods are also useful in subjects undergoing a tissue or organ transplantation procedure.
In addition, pulmonary inhalation of dry aerosolized heparin is valuable in treatment of respiratory diseases such as asthma, allergy, emphysema, adult respiratory distress syndrome (ARDS), lung reperfusion injury, ischemia-reperfusion injury of the lung, kidney, heart, and gut, and lung tumor growth and metastasis. since heparin is known to have anti-inflammatory and anti-allergic properties. 1-leparin is also a well 3p established inhibitor of elastase and tumor gl°owth and metastasis.
We have shown that the dry aerosolized heparin particles are capable of inhibiting elastase induced lung IIl~Llry 111 all aCUte lllllg eI11p11y~0111a Illodel. ASthllla 1S a dlSOI'del' OL' the I'e~pll'atal'}' _ 7g _ system characterized by inflammation, narrowing oFthe airways and increased reactivity OFthe all'WayS t0 111halEd agelltS. Asthma l5 fl"eqLIElltly, although 110t eXG1L1S1VEly, associated with atopic or allergic symptoms. Asthma may also include Exercise induced asthma, bronehocanstr°ictive response to bronchastimulants, delayed-type hypersensitivity, auto immune Encephalomyelitis and related disorders.
Allergies are generally caused by Ig>; antibody generation against allergens. Emphysema is a distention of the air spaces distal to the terminal bronchiole with destruction of alveolar septa. Emphysema arises out of elastase induced lung injury. Heparin is capable of inhibiting this elastase induced injury. Adult respiratory distress syndromE
is a term which encompasses many acute defuse in~lfrative lung lesions of diverse ideologies Which are accompanied by severe atrial hypoxemia. One of the most frequent causes of ARDS is sepsis. Other types of inFlammatory diseases which are treatable with HLGAGs arE refractory ulcerative colitis, non-specific ulcerative colitis and interstitial cystitis.
In one Embodiment, the HLGAG preparations are used for inhibiting angiagenesis. An effective amount for inhibiting angiogenesis of the HIeGAG
preparation is administered to a subject in need of treatment thereoF.
Angiogenesis as used herein is the inappropriate formation of new blood vessels.
"Angiagenesis'" often occurs in tumors when Endothelial cells secrete a group of growth factor°s that are mitagenic far endothelium causing the elongation and proliferation of Endothelial cells which results in a generafian of new blood vessels. Several of the angiagenic mitogens are heparin binding peptides which are related to Endothelial cell growth Factors. The inhibition of angiogenesis can cause tumor regression in animal models, suggesting a use as a therapeutic anticancer agent. An effective amount for inhibiting angiogenesis is an amount of HLGAG preparation which is suFFicient to diminish the number of blood vessels growing into a tumor. This amount can be assessed in an animal model of tumors and angiogenesis, many aCwhich are known in the art. Angiogenic disorders include, but are not limited to, neovascular disorders of the eye, osteoporosis, psoriasis.
and arthritis.
The I-ILGAG preparations are also useFul For inhibiting neovascularizatian associated With eye disease. In another embodiment, the I-ILGAG preparation is _ ?9 _ administered to treat psoriasis. Psoriasis is a connnon derlnatologic disease causes by chronic inflammation.
I-IIsGAG GDIltallllllg ColllpoSltIOnS, play alSO lllhlblt Ca11Ge1" Cell gl'Owtl7 alld InetaStaSlS. ThLIS the 111et17odS of the 111Ve11t1D11 al"e LISeFLII fol' tl'eatlllg alld~01' pl'evelltlng tLIIIIOr Cell prOllferatlon OI' metaStaSls In a SLlblect. Tlle tel'I11S
tcpl'eVellt,~ alld c~pl'eVe11t1l7faT~~
as used herein refer to inhibiting completely or partially the bialogical efFect, e.g., angiogenesis or proliferation or metastasis of a cancer or tumor cell, as well as inhibiting any increase in the biological effect, e.g., angiogenesis or proliferation Dr metastasis oI~ a cancer Dr tumor cell.
The cancer may be a malignant or non-malignant cancer. Cancers Dr tumors include but are not limited to biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endametrial cancer; esophageal cancer;
gastric cancer; intraepithelial neoplasms; lymphomas; liver cancel°; lung cancer (e.g. small cell and non-small cell); melanoma; neuroblastomas; oral cancer; ovarian cancer;
pancreatic cancer; prostate cancer; rectal cancer; sarcomas; skin cancer; testicular cancer; thyroid cancer; and renal cancer, as well as other carcinomas and sarcomas.
A subject in need of treatment may be a subject who has a high probability of developing cancer. These subjects include, for instance, subjects having a genetic abnormality, the presence of which has been demonstrated to have a correlative relation to a higher likelihood of developing a cancer and subjects exposed to cancer-causing agents such as tobacco, asbestos, or other chemical toxins, Dr a subject who has previously been treated for cancer and is in apparent remission.
Cf~ective amounts of the polysaccharides are administered to subjects in need oI' such treatment. EFfective amounts are those amounts which will result in the desired ?S biological effect. The desired biological effect will depend on factors such as the type of polysaccharide being administered and the type of disease being prevented or treated.
T'or instance. when the polysaccharide is an HLGAG, the biological effect may be a reducfion ill cellular proliferatian al- metastasis, a reduction in inl7anlmation, an inhibition of elastase, prevention of respiratory disease, or prevention oI~
coagulation without causing other medically unacceptable side effects. Such amounts can be determined with no more than routine experimentation. It is believed that doses ranr=ing frDlll 1 11a110gra117~lCllogl'alIl t0 1 pd Illllllgl'alnSlkIlOg1'a171, depel7dlllg L117017 the IllodC OF
_3~_ administration, will be effective. The effective percentage of intact HLGAG
may be detel'111111ed Wlth I10 11101'e than roLltlne experllllelltatloll. Tlle abSOlLlte a1110u11t W111 depend upon a variety of factors (including whether the administl°ation is in conjunction with other methods of treatment, the number of doses and individual patient pal°ameters including age, physical condition, size and weight) and can be determined with routine experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgment. The mode of administration may be any medically acceptable mode including inhalation, oral, subcutaneous, intravenous, etc.
In some aspects of the invention the ef~~ective amount of a composition containing I~LGAG is that amount effective to prevent invasion of a tumor cell across a barrier. The invasion and metastasis of cancer is a complex process which involves changes in cell adhesion properties which allow a transformed cell to invade and migrate through the extracellular matrix (ECM) and acquire anchorage-independent growth properties. Liotta, L. A., et al., Cell 64:327-336 (1991). Some of these changes occur at focal adhesions, which are celllECM contact points containing membrane-associated, cytoskeletal, and intracellular signaling molecules. Metastatic disease occurs when the disseminated foci of tumor cells seed a tissue which supports their growth and propagation, and this secondary spread of tumor cells is responsible far the morbidity and mortality associated with the majority of cancers. Thus the term "metastasis" as used herein refers to the invasion and migration of tumor cells away from the primary tumor site.
The barrier for the tumor cells may be an artificial barrier in oitro or a natural barrier in IJino. hmih'o barriers include but are not limited to extracellular matrix coated membranes, such as Matrigel. Thus the HLGAG compositions can be tested for their ability to inhibit tumor cell invasion in a Matrigel invasion assay system as described in detail by Parish, C.R., et al., "A Basement-Membrane Permeability Assay which Correlates with the Metastatic Potential of Tumour Cells," Int. J. Cancer ( 1992) 52:37$-383. Matrigel is a reconstituted basement membrane containing type IV
collagen, laminin, heparin sulfate proteoglycans such as perlecan, which bind to and localize b1~'GF, vitronectin as well as transforming growth factor (TGh), urolcinase-tylae plaslnlnOgCl1 aCtlVat01' {LIPAI, tISSLIG plaSllllllOgell aCtlVatpl' (tPA), alld tl7e Sel'plll 1<110~~'11 as plasminogen activator inhibitor type 1 (PAI-1 ). Other in vitra and in vivo assays for metastasis have been described in the prior art, see, e.g., US Patent No.
x,935,850, issued on August I0, 1999, which is incorporated by reference. An i~~ uioo barrier refers to a cellular barrier present in the body ofa subject.
One advantage of the inhaled heparin is the convenience of administratian, which allow selF administration on an outpatient basis. This will enable a faster initiation of ti°eatment with heparin. Thus a subject may keep a device, such as an inhaler, for self administering the polysaccharide when necessary. This is particularly useful foi°
HLGAGs, which in some cases require rapid administration. The polysaccharides may also be administered by a health care professional, e.g. with the use of a tracheal tube.
Such methods are well known in the art.
In addition to HLGAGs, other polysaccharides have a diverse array of therapeufic utilities. Ghondroitin Sulfate has been used in a complex with cisplatin to reduce the nephrotoxity of cisplatin during chemotherapy. Zhang JS, Imai T, Otagiri M.
Cffecis of a cisplatin-chondroitin sulfate A complex in reducing the nephrotoxicity of cisplatin.
,xlrch Toxicol 2000 Aug,7d(6):300-7). Hyaluranic acid and derivatives thereof have been shown to be a pharmalogical class of slow acting drugs for the treatment of osteoarthritis.
Watterson JR, >Jsdaile JM, Viscosupplementation: Therapeutic Mechanisms and ~'linical Potential in Osteoarthritis of the Knee, JAnZ Acad Oj~tlzo~ Sz~rg 2000 Oct;8(5):277-?8~).
Ohitin, which is a non-sulfated polysaccharide, can be sulfated chemically to produce a modified polysaccharide, e.g., 6-0 sulfated carboxymethyl chitin which is capable of inhibiting lung metastasis of melanoma. Murata J, Sailci I, Malcabe T, Tsuta Y, Tolcura S, Azuma I, Inhibition of tumor-induced angiogenesis by sulfated chitin derivatives.
Camej~ Res 1991 Jan 1;5 I ( 1 ):22-6. Nishiyama Y, Yoshikawa T, Kurita K, Hoj o K, Kamada H, Tsutsumi Y, Mayumi T, Kawasaki K. Regioselective conjugation ofchitosan with a laminin-related peptide, Tyr-Ile-Gly-Ser-Arg, and evaluation of its inhibitory effect on experimental cancer metastasis. C.'lTem Phrcrf~~ W tll (Toy°p) 1999 Mar;~7(3):~151-3. Polysaccharide isolated From phellinus linteus are also useful for treating and preventing melanoma, especially when administered in combination with adriamycin. I Ian SI3, I~~:c OW. ,Icon 1'.l. 1 Ionf~ I~1~1~_ Yoo ll~, Ynnf~ hl I him 1 II~~I 'hhe inhibitory effect of polysaccharides isolated from Phellinus linteu s on tumor growth and metastasis. Imnnmopharmacology, 1999 l~eb;~ll(2):157-6d.j. Calcium spirulan, i~olatcd from a blue-green algea, spirulina platensis, is a sulfated polysaccharide that is mainly composed of rhamnose and has been demonstrated to inhibit tumor invasion and metastasis. Hayalcawa Y, 1-Iayashi T, Lee .IB, Ozawa 'h, Sal<uragawa N.
Activation of heparin cofactor II by calcium spirulan. .l Biol C'hei7? 2000 Apr 11;275{
15);1 1379-82 )_ Heparin mimetics such as oligosaccharides and pentasaccharides are useful far preventing coagulation and thrombosis. Other glycomimeties have been used for prevention a~ coagulation as well as treatment of inflammatian, cancer and other immunologic disorders. (Barchi, J.J., Curr. Pharm. Des., 2000, 6(4):185-501 ) Synthetically derived sulfated polysaccharides, such as laminarin are useful for inhibifing heparinase and thus for inhibiting in flammation, tumor progression, etc. (Mar chelfi, D.
et al., Cancer Res., 2000, 60:1767-70). PI-88 is a mixture of highly sulfated oligosaccharides derived from the sulfation o~f phosphomannum which is purif ed from a high molecular weight core praduced by ~fErmentation of the yeast picl?icr l7olslii. The main constituent is a pentamannose, however, small amounts of tetrasaccharide and minor amount of hexasaccharide are also present. PI-88 is currently undergoing clinical trials for its anticoagulant/antithrombotic properties. PI-88 is also a potent inhibitor of heparan sulfate binding and inhibits h eparinase enzymatic activity. (Parish, C.R., et al., Cancer Res., 1999, 59:3133-~1).
Other polysaccharides which are useful according to the invention are polysaccharide vaccine antigens. These antigens can be delivered alone or in combination with standard vaccine adjuvants for the purpose of stimulating an immune response. The polysaccharide antigen is a polysaccharide which is capable of eliciting an immune response against a microorganism in a host. Those include, but are not limited to, capsular polysaccharides, lipopolysaccharides and other subcapsular (surface) polysaccharides. Examples of capsular polysaccharides include those isolated from HCIL'i7701717111I,S li?flNC'i?2CrL', r~L'1,5',5'LI"lcr 177Li71i?~'I~ICIZS, Sl1"C'l7/OL'OL't'1CS 17I2C1Ci770i?lcl('.
Slrepln~o~mrs a~crlcrcticre, Sali7roi?~lla ly/7hi, Ea'~l7ei-iL'l2icr coli, and ~flcrpl?vlui~'coc~rts crrri"e?ta". Cxamples of lipopolysaccharides are those isolated from lVei~s°s"t~ricr rner7in~lilicli,s'.
Escl?ericl7ia coli, ~faln7oi?ellcr lyphi, and Pa'eudomoi?crs crer?igii?vsu.
hxamples of oth er 3Q _subcapsular polysaccharides are the common polysaccharide antigen (c-substance) of Group A, I3 and C 4Slre/~locoL°L'i and the common polysaccharide antigc~v (c-sLibstance) of ~Strel.~ioL°uL"Lms pi7Glri77oi7icrc. 'fhe immunology of polysaccharide vaccines has been reviewed by .Iennings et al, ''The Polysaccharides" (Editor; G. O. Aspinall), Volume 1, 291-X29 ( 1982). See also "Carbohydrate Chemistry,'' ed. by .Iohn b".
Itennedy, Clarendon Press, Oxford, 1988; "The Carbohydrates, Chemistry and Biochemistry." ed.
by W. Pigman and D. I-Iorton, Academic Press, Inc., 197p; and "Chitin, Chitosan, and Related Enzymes," ed. by .Iohn P. Zikalcis, Academic Press, Inc.. 1984.
In some aspects of the invention also encompasses kits. The kits o1' the invention include an inhalation apparatus, polysaccharide dry aerosol particle formulation and a detection system. An inhalation apparatus, as used herein, is any device for administering a dry aerosol. This type of equipment is well known in the art and has been described in detail, such as that description found in Remington: The Science and Practice of Pharmacy, 19i~' Edition, 1995, Mac Publishing Company, Eastan, Pennsylvania, pages 1676-1692. Many LLS. patents also describe inhalation devices, such as U.S. Paten tNo. 6,116,237.
A detection system is particularly useful for the administration of polysaccharides I 5 which are dependent upon a therapeutic level in fine blood. Detection systems can be invasive or non-invasive. An example of an invasive detection system is one which involves the removal of a blood sample and can further involve an assay such as an enzymatic assay or a binding assay to detect levels of the polysaccharide in the blood. A
non-invasive type of detection system is ane which can detect the levels of the 2p polysaccharide in the blood without having to break the skin barrier. These types of non-invasive systems include, for instance, a monitor which can be placed on the surface of the skin, e.g., in the form of a ring or patch, and which can detect the level of circulating polysaccharide. One method for detection may be based on the presence of fluorescence in the polysaccharide which is administered. Thus, i f a fluorescently labeled heparin is 25 administered and the detectian system is non-invasive, it can be a system which detects fluorescence. This is particularly useFul in the situation when the patient is self-administering heparin and needs to know the blood concentration or an estimate thereoF
in order to avoid side eFFects or to determine when another dose is required.
The polysaccharides may be administered alone ar in combination with other 3p polysaccharides or other therapeutic agents, delivered by conventional therapeutic means. In general, when administered For therapeutic purposes, the other therapeutic agents may be applied in pharmaceutically acceptable solutions. Such preparations may _3q._ routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.
The therapeutic agents may be administered per se (neat) or in the Corn? of a S pharmaceutically acceptable salt or in a pharnaceutically acceptable carrier. When used 111 medlClne tl7e Salts ShoLlld be phal'117aceLltIGally aGGeptable, bLlt 17017-phal'nlaceLltIGally acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof and are not excluded from the scope of the invention. Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared 1i'om the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, malefic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, Formic, n7alonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.
Suitable buffering agents include: acetic acid and a salt (1-
POLYSACCHARIDES
I'IEI'D OF TI-IE INVENTION
The present invention relates to methods and products associated with pulmonary delivery orpolysaccharides. In particular methods and products for delivering both unformulated and formulated polysaccharides are described.
BACKGROUND OF THE INVENTION
Recent advances in medicine have produced several alternative modes of drug delivery. Drugs which were previously only available in injectable forms, are now available in less invasive forms such as oral tablets or capsules, sustained release devices, and transdermal patches. Many of these advances, however, have occurred with protein based or small molecule drugs. Delivery of polysaccharides for therapeutic or 1 S prophylactic purposes is still associated with some problems.
Oral delivery of drugs is often preferred. The rapid metabolism of polysaccharides in the gastrointestinal tract, however, has prohibited their oral administration. Pulmonary delivery of drugs has also been proposed to be a preferred route of drug administration because of the large surface area of blood vessels in alveoli.
The thin barrier between the rich capillary bed and the air coupled with the very high blood flow rate makes alveoli of lungs one of the most desirable drug delivery sites.
Pulmonary delivery of protein based drugs has been quite successful.
Lnvestigators, however, have been trying for over 30 years to administer polysaccharides such as heparin by pulmonary delivery, with much less success. For instance, delivering heparin by conventional liquid aerosol spray or instillation only received limited success due to its poor penetration to the deep lung and resultant poor pharmacolcinetics perFormance.
An exceedingly high dose ol~ heparin is rcquii°ed to generate mcaninghul pharmacological elFects when inhaled as liquid heparin.
Natural polysaccharides such as heparin are polydisperse mixtures containing a large number of chains having different molecular weights (M Ws~ and as such the pharmacokinetics of these compounds are complicated. The anticoagulant response o(' heparin, (or instance, increases disproportionately in intensity and duration as the dose increases. t~s a result, anticoagulant e(~Uect ol~ heparin often has to be closclyr monitored _7_ t0 1111111m1Ze the OCCLIrreIlCe Of pOtelltlally dallgel'OL1S he11101'I'h age, Whlcl7 1S the 111OSt G0111m017 al7d 111x101' Slde etfeCt Of hepal'117. S111Ge hepal'lll 1S llOt a 5117g1e cllellllcal l lltlty and its disposition is determined by a number of pathophysiologic factors, its pharnlacolcinetic parameters vary substantially among differen t individuals and thus require dose adjustment for each specific individual. The frequency of side effects is associated with the routes of administration. The risk is higher in intermittent ( 1 ~l.?"%t>) and continuous (6.8°l°) infusion than the subcutaneous I°oute (~I.1 %).
SUMMARY OF THE iNVE~ITION
The invention relates to improved methods and products for delivering polysaccharides for prophylactic and therapeutic purposes. The inven tion is based in some aspects on the surprising discovery that pulmonary administration of polysaccharides in a dry aerosol form, in a formulated or unformulated form, results in an extremely rapid and efficient delivery of dle polysaccharide locally and systemically.
Many attempts have been made in the past to deliver polysaccharides such as heparin by inhalation. In general these attempts have been unsuccessful. It is well established that when heparin is delivered in a liquid aerosol, the amount of heparin that is absorbed in the blood is extremely low. It was discovered according to the invention that polysaccharides could be administered by pulmonary delivery in a dry aerosol with 2Q excellent results, including rapid absorption and good bioavailability, resulting in significant therapeutic benefits.
Thus, in some aspects, the invention is a method for delivering a polysaccharide to a subject in an unformulated dry powder. For instance, a method for producing a therapeutic effect by administering to a pulmonary tissue of a subject an unformulated dry polysaccharide particle ill an effective amount for producing a therapeutic effect, wherein the unformulated dry polysaccharide particle has a mean geometric diameter of I-SOQ microns, is provided.
In other aspects the invention is a method for delivcrin~~ at least 5% anti preferably at least 10°,~0 of a polysaccharide to the lower respiratory tract by administering to a pulmonary tissue of a subject an unforn7ulated dry polysaccl7aridc particle, wherein the unformulated dry polysaccharide particle has a mean ~~EOnletric diameter of 1-500 microns, and wherein at least 5°~'° or 10% of the polysaccharide administered is delivered to the lower respiratory tract.
In yet anather aspect the invention is a method for systen7ically delivering a polysaccharide to a subject by administering to a pulmonary tissue of the suhject an unformulated dry polysaccharide particle, wherein the un formulated dry polysaccharide particle has a mean geometric diameter of 1-500 n7icrans.
The palysaccharide usefill in the methods is any type of polysaccharide which has a prophylactic or therapeutic utility. In one embodiment the polysaccharide is a glycosaminoglycan, such as, for example, a heparin, a heparin sulfate, a low molecular weight heparin, a biotechnology derived heparin, a chemically modified heparin, a heparin mimetic {e.g., a monosaccharide, oligosaccharide or polysaccharide that has at least one heparin-like function such as AT-DI binding), or an unfi'actionated heparin preparation.
Generally the unformulafed dry polysaccharide particle has a mean geometric diameter of 1-500 microns, or any range of integers therebetween. In some embodiments the unformulated dry polysaccharide particle has a mean geometric diameter of 1-50, 1-200, 53-106, 1-5, 1- 20, 20-53, 53-75, or 75 -106 microns. In other embodiments the unforlnulated dry polysaccharide particle has a mean aerodynamic diameter of 1-5, 5-35, I-35, 35-70, 35-75, or 1-50 microns. In yet other embodiments the unformulated dry polysaccharide has a tap density of 0.01 - 0.4 g/cm~ or greater than 0.4 glcm3.
The prophylactic or therapeutic utility of the polysaccharide being delivered varies depending an the type of polysaccharide as well as the subject being treated.
Some polysaccharides, for instance, arc useful as vaccine antigens. These are generally used for prophylactic purposes, but, ill some oases call be used therapeutically as well.
Other polysaccharides have very diverse utilities, such as, the glycosaminoglycans, and in particular heparin-like-glycosaminoglycans. Glyeosaminoglycans have been established to be useful for treating and preventing coagulation disorders, thrombotic disorders, cardiovascular disease, vascular conditions, atherosclerosis, respiratory disorders, cancer, and an~iogenic disorders.
ThLIS, Ill SC)Ille elnbodlnlentS the SLlbleCt haS 01' is at I'1Sk C)I' a CC)aglllatl011 dISOI'C1C1' alld the thel'apeUtlC effect Ot the glyCOSa1171I1Og1yCd11 1S a11t1-COagLllatloll 01' alltlthro111bOS1S. Ill othel' e117boC11111e11tS the gIyCOSan71170g1yCa11 1S
LIS('l~Lll 1'C11' tl'CEltlll~
cardiovascular disease, such as For instance, acute myocardial inFarction, unstable angina, ischemic stroke, and atria( fibrillation, and vascular conditions, such as For instance, deep venous thrombosis, stroke, and pulmonary cnlbolisnl. In other embodiments the subject is preparing to undergo, is undergoing or is recovering l~ronl a surgical procedure or the subject is Undergoing a tissue or organ transplant.
Surgical procedures include but are not limited to cardiac-pulmonary by-pass surgery, corollary revascularization surgery, orthopedic surgery, and prosthesis replacement surgery.
The subject in other embodiments leas or is at risk oFatherosclerosis, a respiratory disorder, a cancer or metastasis, an inflammatory disorder, an allergy, andlor an angiogenic disorder. Respiratory disorders include but are not limited to asthma, emphysema, adult respiratory distress syndrome CARDS), and lung, kidney, heart gut, brain, skeletal muscle ischemial-reperfusion injury. Angiogenic disorders include but are not limited to neovaseular disorders of the eye, osteoporosis, psoriasis.
and arthritis.
In other embodiments the polysaccharide is a chondroitin sulfate, dermatan sulfate, hyaluronic acid, pectin or pectin derivative, oligosaccharide or pentasaccharide that binds to AT-III, laminarin, PI-$8, sulfated chitin, or other animal-derived, plant-derived, microorganism-derived, natural, synthetic, or modified polysaccharide. Pectin s and pectin derivatives are useful for anti-tumor applications.
In same embodiments when the polysaccharide is a glycosaminoglycan being administered for anticoagulant purposes, it is administered in an amount eI=f~ective to produce a minimum therapeutic level of approximately 0.X5 IUlml anti-Factor Xa activity.
The LmFormulated dry polysaccharide may be self administered by the subject or it may be administered by another, such as a health care professional. her instance, tile unformUlated dry polysaccharide may be administered through a tracheal tube.
In other aspects, fhe invention is a composition consisting oCunFormUlated dry glycosaminoglycan leaving a mean geometric diameter of I-500 microns. In some embodiments the unFormulated dry polysaccharide particle has a mean geometric diameter of 1-50, I- 200, S3-l OG, 1-5, 1- 2p, '?0-53, 53-75, or 75 flOG
microns. In other etIlbOd1111e11tS the L111foI'nlLllated dl'y polySaCCha1'Ide pal'tlCle 11W El Illeall ael'odyllaInIC
diameter of I-S, 5-35, 1-35, a5-70, 35-75, or 1-50 microns.
The glyc0saminoglycan in some embodiments may be a heparin, a heparin sulfate, a low molecular weight heparin, a biotechnology derived heparin, a chemically modified or synthesized heparin, heparin mimeties and an unfraclianated heparin preparation.
OptlOllally the cO111pOSlt1o11 play add1tl011al1y IIIGILIde a f01'lllLllated CII'y glycosaminoglycan preparation. 'rile glycosaminoglycan of the formulated dry glycosaminoglycan preparation may also be a heparin, a heparin sulfate, a low molecular weight heparin, a biotechnology derived heparin, a chemically modified Nepal°in, a heparin mimetic, and an unfractionated heparin preparation.
In same embodiments the glycosaminoglycan of the formulated dry preparation is the same as the glycosaminoglycan of the unformulated dry preparation and in other embodiments the glycosaminoglycan of the formulated dry preparation is different than the glycosaminoglycan of the unformulated dry preparation.
Optionally, the formulated dry glycosaminoglycan preparation includes a 7 5 polymer to effect slow release of the glycosaminoglycan. Thus the glycosaminoglycan of the unfonnulated preparation will be released rapidly and the glycosaminoglycan of the formulated preparation will be released slowly over time. In some embodiments the polymer is selected from the group consisting of poly lactic acid (PT.rA), polyglycolic acid (PGA), poly (D,I~, -lactic-co-glycolic acid) (Pf,GA), polyamides, polycarbonates, poly(ethylerLe oxide), polyvinyl compounds, poly vinyl ethers, polymers of acrylic and methacrylic acids, celluloses, and other polysaccharides. In other embodiments the formulated dry glycosaminoglycan preparation includes a surfactant, such as DPPC.
polyoxethylene-9-; auryl ether; palmitic acid; oleic acid; sorbitan tri0leate (Span 85);
glycocholate; surfactin; poloxomer; sorbitan fatty acid; sorbitan trioleate;
tyloxapol; and phopholipids.
A method for delivering a glycosaminoglycan to a subject by administering to a pulmonary tissue of a subject the above-described compositions is also disclosed according to the invention.
In other aspects the invention relates to methods of delivering either or both ~0 f01'IllLllated alld Llllf0l"mLllated pOlySilCGha1'ldeS by pLlllllollal'y adI111111SI1'at1011. ThLIS the invention in one aspect is a method of rapidly delivering a polysaccharide to a subject by adn11111SteI'lllg a Ch'y ael'0501 G011talllltlg a polySaCGhal'lde t0 a pLlllll0llal'y tISSLIG 01_ El -G-subject in an effective amount to produce a peak plasma concentration o1' laolysaccharide within three and preferably two hours.
In other aspects tl7e invention is a method oI~ rapidly delivering a polysaccharide t0 a SLIbIeCt by ad1771171S1e1'117g a dl'y ael'oS01 COlltalt1117g a pOlySaCCl7a1'lde t0 a pL11117017a1'~~
tissue of a subject in an effective amount to produce a peak thcrapeu tic activity ol~
polysaccharide within three or preferably two hour°s, In some embodiments the dry aerosol containing a polysaccharide is administered in an eFPective amount to produce the peals concentration or activity of polysaccharide within one and one half hours, In other embodiments the dry aerosol containing a polysaccharide is administered in an effective amount to produce the peals concentration or activity of polysaccharide within one hour or preferably within a half hour.
The polysaccharide in some embodiments is a glycosaminoglycan, Glycosaminoglycans include but are not limited to low-molecular-weight heparin, heparin, heparin sulfate, biotechnology derived heparin, chemically modified heparin, heparin mimetic, and unfractionated heparin preparation.
In some embodiments the dry aerosol contains an unformulated dry polysaccharide and in other embodiments it contains a fornnllated dry polysaccharide preparation or some combination thereof. Optionally the dry aerosol contains a dry polysaccharide formulated in a surfactant, such as DPPC. Tl7e SurFactant may optionally be coated on the particle surface or incorporated into the formulation.
In other embodiments additional molecules may optionally be administered.
These include, for instance, proteins, peptides, nucleic acids (e.g., IZNA, DNA, PNA, multiplexes of them (e.g.: triplex), and, small organic molecules).
The invention in another aspect relates to a method oC rapidly delivering a polysaccharide to a subject by administering a dry aerosol containing a polysaccharide to a pulmonary tissue of a subject in an effective amount to deliver at least 5°~0 of the polysaccharide to the blood within one hour. In some embodiments at least 5°,~0 oi~thi polysaccharide is detectable in the blood within one hour. In other embodiments at least 10°l0, 20%, 30°~'a, X10°.~°, 50%, 60%, 70°~'0, 8d°~o, or 90°.~0 oC the polysaccharide is delivered to or detectable in the blood within one hour.
In other aspects the invention is a method far producing a rapid therapeutic cIAIect by administering a dry aerosol containing a polysaccharide to n pulmonar>>
tissue of' a _ '7 _ subject in an effective amount for producing a therapeutic effect within 1 hour of administration. In some embodiments the dry aerosol is administered in an effective a1710L111t tOl' prOdLlClllg a thel'apeLltlG GfleGt Wlthlll 15 117111LIteS Of ad1171171S11'at1011. 111 yC;t Other eIllbOdImeIltS the dl'y ael'OSOI 1S ad1n1111Ste1'ed 111 all el'feCtlVC
a177OU17t 101' pl'OdL1C117t, a thel'apeLltlC CffeCt Wlt17111 1 Q InlnLlteS Of adIn1171StratIOl7.
The 111Ve11tIO11 117 anOtheI' aspect 1S a COIIIpOSlt1011 G0111p1'lslllg a dl'y ael'OSO1 formulation of particles containing a heparin-like glycosaminoglycan, wherein the particles have a mean geometric diameter of greater than 30 microns. In some embodiments the particles are spherical and in other embodiments the particles are non-1 Q spherical. In yet other embodiments the particles are porous and in other embodiments the particles are non-porous.
A composition of a dry aerosol formulation of particles containing a heparin-like glycosaminoglycan, wherein the particles have a mean aerodynamic diameter of greater than 5 microns is provided according to another aspect of the invention.
15 In another aspect the invention relates to a composition of a dry aerosol formulation of particles containing a heparin-like glycosaminoglycan, wherein the particles have a tap density of greater than O.4 glcm3.
Kits are provided according to yet other aspects of the invention. The kit is a lit for administering a dry aerosol containing a polysaccharide to the respiratory tract of a 20 subject and includes an inhalation apparatus, a polysaccharide dry aerosol particle preparation and a detection system. The polysaccharide dry aerosol particle is formulated to release at least 5°J° ofthe polysaccharide within three or preferably two hours.
In one embodiment afthe kit, the polysaccharide is a glycosan7inoglycan, such 25 as, a low-molecular-weight heparin, heparin, heparin sulfate, biotechnology derived heparin, chemically modified heparin, heparin mimetic and unfraGtionatEd heparin preparation.
The dry aerosol polysaccharide play be a formulated or unformulated polysaccharide particle preparation. The dry polysaccharide particle play have a mean 3Q geometric diameter of 1-500 microns, or any range of integers therebetween.
In same embodiments the particle has a mean geometric diameter of I-50, 1- 2pp, >~-106, I-~. 1-~~, ~~-S~, J~3-7~, OI' 75 ---I a~ 1I11C1'OtlS. Ill Othel' eIllbOd1111eI1tS the L1171'OI'111Lllated cll'V
-g_ polysaccharide particle has a mean aerodynamic diameter of I-5, 5-35. 1-35, 35-70, 35-75, or 1-SO microns.
According to other aspects of the invention a composition including both a formulated dry polysaccharide preparation and an unformulated dry polysaccharide preparation is provided. The polysaccharide may optianally be a glycosanlinoglycan.
Glycosaminoglycans include but are not limited to a heparin, a heparin sulFate, a low molecular weight heparin, a biotechnology del°ived heparin, a chemically modified heparin, a heparin mimetic, and an unfractionated heparin preparation.
In some embodiments, the polysaccharide of the formulated dry preparation is the same as the polysaccharide of the unformulated dry preparation and in other embodiments the palysaccharide of the formulated dry preparation is dil~Ferent than the polysaccharide of the unformulated dry preparation.
Optionally, the formulated dry polysaccharide preparafion includes a polymer to effect 510W I'eleaSe Of the pOlySaGGhal'Ide. ThLl9 the pOlySaGGharlde Of the Lln'~OI'InLllated preparation will be released rapidly and the polysaccharide of the formulated preparation will be released slowly over time. h some embodiments the polymer may be PLA, PGA, or PI'GA. In other embodiments fihe formulated dry polysaccharide preparation includes a surfactant, such as DPPC.
In some embodiments the ratio of unformulated pl°eparation to formulated preparation is 90:10, 70:30, 50:50, x0:70, or 10:90.
In other aspects the invention is a method for delivering a polysaccharide to a subject by administering to a pulmonary tissue of the subject the above described composition, e.g., a dry aerosol formulation comprising an unformulated dry glycosaminoglycan preparation and a formulated dry glycosaminoglycan preparation to deliver the polysaccharide fo the subject.
each of the limitations of the invention Gall encompass various embodiments oC~
the invention. It is, therefore, anticipated that each of the limitations ol~
the: invention IIIVOIVIIlg ally Olle elelllellt Or COnIbIIlat1011S OfelemelltS Gall be I11C1LlCled 111 eaCll aSpeCt OC' the invention.
13RICF D~SCRIPTIO~ ~ OI~ TI-IE DRAWINGS
Ia figure 1 is a set of graphs depicting the pharmacol:inetics of~ L1PI-1 particles af~tr:r inhalation: a) pharmacol:inetics of LJI°H as unformulated dry powder ( 1-~0() ym)C 1?
mg/1<g) or t'orlnulated nonporous small particles (I-3 LLlll) with DPPC as escipient (60'l°
UFI-I 40% DPPC) X10 mglkg) in rats. b) lavage study oFun t'ormulated UFI-I in rats at 1?
mglkg. The amount oI' UFI-I in lavage fluid and plasma were determined by whole blood clotting assay method. The total amount oFUFI-I sound in lavagc Iluid at ildicated tiu~c:
points was compared to the total amount of arcleparin in rat circulation at the c01'reSpolldlllg tune poIlltS. I ~ Inl plasma VOlLlllle as LlSed t"01' CoIlVe1"tlllg CollCEllt1"atlol7 t0 total amount of U~FH in circulation.
Figure 2 is a set of graphs depicting the pharmacolcinetics of 100°/'o unt'ormLllated ardeparin particles in rabbits: a) the pharmacokinetics of anti-Xa activity of un~ormLllated ardeparin of different particle size ranges in rabbits at 600 IUllcg. b) the pharmacol:inetics of unl'ormulated ardeparin is compared to s.c.
administration at 600 IUlkg. c) comparison of pharmacolcinetics between 600 and 300 IUII<g doses for unformulated ardeparin particle of 1-20 Iun size in rabbits. d) comparison of pharmacolcinetics between 600 and 300 tUllcg doses for unformulated ardeparin particles of 1-53 ltm size. e) comparison ofpharmacokinetics between s.c. administered ardeparin and dry unCormulated ardeparin of difFerent size ranges at 300 IUllcg. t]
results of lavage study after inhalation o~dry unformulated ardeparin of I-53 Lun size. The total amount of ardeparin in the lavage fluid and plasma was determined by anti-Xa assay, g) lavage study results of dry unformulated ardeparin o~ 1-53 dun size. The total amount of ?0 ardeparin in the lavage fluid and plasma was determined by anti-Xa assay.
Figul°e 3 is a set of graphs depicting a) comparison of pharmacolcinetics ol~
formulated ardeparin (~10°,~'o ardeparin 60°~'o DPPC, 3-7 llm geometric diameter) and unformulated ardeparin (100°~'° ardeparin, 1-20 ltm geometric diameter) at 600 IUlkg. h) pharmacokinetics of ardeparin after instillation in rabbits at 300 and 600 IUlkg.
Figure 4 is a graph depicting the el-fect of depth ol~ delivery site on the pharmacokinetics of formulated ardcparin particles (3- 7 1.1m, ~IOv'o ardeparin 60°'t>
DPPC). 'l"he delivery tube was placed either 1-2 cm or ~I-5 cm above bifurcation point" 6 ml oFair was used to aerosolize the powder for the lower tube position and 3 ml oI'air was used for the higher tube position.
Figure 5 is a graph depicting the pharmacokinetics of arcleparin aFtcr i.v.
bolus injection at 300 and 600 IU~/l:g doses.
Figure 6 is a graph depicting the protection of acute injury induced by human sputum leucocyte elastase (HSLE) in lung tissue by pulmonary inhalation of heparin particles. rormulated UFI-I (60°~'o UFI-I ~0% DPPC, 1-3 11m) at 1'~
mgh:g or un(ornlulate;d ardeparin particles ( 1-20 lam) at 600 IU/1<g were administered by inhalation to rats 1 hour S p1'101' to instillation oF0.25 ml oFl-ISLE (250 ltg). Rats were sacrilicecl ?4 hours later, the lungs were harvested and lavaged. The hemoglobin level in the lavage fluid was assayed.
Control group received no heparin was included for comparison.
FIgLlre 7 1S a plCtLlre deplGtlng the SGalllllllg electl'011 1111GI'OSCOpe tSEM) plCtLl1'eS
of heparin particles. The size, porosity, and the texture of the heparin of both Formulated and unformulated heparin particles were compared. The images were lateen with .IEOL
JSM-6320 FV Scanning Electron Microscape at 1 KV. a) The SEM oC unl:ormulated UFH particles showing a single pal-ticle. b) The SEM oCunformulated UFI-I
showing multiple particles. G) The SEM of Formulated UFH particles (60°lo UFH
X10°Jo DPPC).
DETAILED DESCRIPTION
In general, intrapulmonary delivery of polysaccharides has met with very little success. The prior art techniques For intrapulmanary delivery have involved administration in the form of a liquid aerosol or intratracheal liquid instillation. Whether given as liquid aerosol or intratracheal liquid instillation, the bioavailability o'F
polysaccharides such as heparin or LMWH delivered by an intrapulmonary route is consistently less than 10% of that achieved by s.c. subcutaneous) or i.v.
(intravenous) administration. When delivered as liquid heparin aerosol, the majority oFheparin is trapped in the upper airways and only less than 10°r~o oFthe delivered dose reaches the deep lung. Thus extremely high doses must be administered to achieve any therapeutic ?5 result. IF heparin is administered at the same doses as that which is ordinarily used For S.G. Or 1.V. adn11111Strat1011, IlO detectable hepal'lll 1S tOLllld 111 the blOOd C11'ClllatlOn altel' pulmonary delivery. An 8-10 times higher dose oFheparin is required For intrapulmonary heparin fo pravide a similar heparin concentration in the blood circulation as that which is achieved with s.c. administration. Additionally tile fate oi~
abS01'pt1011 01'hepal'lll Fr0111 the ILIIlg atteI' 111trapLllnlOllal'y dellVei'y OL' llqllld hCpal'l11 1S
IIILICh S10W°eI' than that OI' S.C. adn11111St1'atl0n. ti~~;i~ (the tulle ~Vllell pear aCtU?lty 1S I'('~1C11Gd~
1S typlCall)' ObSeI'Ved ~ 11OLI1'S aFtel' llltl'apL11n1O11a1'y dCllVCt'y.
SllbStalltlal a11101111tS OI' heparin have been observed to be remaining in the lung many hours after inhalation.
hurther, there has been no close dose-response relationship observed alter intrapulmonary delivery oFheparin. Consider"able variations in the pharmacokinetics of lntrapLllmollary heparin have been reported, SLlggeStlllg that 11115 I'oLlte ol'dellVel'y Inlay be dangerous because of the risk of heparin associated side eFfects.
There are several problems associated with pulmonary delivery ol~
polysaccharides. firstly, the presence of multiple membrane structures which separate the upper respiratory tract From the capillal°y circulation can lead to poor absorption.
These lipid membrane structures are impermeable to hydraphilic macromolecules such as heparin and low molecular heparin which are highly negatively charged polymers.
Delivery routes such as s.c. administration allow the polysaccharide to directly contact capillary vessels and thus be immediately absorbed. lPulmonary delivery methods also result in a large proportion of the drug being trapped in the trachea ar upper respiratory tract.
It was unexpectedly discovered according to the invention that intrapulmonary administration of polysaccharides using a dry aerosol particle preparation resulted in excellent absorption and bioavailability, producing significant therapeutic results in nivo.
Even snore surprising, it was discovered that the dry aerosol particles did not even need to be fornlulated to produce these results. It has been well documented in the prior art 2p that when proteins are administered as dry powder, the particles undergo two difFerent fates. The particles either become trapped in the upper respiratory tract or are delivered to the lower respiratory tract or in some cases the deep lung. In the upper respiratory tract, ciliated epithelia contribute to a process referred to as the "mucosiliary escalator""
in which particles are swept from the airways toward the mauth. In the deep lungs, alveolar macrophages phagocytosize the particles soon alter their deposition.
Small particles (diameter' <5 11M) get phagocytosed to a higher degree than larger particles.
The human lungs can remove or rapidly degrade deposited aerosols over periods ranging Iron minutes to hours. As the diameter oFthe particle increases, there is increasingly less phagocytosis by macrophages. However, increasing the particle size also minimizes the probability oFparficles (possessing Standard mass density) entering the airways and acini due to excessive deposition in the oropharyngeal or nasal regions (upper respiratory tracfi). Thus, the large particles (diameter > 5 1.~M) are known to get deposited excessively in the upper airways.
As a result of these teachings it is generally believed in the art fihat i1'a protein has to be delivered as a dry powder via pulmonary delivery, the protein must be Formulated in a certain way to achieve maximal therapeutic beneCt. l~or example, iFa protein is Formulated into dry particles which are made to be aerodynamically light, it can be delivered Formulated wifih a surfactanfi via pulmonary delivery (U'S Patent 1\lumber 5,855,913). It was discovered surprisingly according to the invention that delivery of polysaccharides can be accomplished wifihout adhering to these teachings.
Polysaccharides behave in a way thafi is totally different -Fram that predicted for an unformulated protein or other macromolecule. The data described in the Itxamples show that polysaccharides can be delivered via pulmonary inhalation, and that this process is independen t o~fihe size of the particle (within a broad range), texture, porosity, density, shape, and fine presence or absence of additives.
The polysaccharides can be signiFicantly absorbed as dry aerosol particles of defined sizes with or withoufi exipients. Thus, a "dry aerosol containing a polysaccharide" encompasses both unfarmulated dry aerosol polysaccharide particles or preparations and formulated dry aerosol polysaccharide particles or preparations. An '°unformulated dry aerosol polysaccharide particle or preparation" as used herein rej~ers ?0 to a composition which is composed of a polysaccharide in the form of dry particles having a mean geometric diameter of 1 - 500 microns and which does not include a carrier or other excipient to enhance delivery or result in slow release. The unformulated dry aerosol polysaccharide particle may include non-essential agents which are nofi expected to influence the delivery or absorpfiion of the polysaccharide.
Materials which are known to inE7uence polysaccharide release or absorption are polymeric materials and surfactants. Thus, both offihese materials may be found in the formulated particles buff not in the unFormulated particles. The unFarmulated particles, however, may include compounds other than polymers (except For polysaccharides) and surFaetanis, as long as fihe particle includes at least one therapeutically acfiive polysaccharide.
These include.
For instance, buff are not limited to, proteins. nucleic acids, small organic or inorganic molecules, carriers that do not have slow release properties. lareservatives, etc.
The unformulated {as well as the formulated} polysaccharide particles play include a single polysaccharide or multiple polysaccharides. Thus, the particles May include only one polysaccharide, more than one polysaccharide but only one polysaccharide which has a therapeutic activity, or more than one polysaccharide having a therapeutic activity.
A sot of particles having a "mean geometric diameter of I - 500 microns" is a set of particles having at least 50°I° of the particles falling within the size Tango of 1-500 microns or any range of integer numbers falling within 1-500 mice°ons.
The mean geometric diameter can be determined by one of skill in the art using routine methods.
For instance, moan geometric diameter can be established by scanning electron microscopy {SEM) or atomic force microscopy {AFM), which can be use to determine particle size, porosity and surface texture, as well as a coulter multisizer II{Goulter Electronics, Futon, Beds, England). In some embodiments the particles have a geometric size distribution of I-250, 1-100, I-50, 5-200, 10- 500, 10-250, 10-1p0, 100-200, 100-150, 53-106, I-5, 1- 20, 20-53, 53-75, or 75-I06 microns.
Unfonnulated dry aerosol particles can be propal°ed by any means known in the art for generating particles. One method for preparing the particles involves obtaining a dry pure preparation of the polysaccharide and grinding it to produce particles, optionally coupled with a step for selecting particles of a particular size range.
Cxamples of this typo of method al°e provided in the examples below. For instance, the polysaccharide can be ground into particles using a coffee grinder and then separated by size by using sieves of different mash sizes. Other methods include single or double emulsion solvent-evaporation procedures and spray drying. Particles of speci6o sizes can be generated by cryogrinding. This is accomplished by cooling the particles to a very low temperature, such as -190° C, e.g., using liquid nitrogen, and then grinding the particles. Additionally, polysaccharide Inay be dissolved in a suitable solvent {e.g., water and a volatile organic solvent like methylene chloride) and than nebulized (i.e., passing it through a small orifice at high pressure}. The solvent is then rapidly removed at a high ten lperature and the particles collected. An olectrospray injector can be used for this purpose.
In addition to the moan geometric diameter the particles may have a specific range of aerodynamic diameters. In one embodiment the particles have a mean ael'ody11a1111C dIa111etel' ol' 1-50 I111C1'o115. A x'meall aCl'odyt1al111C
C11a111CtC1'~~ 1'CI'el'S t0 tIIC
diameter that a particle appears to possess on the basis of its in-Flight speed, where it is assumed to be spherical and to possess a mass density of lglcnl~, The geometric diameter oFa spherical particle possessing unit mass density (Iglcnl~) is equivalent to its aerodynamic diameter. The aerodynamic diameter (cl;,~.,.) relates to a particle's geonletric dlallletel' ~C~~ aild nlaSS denSlty (f7) with the ~LIIICtIOn: t7~;,~~-=C7~(J
~1~. In SOIlIe en1170C11171eIltS
the particles have a meats aerodynamic diameter of 1-5, 1-35, 1-75, 35-75, ar microns.
The polysaccharide particles with sizes ranging from 1-500 l.Lm, porous or non-porous, spherical or non-spherical, light or heavy were associated with significant ) 0 absorption profiles. Although the prior art has taught that these Features are critical For promoting delivery of the particles to the deep lung, the data of the instant invention demonstrates that these properties are not critical for delivery to the deep lung. 'Thus the dry un formulated particles may have any physical properties, such as porosity or shape.
The porosity and shape of the particle influence the aerodynamic properties of the 15 particle. In some embodiments the particles may be aerodynamically light, but in other embodiments they may be heavy. The aerodynamic weight of the particle can be measured in terms of tap density. A particle that is aerodynamically light has a tap density of less than 0.~1 g/cm3 and preferably has a tap density in the range of x.01 glens'' 0.~1 g/cm3. A particle that is aerodynamically heavy has a tap density of greater than 20 0.~ gJcnl3. Tap density refers to the mass density of the particle, which is calculated as the mass of the particle divided by the minimum sphere volume within which it can be enclosed. A measurement of tap density may be obtained using equipment such as a GeoPyc~hM (Micronletrics Instrument Gorp., Georgia).
The unformulated polysaccharide particles showed unique pharmacolcinetics 25 featuring an extremely rapid absorption rate and a comparable elimination rate to that of s.c. administration. The addition of exipients such as DPPC to the particles did not appear to alter the pharmacolcinetic prafiles signil°icantly. Thus, the invention also encompasses the use aFformulated dry aerosol polysaccharide particles. A
~Clormulated dry aerosol polysaccharide particle or preparation" as used herein refers to a conlposilion 30 which is composed oFa polysacchal-ide in the Form oFdry particles having a mean geometric diameter oI' 1 - 5pQ microns and which ivrther includes a carrier or other excipieni to enhance cielivcry or achieve slow release oFthe polysaccharide:.
Similar to the unformulated polysaccharide particles, the porosity and shape were not critical.
Particles that were porous or non-porous, spherical al' non-spherical, light or heavy were aSSOGlated Wlth SlgnIIICaIlt abs01'pt1011 pl'OtlleS. Ill Olle eIl7bOdllllellt the 101'171LlIateCl particles are those having the properties described in US Patent Nos.
5,855,913 and 5,985,309. These formulated dry particles are aerodynamically light and have a mean geometric diameter o~ 5-30 microns, a tap density of less than O.~I g/enl~ and an aerodynamic diameter of 1-5 microns. In other embodiments the formulated dry particles are those having different properties than those described in US
Patent Nos.
5,855,913 and 5,985,309. For instance, it is possible that the formulated particles of the invention have a mean geometric diameter of 1-5 or 30-500 microns, a tap density of greater than 0.4 glcm~ and/or an aerodynamic diameter of 5-75 microns.
The formulated particles include at least one carrier or excipient. In one embodiment the excipient is a surfactant. A "surfactant" as used herein refers to a compound having a hydrophilic and lipophilic moiety, which promotes absorption of a drug by interacting with an interface between two innniscible phases.
SurFactants are useful in the dry particles for several, reasons, e.g., reduction of particle agglomeration, reduGtlOll O~ InaGPOphage phagOGytOSIS, etC. Whell COLlpled wlth ILIIlg SLII'faGtallt, a I11O1'e efficient absorption of polysaccharides can be achieved because surfactants, such as DPPC, will greatly facilitate diffusion of polysaccharides, such as heparin across the membrane surface of the alveoli by disguising the hydrophilic, charged groups of the heparin polymer. Surfactants are well known in the art and include but are not limited to phosphoglycerides, e.g., phosphatidylcholines, L-alpha-phosphatidylGholine dipalmitayl (DPPC) and diphosphatidyl glycerol (DPPG); hexadecanol; fatty acids;
polyethylene glycol (PEG); polyaxyethylene-9-; auryl ether; palmitiG acid; oleic acid;
sorbitan trioleate (Span 85); glycocholate; surfactin; poloxomer; sorbitan fatty acid ester; sorbitan trioleate; tyloxapol; phospholipids. 'I"he surCactan t may be incorporated within the particle or it may be coated on the surface oFthe particle.
Controlled release of polysaccharide can also be achieved with appropriate exipient materials that are biacompatible and biodegradable. These polymeric materials which ef=fect slow release of the polysaccharide may be any suitable polymeric material for generating particles, including, but not limited to, nonbioerodable/non-biodegradable and bioerodable/biociegradable polymers. Such polymers have been described in ~,~r~at detail in the prior art. They include, but are not limited to: polyalides, polycarbonatcs, polyallcylenes, polyallcylene glyeols, polyall:ylene oxides, polyall:ylenc tcrcpihalates.
polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides.
polyvinylpyrrolidone, polyglycolides, polysiloxancs, polyurethanes and copolymers thereof, alkyl cellulose, hydraxyall<yl celluloses, cellulose ethers, cellulose esters, vitro celluloses, polymers of acrylic and methacrylie esters, methyl cellulose, ethyl cellulose, hydroxyprapyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, poly (methyl methacrylafe), poly(ethylmethacrylate), poly{butylmethacrylate), poly(isobutylmethacrylate), poly(hexllethacrylate), poly(isodecylmethacrylate), poly(lauryl lethacrylate), poly (phenyl methacrylate), poly{methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), polyethylene, polypropylene poly{ethylene glycol), polyethylene oxide), poly{ethylene terephthalate), polyvinyl alcohols), polyvinyl acetate, poly vinyl chloride polystyrene, polyvinylpryrrolidone, hyaluronic acid, and chondroitin sulfate.
>jxamples of preferred non-biodegradable polymers include ethylene vinyl acetate, poly(meth) acrylic acid, polyalides, copolymers and mixtures thereof.
Cxamples of preferred biodegradable polymers include synthetic polymers such as polymers of lactic acid and glycolic acid, polyanhydrides, poly{ortho)esters, polyurethanes, poly{butic acid), poly(valeric acid), poly(caprolactone), poly(hydroxybutyrate), poly(lactide-co-glycolide) and poly(lactide-co-caprolactone), and natural polymers such as alginate and other polysaccharides including dextran and cellulose, collagen, chemical derivatives thereof {substitutions, additions ol~ chemical ?5 groups, for example, alkyl, allcylene, hydraxylations, oxidations, and other modifications routinely lade by those skilled in the art), albumin and other hydrophilic proteins, zero and other prolamines and hydrophobic proteins, copolymers and mixtures thcreoi~. In general, these materials degrade either by enzymatic hydrolysis or exposure to waver in lalla0, by SLII'faCe 01' bLlllf erOS1011_ The lol'eg0111g Illatel'lalS may be used alone, aS 1711}'SICaI
InlXtLlreS {blelldS), 01' aS CD-polymers. The ITloSt pl'Ct~EI'I'CCl pOlymel'S
al'e pOlyeStEI'S.
polyanhydrides, polystyrenes and blends lhcreof~.
I11 SOlne 111Sta11CeS, the lllVent1017 ellCOInpaSSeS a GOnlblllat1011 Of f01'171Lllated alld LIIIfOr111Lllated pOlySdCCharIdeS. rFhe Colnblllatl011 111ay C011ta111 ally I'atlo OI' pl'OpOrt1011 OI' FO1'mLllated:Llllt0l'llllllated pI'epal'at1017. 10l' 111StallCe, the COlllblllatlOll 171 ay IIICILIdC; a 1'rltlo of 10:90, 20:80, 30:70, ~10:G0; 50:50; 60:10, 70:30, 80:20, or 90:10. When the ratio is 0:50, the aGtLlal anlOLlllt OF p0lySaCGha1'lde IIl the f'01'111L11atEd pOrtloll 0I' the G0171bI11atlOn may be less than the actual amount of polysaccharide in the unFOrmulated portion because the formulation includes excipients which account for some of the mass of the formulated particles. The relative amounts may also be calculated as a relative ratio of fOrmulated:ullformulafed particles. The relative ratios of formulated:unformulated particles include, but are not limited to, 10:90, 20:80, 30:70, X10:60, 50:5p.
60:0, 70:30, 80:20, and 90:10. When the relative ratio of the combination preparation is 50:50, the preparation includes an equivalent actual amount of polysaccharide in the preparation.
The type of polysaccharide in the two components of the combination preparation may be the same or different. Thus? the polysaccharide that is in the formulated preparation may be the salve type of polysaccharide that is in the unformulated preparation, i.e., both may contain I,MWH. Alternatively, the type of polysaccharide may be different. For example, the unf0rmulated polysaccharide preparation may be LMWH and the formulated polysaccharide preparation may be UFH.
The dry aerosol particles of the invention are administered by inhalation to pulmonary tissue. The term "pulmonary tissue" as used herein reFers to any tissue of the respiratory tract and includes both the upper and lower respiratory tract, except where otherwise indicated. The particles may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichl0roflu0romethane, dichlor0tetrafluoroethane, carbon di0hide Or other suitable gas. In the case of a pressurized aerosol, the dosage unit' may be determined by providing a valve to deliver a metered amount. Capsules and cartridges For use in an inhaler or insufllator may be formulated containing a powder mix of the polysaccharide and a suitable powder base such as lactose or starch, iFthe particle is a formulated particle. In addition t0 the formulated or unformulated particles administered, other materials such as 100°'~o DffC
or other surfactant particles can be mixed in the dry aerosol particles to Iaromote tl7e delivery and dispersion oFthe dry Formulated or unFormulatcd particles.
'I"here arc separate and distinct from the formulated or un formulated particles, but are optionally included to enhance same aspect of the delivery process.
The dry aerosol particles when administer are rapidly absorbed and can produce a rapid local or systemic therapeutic result. A local therapeutic efFect refers to a biologic effect that occurs to the lung tissue. For instance, when the poly saccharide is a heparin, it may be desirable to produce a local effect for the treatment of a respiratory disease. A
systemic effect refers to a biologic effect that occurs outside of the lung tissue, e.g., in the blood. It has been discovered that the peak activity of the delivered polysaccharide can be achieved within 3 hours and preferably within two hours. In some embodiments the peals activity can be achieved even mare quickly, e.g., within one half hour or even within ten minutes. The surprisingly fast absorption of heparin, in particular, after inhalation as a dry aerosolized particle is believed to be extremely valuable in management of clinical conditions where a fast convenient non-invasive administration is desired. Heparin particles, especially 100°~'o heparin (UFH and LMWH) particles, can be used in acute coronary syndrome such as unstable angina to prevent the development of MI or death. Presently, acute coronary syndrome is being Treated either with i.v. UF~I
or s.c. administered LMWHs. Inhaled heparin particles will allow a rapid anticoagulationlantithrombosis state in the blood which cannof be achieved with s.c.
administration of LMWHs. Both i.v. UFH and s.c. LMWHs are being used for this purpose. The rapid absorption of heparin after inhalation call be combined with subsequent s.c. administration of LMWHs to improve the efficiency of antithromboticlanticoagulation treatment. Alternatively, heparin particles formulated for longer biological half life can be used as an alternative for s.c.
administration of LMWHs. Similar regimens can also be adopted for use of heparin in cerebral vascular diseases such as stroke, which require immediate early intervention. These and other therapeufic uses are described in more detail above.
In one embodiment, the polysaccharide is delivered in an amount such that 5%
of the polysaccharide is delivered to the lower respiratory tract or the deep lung. Although not being bound by a mechanism, it is believed that the methods for pulmonary delivery of polysaccharides have been successFul because the methods result in efficient and rapid delivery to the lower respiratory tract or deep lung alveolar surface. Deep lung has the I'1c11eSt Caplllal'y IletWOrk IOLltld 111 all al'gall 111 the hL1111a11 body, alld the 1'('.5plt'atoI'y membrane separate capillary lumen From alvealar air space is very thin {__<G
lam) and extremely permissible. In addition, the liquid layer lining the alveolar surface is rich in lung surfactants. In other embodiments at least 10°~'0, 20°~'0, 30°~'°, ~0°~'°, 50%, or ~0°/~ is delivered to the lower respiratory tract or to the deep lung. Delivery to either or both of these tissues results in efficient absorption of the polysaccharide and high bioavailability.
The amount of polysaccharide delivered to the lower respiratory tract or deep lung can be determined using routine methods. For instance, in a test system, ravage of animal lungs at indicated time intervals after inhalation can be used to determine the amount of heparin delivered to the lower respiratory tract. This data can be correlated to that amount which would occur in humans or animals being treated.
Alter°natively, a label, such as a radioactive or fluorescent label can be attached to the polysaccharide and used to determine the distribution of inhaled polysaccharide. The amount of polysaccharide delivered to the lower respiratory tract or deep lung also can be determined as the amount of therapeutic effect resulting from the presence of the polysaccharide in the lower respiratory tract or deep lung or in the region where the biological activity is occurring, e.g., the blood, or the blood plasma concentration of the polysaccharide. The type of parameter used to assess the effectivity of the delivery will vary depending on a variety of factors including the type of subject, the type of equipment available, and the disorder being treated or prevented. The peals plasma ?0 concentration ofa polysaccharide can be determined by measuring the level of polysaccharide present in the blood over time and determining when the peals level of concentration is reached. The amount of a therapeutic effect or a peals plasma acfivity can be identified using routine assays. The type of these effects will depend on the therapeutic parameter being assessed. For instance, if the polysaccharide is administered in order to prevent coagulation the amount of inhibition of factor Xa activity can be assessed. It is known that a minimum therapeu tic level of heparin-like glycosaminoglycan For producing therapeutic anticoagulant eFFect is approximately 0_35 IU/ml anti-Factor Xa activity. HLGAGs are also useful for inhibiting enzymatic activity, Sllch aS human leLICOGyte elaStaSe. 111 general, the ICAO Of I-1LGAGS OIl hlllllall ICLIIvOC ftC
elastase ranges from 1 nginll to 50 microgranl/ml. Alternatively, the .~1;
values of I-1LGAGs ranges from 10 nm to 10 IIM. In other instances, when the polysaccharide is a pOlySaCChal'lde ISOlated frOlll phellIIILIS llllteLIS, the blOlOglCal aCtlvltv w111C11 Call 1)C
aSSESSed 111C1udeS bOfill Gell-Inedlated 11T1n1Llnlfiy alld hLlln01'al In1111Lllllty. ThLIS, tile 1CVG1 OFGelI-lnedlated 1m111Lllllty oI' alltlbOdy pl'OdLlCfil011 111ay be 111caSLll'ed IIl ol'dcl' tp Ghal'aGfiel'lle the thel'apeUtlG ef'TeCt OTpealC blolOgIGa1 aGfilVlty Of these C0117pOLlIIdS. ()tll('.1' assays are well known to those oFordinary skill in fine arfi for each oFthe dil~Fel'ent polysaccharides.
Thus, the invention relates to intrapulmonary administrafiion of polysaccharides.
A "polysaccharide" is a polymer composed of monosaccharides linked to one another.
In many polysaccharides the basic building block of the polysaccharide is acfiually a disaccharide unit, which can be repeating or non-repeating. Thus, a unit when used with respecfi to a polysaccharide refers to a basic building bloG1< o1' a polysaccharide and can include a monomeric building block (monosaccharide) or a dimeriG building block (disaccharide). Polysaccharides include buff are not limited to heparin-like glycasaminoglycans, chondroitian sulfate, hyaluronic acid and derivatives or analogs thereof, chitin in derivatives and analogs thereof, e.g., 6-0-sulfafied carbo~ymefihyl chitin, 7 5 immunogenic polysaccharides isolated Pram phellinus linteus, PI-88 (a mixture of highly sulfated oligosaccharide derived from the sulfafiion of phosphomannum which is purif7ed from the high molecular weighfi core produced by fermentation of the yeast /~ichic~
lzolstii) and its derivafiives and analogs, polysaccharide antigens for vaccines, and calcium spirulan (Ca-SP, isolated from blue-green algae, spirulina platensis) and derivatives and analogs thereof.
The mefihods taught herein are sometimes described with reference to heparin-like glycosaminoglycans (I~LGAGs) but the properties taught herein can be extended to other polysaccharides, and unless a claim specifies ofiherwise the claims encompass any polysaccharides having a therapeutic utility. As used herein the terms "HhGAG"
and ?5 "glycosaminoglycans" are used interchangeably to refer to a family of molecules having heparin like structures and properties. These molecules include but are slot limited to low molecular weigh fi heparin (LMWI-I), heparin, biotechnologically prepared heparin, chEmlGally 1110C11~ed heparln, SyllfihetlC h epar111, heparlll 1111111et1GS
alld hepal'lll SLllfatC:.
The fierm "biotechnological heparin" encompasses heparin fihat is prepared from natural sources of' polysaccharides which have bEen chemically modified and is described ill Razi et al., l3ioche. .I. 1995 ,ILII 15;309 (Pfi 2): ~1G5-7?. Chemically modif7ed heparin is described in Yates et al., Carbohydrate Res ( 1996) Nov ~0;?9~1_ 15-27, and is known to those of skill in the art. Synthetic heparin is well lenown to those of shill iv the art and is described in Petitou, M. et al., Bioorg Med Chem Lett. (1999) Apr 19;9(8):1 1G1-G and Vlodavsky et al., Int. J. Cancer, 1999, 83:~2~1-X131. I-Ieparan SulFate rcl~ers to a glycasaminoglycan containing a disaccharide repeat unit similar to heparin, but which has more N-acetyl groups and fewer N- and O-sulFate groups. I-Ieparin mimetics are monosaccharides (e.g., suci°alfate), oligosaccharides, or polysaccharides having at least one biological activity of heparin (i.e., anticoagulation, inhibition of cancer, treatment of lung disorders, etc.). Preferably these molecules are highly sulfated. Heparin mimetics may be naturally occurring, synthetic or chemically modified. (Barchi, ,1J., Curr. Pharm.
Des., ?000, Mar, G(~):485-501).
LMWH as used herein refers to a heparin preparation having a molecular weight of about 3,000 daltons to about 8,000 daltons.
Several LMWH preparations are commercially available, but, LMWHs can also be prepared from heparin, using e.g., HLGAG degrading enzymes. HLGAG degrading 1 S enzymes include but axe not limited to heparinase-I, heparinase- II , heparinase-III, D-glucuronidase and L-iduronidase. The three heparinases from Flcrvobcrcic~rium lze~ar~inzrr~~ are enzymatic tools that have been used for the generation of LMWI-I (5,p00-8,000 Da) and ultra-low molecular weight heparin (3,000 Da). I-Ieparinase I
cleaves highly sulfated regions of HLGAGs at 2-O sulfated uronic acids, whereas heparinase I I
has a broader substrate specificity and cleaves glycosidic linkages containing both 2-O
sulfated and nonsulfated uronic acids ( Ernst, S., Langer, R., Gooney, C. L. &
Sasiselcharan, R. (7 995) Cr~il Rev Bioclzem Mot Biol 30, 387-~~~). Heparinase III, as opposed to heparinase I, cleaves primarily undersulfated regions of I-TLGAGs, viz"
glycosidie linkages containing a nansulfated uronic acid (Ernst, S., Langer, R., Caancy, C. L. & Sasiselcharan, R. (1995) C'r°ii Rev Biochem ~llol Biol 30, 387-~l~l~), Commercially available LMWI-I include, but are not limited to, enoYaparin (brand name Loveno~; clexane by Rhone-Poulenc Rorer), dalteparin (Fragmin, Pharmacia and Upjohn), certoparin (Sandobarin, Novartis), ardeparin (Normillo, Wyeth L~c~dcrlc), nadroparin (P"raxiparine, Sanofi-Winfhrop), pharnaparin (hlu~um, Wassermann), reviparin (Clivarin, Knoll AG), and tinzaparin (Innohep. Leo Laboratories.
Logiparin.
Novo Nordisk).
_ ?? _ The compositions may be administered therapeutically to a subject. As used hel'e111, a SLlbleCt IS a Ver'tebr'ate SLICK aS a hL1111a11, nOl1-hL1111an pl'1111ate, COw, hOl'Se, plg sheep, goat, dog, cat, or rodent.
I-ILGAGs have many therapeutic utilities. Tlle I-ILGAG compositions o(~
the invention can be used For the treatment of any type of condition in which I-ILGAG
therapy has been identified as a useful therapy. Thus, the invention is useFul in a variety of ll7 VZIZ'O, ila vivo and ex vivo methods in which HLGAG therapies are useFul. For instance, it is known that HLGAG compositions are useFul for preventin g and treating coagulation, angiogenesis, thrombotic disorders, cardiovascular' disease, vascular conditions, atherosclerosis, respiratory disorders, circulatory shock and related disorders, Alzheimer"s disease, as well as inhibiting cancer cell growth and metastasis.
Each of these disorders is well-known in the art and is described, for instance, in H~lrri,s~ol~ ',s Prilmiples of Iliierlzal Medicine (McGraw Hill, Inc., New York), which is incorporated by reference. The use of HLGAG compositions in various therapeutic methods is described and summarized in 1-Iuang, J. and Shirnamura, A., Coagulation Disorders, 12, 1251-1281 (1998).
Thus, the HLGAG preparations are useful for treating or preventing disorders associated with coagulation. A "disease associated with coagulation" as used herein refers to a condition characterized by local inflammation resulting from an interruption in the blood supply to a tissue due to a blockage of the blood vessel responsible For supplying blood to the tissue such as is seen for myocardial or cerebral infarction.
Coagulation disorders include, but are not limited to, cardiovascular disease and vascular conditions such as cerebral ischemia.
The methods of the invention are useful for treating cardiovascular disease.
Cardiovascular diseases include, but are not limited to, acute myocardial infarction, unstable angina, and atrial fibrillation. Myocardial infarction is a disease state which accurs with an abrupt decrease in coronary blood flow that follows a thrambotic occlusion of a coronary artery previously narrowed by atherosclcrosis. Such injury may be produced or facilitated by Factors such as cigarette smoking, hypertension, and lipid accumulation. Acute angina is due to transient myocardial ischemia. This disorder is LISLlally aSSOClated Wlth a heaV111eSS, preSSLlre, StlLleezlllg, 51110theI'111g, OI' ChOklllg FeC;llllg _ 7 j _ below the sternum. Episodes are usually caused by exertion or emotion, but can occur at rest.
Atrial Fibrillation is a common form of arrhythmia generally arising as a result of emotional stress or following surgery, exercise, or acute alcoholic intoxication.
Persistent forms of atrial fibrillation generally occur' in patients with cardiovascular' disease. Atrial fibrillation is characterized by disorganized atrial activity without discrete P waves on the surface ECG.
The compounds oFthe invention can be used for the treatment of cardiovascular disorders alone or in combination with other therapeutic agents for reducing the risk of a cardiovascular disease or For treating the cardiovascular disease. Other therapeutic agents include, but are not limited to, anti-inflammatory agents, anti-thrombotic agents, anti-platelet agents, fibrinolytic agents, lipid reducing agents, direct thrombin inhibitors, and glycoprotein IIbIILIa receptor inhibitor's.
Anti-inflammatory agents include Alclofenac; Alclometasone Dipropionate;
Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium;
Amiprilose Hydrachloride; Analcinra; Anirolac ; Anitrazafen; Apazone;
Balsalazide Disodium; Bendazac; Benoxaprofen ; Benzydamine Hydrochloride; Bromelain s;
Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen;
Clobetasal Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate;
Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoxinletasone; Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate;
Diflumidone Sodium; Diflunisal ; Difluprednate; Diftalone; Dimethyl Sulfoxide;
Drocinonide; Endryson e; Enlimomab ; Enolicam Sodium ; Epirizole ; Ctodolac;
Etofenamate ; Felbinac; Fenamole; Fenbufen; Fenclofenac; T'enclorac; Fendosal;
Fenpipalone; rentiazac; Flazalone; Fluazacort; Flufenamic Acid; Flumizole;
Flunisolide Acetate; F1LII11xrn ; FlLlIllXln lVleglLlllllne ; FIuOCOrt111 BLltyl;
FluoC0lnethOlQlle Acetate;
Fluquazone; FlurbiproFen ; FluretoFen; Fluticasone Propionate; Furaprofcn;
furobufen;
I-Ialcinonide; Halobetasol Propionate; I-Ialopredone Acetate; Ibufcnac ;
Ibuprofen;
Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap; Indomethacin; Indamcthacin Sodium; Indoprofen ; Indoxole ; Intrazole; IsoFlupredone Acetate; Isoxepac;
Isoxicam;
KetoproFen; Lafemizole hydrochloride ; Lornoxicam ; I;oteprednol Etabonate;
IVIeG101'el1a111ate ~~.OdlLlln; IVIeCIOfeIlaI111G AC:Id; lVleClorlSOlle DlbLltyl'ate; NlelenallllC AC1C1 Mesalamine; Meseclazone; Methylprednisolone Suleptanate; Morniflumate;
Nabumetone; Naproxen ; Naproxen Sodium ; Naproxol ; Nimazone; Olsalazine Sodium;
Orgotein ; Olpanoxin; OXaprozin; Oxyphenbutazone; Paranyline I-Iydrochlot"ide;
Pen town Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pirfenidonc ;
Piroxicam;
PlrOX1Ga111 ~11111aI11atG; PlrOX1Gd111 OlaI11111e; PIrprOfen; PI-ednazate;
Prlfelone; frodollc Acid; Proquazone; Proxazole; Proxazole Citrate ; Rimexolone; Romazarit ;
Salcolex ;
Salnacedin; Salsalate ; Salycilates; Sanguinarium Chloride ; Seclazone ;
Sermetacin;
Sudoxicanl; Sulindac; Suprofen; Talmetacin; Talniflumate ; 1'alosalate ;
Tebufelone ;
Tenidap; Tenidap Sodium; Tenoxicam; Tesicam; Tesimide; Tetrydamine; TiopinaC;
Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide;
TI°iFlumidate; Zidometacin;
Glucocorticoids; ZomepiraG Sodium.
Lipid reducing agents include gemfibrozil, Gholystyramine, colestipol, niCOtiniG
acid, probu Gol lovastatin, Fluvastatin, simvastatin, atorvastatin, pravastatin, cirivastatin.
Glycoprotein IIbIIIIa receptor Inhibitors are both antibodies and non-antibodies, and include but are not limited to ReoPro (abcixamab), lamifiban, tirofiban.
Anti-thrombotic agents and anti-platelet agents are described in more detail below.
The HLGAG preparations are also useful for treating vascular Conditions.
Vascular conditions include, but are not limited to, disorders such as deep venous thrombosis, cerebral ischemia, including stroke, and pulmonary embolism. A
cerebl"al ischemic attack or cerebral ischemia is a form of ischemic condition in which the blood supply to the brain is blocked. This interruption in the blood supply to the brain may result from a variety of causes, including an intrinsic blockage or occlusion of the blood vessel itself, a remotely originated source of occlusion, decreased perfusion pressure or increased blood viscosity resulting in inadequate Cerebral blood Flow, or a ruptured blood vessel in the subarachnoid space or intraCerebral tissue.
'the methods of the invention are useful for treating cerebral ischemia.
Cerebral ischemia may result in either transient or pertllanent deficits and the seriousness of the neurological damage in a patient who has experienced cerebral ischemia depends on the intensity and duration of the ischemic event. A transient ischemic attack is one in which the blood Flow to the brain is interrupted only briefly and causes temporary neurological deficits, which often are clear in less than 2~1 hours. Symptoms of TIA
include nunlbne:ss or weakness of face or limbs, loss of the ability to speak clearly and/or to understand the speech of others, a loss of vision or dinnless of vision, and a feeling of dizziness.
Permanent cerebral ischemic attach, also called stroke, are caused by a longer lnterl'L1pt1011 Ill blood l7ow t0 the bl'alll reSUltlllg fl'Olll elthel' a thl'OnlbOEl11bO11S111. A
Stroke GaLISES a LOSS Of 11eL1rOIIS typically reSUltlllg 111 a IleLll'OIOgIG
dellClt that May improve but that does not entirely resolve. Thromboembolic stroke is due to the occlusion of an extracranial or intracranial blood vessel by a thrombus or embolus.
Because it is often difficult to discern whether a stroke is caused by a thrombosis or an embolism, the term "thromboembolism" is used to cover strokes caused by either of These mechanisms.
The rapid absorption of HLGAGs, such as UFII or LMWH, after inhalation as dry particles can be very valuable ill the treatment of venous thromboembolism.
Intravenous administration of UFI-I has been used widely for treatment of venous fhromboembolism in combination with oral Warfarin. Due to the improved efficacy and reduced risks, however, LMWI-Is have been increasingly used as all alternative to intravenous UFH in treatment of venous thromboembolism. It has been established that efficacy of heparin therapy depends on achieving critical therapeutic levels (0.35- 0.7 Ulml anti-factor Xa activity) within the first 2~ hours of treatment.
Intrapulmonary delivery of heparin particles to achieve rapid therapeutic levels of heparin in the early stage of thromboembolism, could also be combined with either s.c.
administration of LMWHs or formulated heparin particles for prolonged antithrombotic/an ticoagulant effect.
The methods of the invention in some embodiments are directed to the treatment of acute thrombaembolic stroke using HLGAGs. An acute stroke is a medical syndrome involving neurological injury resulting from an ischemic event, which is an interruption in the blood supply to the brain.
An Effective amount of a I-ILGAG preparation alone or in combination with another therapeutic for the treatment of stroke is that amount suf'ticient to reduce in rilo brain injury resulting from the strolcE. A reduction of brain injury is any prevention of 3p injury to the brain which otherwise would have occurred in a subject experiencing a thromboembolic stroke absent the treatment of the invention. Several physiological parameters may be used to assess rEduction of brain injury, including smaller infarct sirE, improved regional cerebral blood flow, and decreased intracranial pressure, For example, as compared to pretreatment patient parameters, untreated stroke patients or stroke patients treated with thrombolytic agents alone.
The pharmaceutical I-ILGAG preparation may be used alone or in combination with a therapeutic agent f'or treating a disease associated with coagulation.
Bxamples of therapeutics useFul in the treatment o~diseases associated with coagulation include anticoagulation agents, antiplatelet agents, and thrombolytic agents.
Anticoagulation agents prevent the coagulation o~ blood components and thus prevent clot formation. Anticoagulants include, but are not limited to, war farm, coumadin, dicumarol, phenprocoumon, acenocoumarol, ethyl biscoumacetate, and indandione derivatives.
Antiplatelet agents inhibit platelet aggregation and are often used to prevent thramboembolic Stroke in patients who have experienced a transient isehemic attack or stroke. Antiplatelet agents include, but are not limited to, aspirin, thienopyridine derivatives such as ticlopodine and clopidogrel, dipyridamole and sul~inpyrazone. as well as IRGD mimetics and also antithrombin agents such as, but not limifed to, hirudin.
Thrombolytie agents lyse clots which cause the thrombaembolic stroke.
Thrombolytic agents have been used in the treatment of acute venous thromboembolism and pulmonary emboli and axe well known in the art (e.g. see l-Iennekens et al, J~lj~r ~'oll 2Q C"at~diol; v. 25 (7 supp), p. 185-225 (1995); Holmes, et al, JAf~~ G'oll Carcliol; v.?5 (7 supply, p. lOS-17S(1995)). Thrombolytic agents include, but are not limited to, plasminogen, a~-antiplasmin, streptolcinase, antistreplase, tissue plasminogen activator (tPA), and urokinase. '°tPA" as used herein includes native tPA and recombinant tPA, as well as modified forms of tPA that retain the enzymatic or I'ibrinolytic activities of native tPA, The enzymatic activity of tPA can be measured by assessing the ability of the molecule to convert plasminogen to plasmin. The ~'ibrinolytic activity of tPA may be determined by any in uilro clot lysis activity known in the art, such as the purified clot lysis assay described by Carlson, et. al.,~lnrrl. Biorhem. 168, ~l?8-135 (1988) and its modified form described by Bennett, W. p'. Et al., 1991, Sz~pra, the entire contents ol~
which are hereby incorporated by reference.
Pulmonary embolism as used herein refers to a disorder associated with the entrapment of a blood clot in the lumen of' a pulmonary artery, causing severe respiratory _7'7_ dysfunction. Pulmonary emboli often originate in the veins of the lower extremities where clots form in the drop leg veins and then travel to lungs via the venous circulation.
Thus, pulmonary embolism oFten arises as a complication of deep venous thrombosis in the lower extremity veins. Symptoms of pulmonary embolism include acute onset of shol-tness of breath, chest pain (worse with breathing), and rapid hear t rate and respiratory rate. Some individuals may experience haemoptysis.
The products and methods of the invention are also useful for treating or preventing atherosclerosis. Heparin has bean shown to be beneficial in prevention of atherosclerosis in various experimental models. Duo to the fast and morn direct access to the endothelium of the vascular system, inhaled heparin is useful in prevention of atherosclerosis. Atherosclerosis is one form of al-teriosclerosis that is believed to be the cause of mast coronary artery disease, aortic aneurysm and atrial disease of the lower extremities, as well as contributing to cerebrovascular disease.
Due to its fast absorption and variable elimination rate, HLGAG particles with or without exipients can be used as an alternative for the intravenous heparin far surgical and dialysis procedures. For example, HLGAG particles can be inhaled prior to surgery by volunteer inhalation or passively inhaled via trachea tube during the anesthesia prior to or during the surgery. Surgical patients, especially those over the age of 40 years have an increased risk of developing deep venous thrombosis. Thus, the use of HLGAG
particles for preventing the development of thrombosis associated with surgical procedures is contemplated. In addition to general surgical procedures such as cardiac-pulmonary by-pass surgery, coronary revascularization surgery, orthopedic surgery.
prosthesis replacemen t surgery, and abdominal surgery, the methods are also useful in subjects undergoing a tissue or organ transplantation procedure.
In addition, pulmonary inhalation of dry aerosolized heparin is valuable in treatment of respiratory diseases such as asthma, allergy, emphysema, adult respiratory distress syndrome (ARDS), lung reperfusion injury, ischemia-reperfusion injury of the lung, kidney, heart, and gut, and lung tumor growth and metastasis. since heparin is known to have anti-inflammatory and anti-allergic properties. 1-leparin is also a well 3p established inhibitor of elastase and tumor gl°owth and metastasis.
We have shown that the dry aerosolized heparin particles are capable of inhibiting elastase induced lung IIl~Llry 111 all aCUte lllllg eI11p11y~0111a Illodel. ASthllla 1S a dlSOI'del' OL' the I'e~pll'atal'}' _ 7g _ system characterized by inflammation, narrowing oFthe airways and increased reactivity OFthe all'WayS t0 111halEd agelltS. Asthma l5 fl"eqLIElltly, although 110t eXG1L1S1VEly, associated with atopic or allergic symptoms. Asthma may also include Exercise induced asthma, bronehocanstr°ictive response to bronchastimulants, delayed-type hypersensitivity, auto immune Encephalomyelitis and related disorders.
Allergies are generally caused by Ig>; antibody generation against allergens. Emphysema is a distention of the air spaces distal to the terminal bronchiole with destruction of alveolar septa. Emphysema arises out of elastase induced lung injury. Heparin is capable of inhibiting this elastase induced injury. Adult respiratory distress syndromE
is a term which encompasses many acute defuse in~lfrative lung lesions of diverse ideologies Which are accompanied by severe atrial hypoxemia. One of the most frequent causes of ARDS is sepsis. Other types of inFlammatory diseases which are treatable with HLGAGs arE refractory ulcerative colitis, non-specific ulcerative colitis and interstitial cystitis.
In one Embodiment, the HLGAG preparations are used for inhibiting angiagenesis. An effective amount for inhibiting angiogenesis of the HIeGAG
preparation is administered to a subject in need of treatment thereoF.
Angiogenesis as used herein is the inappropriate formation of new blood vessels.
"Angiagenesis'" often occurs in tumors when Endothelial cells secrete a group of growth factor°s that are mitagenic far endothelium causing the elongation and proliferation of Endothelial cells which results in a generafian of new blood vessels. Several of the angiagenic mitogens are heparin binding peptides which are related to Endothelial cell growth Factors. The inhibition of angiogenesis can cause tumor regression in animal models, suggesting a use as a therapeutic anticancer agent. An effective amount for inhibiting angiogenesis is an amount of HLGAG preparation which is suFFicient to diminish the number of blood vessels growing into a tumor. This amount can be assessed in an animal model of tumors and angiogenesis, many aCwhich are known in the art. Angiogenic disorders include, but are not limited to, neovascular disorders of the eye, osteoporosis, psoriasis.
and arthritis.
The I-ILGAG preparations are also useFul For inhibiting neovascularizatian associated With eye disease. In another embodiment, the I-ILGAG preparation is _ ?9 _ administered to treat psoriasis. Psoriasis is a connnon derlnatologic disease causes by chronic inflammation.
I-IIsGAG GDIltallllllg ColllpoSltIOnS, play alSO lllhlblt Ca11Ge1" Cell gl'Owtl7 alld InetaStaSlS. ThLIS the 111et17odS of the 111Ve11t1D11 al"e LISeFLII fol' tl'eatlllg alld~01' pl'evelltlng tLIIIIOr Cell prOllferatlon OI' metaStaSls In a SLlblect. Tlle tel'I11S
tcpl'eVellt,~ alld c~pl'eVe11t1l7faT~~
as used herein refer to inhibiting completely or partially the bialogical efFect, e.g., angiogenesis or proliferation or metastasis of a cancer or tumor cell, as well as inhibiting any increase in the biological effect, e.g., angiogenesis or proliferation Dr metastasis oI~ a cancer Dr tumor cell.
The cancer may be a malignant or non-malignant cancer. Cancers Dr tumors include but are not limited to biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endametrial cancer; esophageal cancer;
gastric cancer; intraepithelial neoplasms; lymphomas; liver cancel°; lung cancer (e.g. small cell and non-small cell); melanoma; neuroblastomas; oral cancer; ovarian cancer;
pancreatic cancer; prostate cancer; rectal cancer; sarcomas; skin cancer; testicular cancer; thyroid cancer; and renal cancer, as well as other carcinomas and sarcomas.
A subject in need of treatment may be a subject who has a high probability of developing cancer. These subjects include, for instance, subjects having a genetic abnormality, the presence of which has been demonstrated to have a correlative relation to a higher likelihood of developing a cancer and subjects exposed to cancer-causing agents such as tobacco, asbestos, or other chemical toxins, Dr a subject who has previously been treated for cancer and is in apparent remission.
Cf~ective amounts of the polysaccharides are administered to subjects in need oI' such treatment. EFfective amounts are those amounts which will result in the desired ?S biological effect. The desired biological effect will depend on factors such as the type of polysaccharide being administered and the type of disease being prevented or treated.
T'or instance. when the polysaccharide is an HLGAG, the biological effect may be a reducfion ill cellular proliferatian al- metastasis, a reduction in inl7anlmation, an inhibition of elastase, prevention of respiratory disease, or prevention oI~
coagulation without causing other medically unacceptable side effects. Such amounts can be determined with no more than routine experimentation. It is believed that doses ranr=ing frDlll 1 11a110gra117~lCllogl'alIl t0 1 pd Illllllgl'alnSlkIlOg1'a171, depel7dlllg L117017 the IllodC OF
_3~_ administration, will be effective. The effective percentage of intact HLGAG
may be detel'111111ed Wlth I10 11101'e than roLltlne experllllelltatloll. Tlle abSOlLlte a1110u11t W111 depend upon a variety of factors (including whether the administl°ation is in conjunction with other methods of treatment, the number of doses and individual patient pal°ameters including age, physical condition, size and weight) and can be determined with routine experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgment. The mode of administration may be any medically acceptable mode including inhalation, oral, subcutaneous, intravenous, etc.
In some aspects of the invention the ef~~ective amount of a composition containing I~LGAG is that amount effective to prevent invasion of a tumor cell across a barrier. The invasion and metastasis of cancer is a complex process which involves changes in cell adhesion properties which allow a transformed cell to invade and migrate through the extracellular matrix (ECM) and acquire anchorage-independent growth properties. Liotta, L. A., et al., Cell 64:327-336 (1991). Some of these changes occur at focal adhesions, which are celllECM contact points containing membrane-associated, cytoskeletal, and intracellular signaling molecules. Metastatic disease occurs when the disseminated foci of tumor cells seed a tissue which supports their growth and propagation, and this secondary spread of tumor cells is responsible far the morbidity and mortality associated with the majority of cancers. Thus the term "metastasis" as used herein refers to the invasion and migration of tumor cells away from the primary tumor site.
The barrier for the tumor cells may be an artificial barrier in oitro or a natural barrier in IJino. hmih'o barriers include but are not limited to extracellular matrix coated membranes, such as Matrigel. Thus the HLGAG compositions can be tested for their ability to inhibit tumor cell invasion in a Matrigel invasion assay system as described in detail by Parish, C.R., et al., "A Basement-Membrane Permeability Assay which Correlates with the Metastatic Potential of Tumour Cells," Int. J. Cancer ( 1992) 52:37$-383. Matrigel is a reconstituted basement membrane containing type IV
collagen, laminin, heparin sulfate proteoglycans such as perlecan, which bind to and localize b1~'GF, vitronectin as well as transforming growth factor (TGh), urolcinase-tylae plaslnlnOgCl1 aCtlVat01' {LIPAI, tISSLIG plaSllllllOgell aCtlVatpl' (tPA), alld tl7e Sel'plll 1<110~~'11 as plasminogen activator inhibitor type 1 (PAI-1 ). Other in vitra and in vivo assays for metastasis have been described in the prior art, see, e.g., US Patent No.
x,935,850, issued on August I0, 1999, which is incorporated by reference. An i~~ uioo barrier refers to a cellular barrier present in the body ofa subject.
One advantage of the inhaled heparin is the convenience of administratian, which allow selF administration on an outpatient basis. This will enable a faster initiation of ti°eatment with heparin. Thus a subject may keep a device, such as an inhaler, for self administering the polysaccharide when necessary. This is particularly useful foi°
HLGAGs, which in some cases require rapid administration. The polysaccharides may also be administered by a health care professional, e.g. with the use of a tracheal tube.
Such methods are well known in the art.
In addition to HLGAGs, other polysaccharides have a diverse array of therapeufic utilities. Ghondroitin Sulfate has been used in a complex with cisplatin to reduce the nephrotoxity of cisplatin during chemotherapy. Zhang JS, Imai T, Otagiri M.
Cffecis of a cisplatin-chondroitin sulfate A complex in reducing the nephrotoxicity of cisplatin.
,xlrch Toxicol 2000 Aug,7d(6):300-7). Hyaluranic acid and derivatives thereof have been shown to be a pharmalogical class of slow acting drugs for the treatment of osteoarthritis.
Watterson JR, >Jsdaile JM, Viscosupplementation: Therapeutic Mechanisms and ~'linical Potential in Osteoarthritis of the Knee, JAnZ Acad Oj~tlzo~ Sz~rg 2000 Oct;8(5):277-?8~).
Ohitin, which is a non-sulfated polysaccharide, can be sulfated chemically to produce a modified polysaccharide, e.g., 6-0 sulfated carboxymethyl chitin which is capable of inhibiting lung metastasis of melanoma. Murata J, Sailci I, Malcabe T, Tsuta Y, Tolcura S, Azuma I, Inhibition of tumor-induced angiogenesis by sulfated chitin derivatives.
Camej~ Res 1991 Jan 1;5 I ( 1 ):22-6. Nishiyama Y, Yoshikawa T, Kurita K, Hoj o K, Kamada H, Tsutsumi Y, Mayumi T, Kawasaki K. Regioselective conjugation ofchitosan with a laminin-related peptide, Tyr-Ile-Gly-Ser-Arg, and evaluation of its inhibitory effect on experimental cancer metastasis. C.'lTem Phrcrf~~ W tll (Toy°p) 1999 Mar;~7(3):~151-3. Polysaccharide isolated From phellinus linteus are also useful for treating and preventing melanoma, especially when administered in combination with adriamycin. I Ian SI3, I~~:c OW. ,Icon 1'.l. 1 Ionf~ I~1~1~_ Yoo ll~, Ynnf~ hl I him 1 II~~I 'hhe inhibitory effect of polysaccharides isolated from Phellinus linteu s on tumor growth and metastasis. Imnnmopharmacology, 1999 l~eb;~ll(2):157-6d.j. Calcium spirulan, i~olatcd from a blue-green algea, spirulina platensis, is a sulfated polysaccharide that is mainly composed of rhamnose and has been demonstrated to inhibit tumor invasion and metastasis. Hayalcawa Y, 1-Iayashi T, Lee .IB, Ozawa 'h, Sal<uragawa N.
Activation of heparin cofactor II by calcium spirulan. .l Biol C'hei7? 2000 Apr 11;275{
15);1 1379-82 )_ Heparin mimetics such as oligosaccharides and pentasaccharides are useful far preventing coagulation and thrombosis. Other glycomimeties have been used for prevention a~ coagulation as well as treatment of inflammatian, cancer and other immunologic disorders. (Barchi, J.J., Curr. Pharm. Des., 2000, 6(4):185-501 ) Synthetically derived sulfated polysaccharides, such as laminarin are useful for inhibifing heparinase and thus for inhibiting in flammation, tumor progression, etc. (Mar chelfi, D.
et al., Cancer Res., 2000, 60:1767-70). PI-88 is a mixture of highly sulfated oligosaccharides derived from the sulfation o~f phosphomannum which is purif ed from a high molecular weight core praduced by ~fErmentation of the yeast picl?icr l7olslii. The main constituent is a pentamannose, however, small amounts of tetrasaccharide and minor amount of hexasaccharide are also present. PI-88 is currently undergoing clinical trials for its anticoagulant/antithrombotic properties. PI-88 is also a potent inhibitor of heparan sulfate binding and inhibits h eparinase enzymatic activity. (Parish, C.R., et al., Cancer Res., 1999, 59:3133-~1).
Other polysaccharides which are useful according to the invention are polysaccharide vaccine antigens. These antigens can be delivered alone or in combination with standard vaccine adjuvants for the purpose of stimulating an immune response. The polysaccharide antigen is a polysaccharide which is capable of eliciting an immune response against a microorganism in a host. Those include, but are not limited to, capsular polysaccharides, lipopolysaccharides and other subcapsular (surface) polysaccharides. Examples of capsular polysaccharides include those isolated from HCIL'i7701717111I,S li?flNC'i?2CrL', r~L'1,5',5'LI"lcr 177Li71i?~'I~ICIZS, Sl1"C'l7/OL'OL't'1CS 17I2C1Ci770i?lcl('.
Slrepln~o~mrs a~crlcrcticre, Sali7roi?~lla ly/7hi, Ea'~l7ei-iL'l2icr coli, and ~flcrpl?vlui~'coc~rts crrri"e?ta". Cxamples of lipopolysaccharides are those isolated from lVei~s°s"t~ricr rner7in~lilicli,s'.
Escl?ericl7ia coli, ~faln7oi?ellcr lyphi, and Pa'eudomoi?crs crer?igii?vsu.
hxamples of oth er 3Q _subcapsular polysaccharides are the common polysaccharide antigen (c-substance) of Group A, I3 and C 4Slre/~locoL°L'i and the common polysaccharide antigc~v (c-sLibstance) of ~Strel.~ioL°uL"Lms pi7Glri77oi7icrc. 'fhe immunology of polysaccharide vaccines has been reviewed by .Iennings et al, ''The Polysaccharides" (Editor; G. O. Aspinall), Volume 1, 291-X29 ( 1982). See also "Carbohydrate Chemistry,'' ed. by .Iohn b".
Itennedy, Clarendon Press, Oxford, 1988; "The Carbohydrates, Chemistry and Biochemistry." ed.
by W. Pigman and D. I-Iorton, Academic Press, Inc., 197p; and "Chitin, Chitosan, and Related Enzymes," ed. by .Iohn P. Zikalcis, Academic Press, Inc.. 1984.
In some aspects of the invention also encompasses kits. The kits o1' the invention include an inhalation apparatus, polysaccharide dry aerosol particle formulation and a detection system. An inhalation apparatus, as used herein, is any device for administering a dry aerosol. This type of equipment is well known in the art and has been described in detail, such as that description found in Remington: The Science and Practice of Pharmacy, 19i~' Edition, 1995, Mac Publishing Company, Eastan, Pennsylvania, pages 1676-1692. Many LLS. patents also describe inhalation devices, such as U.S. Paten tNo. 6,116,237.
A detection system is particularly useful for the administration of polysaccharides I 5 which are dependent upon a therapeutic level in fine blood. Detection systems can be invasive or non-invasive. An example of an invasive detection system is one which involves the removal of a blood sample and can further involve an assay such as an enzymatic assay or a binding assay to detect levels of the polysaccharide in the blood. A
non-invasive type of detection system is ane which can detect the levels of the 2p polysaccharide in the blood without having to break the skin barrier. These types of non-invasive systems include, for instance, a monitor which can be placed on the surface of the skin, e.g., in the form of a ring or patch, and which can detect the level of circulating polysaccharide. One method for detection may be based on the presence of fluorescence in the polysaccharide which is administered. Thus, i f a fluorescently labeled heparin is 25 administered and the detectian system is non-invasive, it can be a system which detects fluorescence. This is particularly useFul in the situation when the patient is self-administering heparin and needs to know the blood concentration or an estimate thereoF
in order to avoid side eFFects or to determine when another dose is required.
The polysaccharides may be administered alone ar in combination with other 3p polysaccharides or other therapeutic agents, delivered by conventional therapeutic means. In general, when administered For therapeutic purposes, the other therapeutic agents may be applied in pharmaceutically acceptable solutions. Such preparations may _3q._ routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.
The therapeutic agents may be administered per se (neat) or in the Corn? of a S pharmaceutically acceptable salt or in a pharnaceutically acceptable carrier. When used 111 medlClne tl7e Salts ShoLlld be phal'117aceLltIGally aGGeptable, bLlt 17017-phal'nlaceLltIGally acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof and are not excluded from the scope of the invention. Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared 1i'om the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, malefic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, Formic, n7alonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.
Suitable buffering agents include: acetic acid and a salt (1-
2°I° WlV); citric acid and a salt (1-3% W!V); boric acid and a salt (0.5-2.5°~'o WIV); and phosphoric acid and a salt (0.8-2°f° WlV). Suitable preservatives include benzallconium chloride (0.003-0.03°~0 WlV); chlorobutanol (0.3-0.9°,~° WlV); parabens (0.01-0.?5°,~o WlV) and thin7erosal (0.004-0.02°r'° WlV).
The term "pharmaceutically-acceptable carrier" as used herein, and described more fully below, means one or more compatible solid or liquid filller, dilu tams or encapsulating substances which are suitable for administration to a human or other animal. The term "carrier" denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The ?5 components of the pharmaceutical compositions also are capable of being commingled with the therapeutic agents, and With each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical eftlciency.
Compositions suitable for parenteral administration canveniently comprise a sterile aqueous preparation of the therapeutic agent, which can be isotonic with the blood of the recipient. Amang the acceptable vehicles and solvents that may be employed arc Watel', 1Z117ge1''S SOILItIOn, alld 1SC?t0171G Sod1L1117 Chlol'lde SolLltlOll.
1t7 addltloll, Stet'11C:, 1'IxCd oils are conventionally employed as a solvent or suspending mediun7. 1~or this purpose
The term "pharmaceutically-acceptable carrier" as used herein, and described more fully below, means one or more compatible solid or liquid filller, dilu tams or encapsulating substances which are suitable for administration to a human or other animal. The term "carrier" denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The ?5 components of the pharmaceutical compositions also are capable of being commingled with the therapeutic agents, and With each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical eftlciency.
Compositions suitable for parenteral administration canveniently comprise a sterile aqueous preparation of the therapeutic agent, which can be isotonic with the blood of the recipient. Amang the acceptable vehicles and solvents that may be employed arc Watel', 1Z117ge1''S SOILItIOn, alld 1SC?t0171G Sod1L1117 Chlol'lde SolLltlOll.
1t7 addltloll, Stet'11C:, 1'IxCd oils are conventionally employed as a solvent or suspending mediun7. 1~or this purpose
- 3~ -any bland flXed oll Illay be eI11p10yed 111C1Lldlllg SyllthetlG 1110110- Or dlglyCel'Ides. 111 addition, fatty acids such as oleic acid Cnd use in the preparation of injectablcs. Carrier t0rn1L11at1011S Sllltable f01' SLIbCLItaIle0LlS, IlltranlLlSCLlla1', 111t1'apel'1t011ea1, llltl'aVCIloLIS, C;tC.
administrations may be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Carton, PA.
A varicty of adn linistl'ation routes are available for the other therapeutic agents.
Preferred routes of administration include, but are not limited to, oral, parenteral, intramuscular, intranasal, intratracheal, inhalation, ocular, vaginal and rectal.
For oral administration, the therapeutic agents can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well-known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the I S mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugar°s, including lactose, sucrose, mannitol, or sorbit0l; cellulose preparations such as, for example, maize starch, wheat starch, rice sfarch, potato starch, gelatin, glue tragacanth, methyl cellulose, hydroxypr0pylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVPj. If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. ppti0nally, the oral formulations may also be formulated in saline or buffers for neutralizing internal acid conditions or may be administered without any carriers.
Far buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
The therapeutic agents, when it is desirable to deliver them systemically, play be formulated for parenteral administration by injection, e.g., by bolus injection or COI1t111LlOLIS lnfuS1011. ~OT'IllLilatlOnS for ln~ect10I1 may be pl'esented Ill Lllllt dOSage 1'01'111, e.g., in ampoules or in multi-dose containers, with an added preservative. The G0111poS1t1011S Illay take SLICII t0I'I11S aS SLlSpenS1011s, SOILItlOlls OI' eI11L11S10I1S 111 olly 01' aqLle0LlS VChlcleS, and 111 ay COlltalll 1'ol'mLllatOry agents SLICK aS
SLiSpellCllllg, Stablllllllg and/or dispersing agents.
The therapeutic agents may also be formulated in rectal or vaginal compositions such as suppositories o1° retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glyccrides.
In addition to the formulations described previously, the therapeutic agents play also be formulated as a depot preparation. Such long-acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
The therapeutic agents also may comprise suitable solid or gel phase carriers or 1.0 eXGlpleIltS. ~XanlpleS ofSLlGh Garrler5 oY eXC1p1e11tS 111G1LIde, bLlt art IlOt llllllted t0, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
Suitable Liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleatGd, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be sarafched into the skin. 'the pharmaceutical compositions also include granules, powders, tablets, coated tablets, micro) capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose pl°eparation excipients and additives andlor auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The therapeutic agents are suitable for use in a variety of dru g delivery systems. llor a brief review of methods for drug delivery, see Langer, ~,S'c~iencv 2~19:1527-1533, (1990), which is incorporated herein by reference.
Other delivery systems Gan include time-release, delayed release or sustained release delivery systems. Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer based systems such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactonc;
nonpolymer systems that are lipids includin g sterols such as cholesterol, cholesterol esters and Fatty acids or neutral fats such as mono-, di and triglycerides; hydrogel release systems;
silastic systems; peptide based systems; wax coatings, compressed tablets using conventional binders and excipients, partially fused implants and the like.
Specific examples include, but are not limited to: (a) erosional systems in which the polysaccharide is contained in a Corm within a matrix, Fouled in U.S. Patent Nos,
administrations may be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Carton, PA.
A varicty of adn linistl'ation routes are available for the other therapeutic agents.
Preferred routes of administration include, but are not limited to, oral, parenteral, intramuscular, intranasal, intratracheal, inhalation, ocular, vaginal and rectal.
For oral administration, the therapeutic agents can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well-known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the I S mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugar°s, including lactose, sucrose, mannitol, or sorbit0l; cellulose preparations such as, for example, maize starch, wheat starch, rice sfarch, potato starch, gelatin, glue tragacanth, methyl cellulose, hydroxypr0pylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVPj. If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. ppti0nally, the oral formulations may also be formulated in saline or buffers for neutralizing internal acid conditions or may be administered without any carriers.
Far buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
The therapeutic agents, when it is desirable to deliver them systemically, play be formulated for parenteral administration by injection, e.g., by bolus injection or COI1t111LlOLIS lnfuS1011. ~OT'IllLilatlOnS for ln~ect10I1 may be pl'esented Ill Lllllt dOSage 1'01'111, e.g., in ampoules or in multi-dose containers, with an added preservative. The G0111poS1t1011S Illay take SLICII t0I'I11S aS SLlSpenS1011s, SOILItlOlls OI' eI11L11S10I1S 111 olly 01' aqLle0LlS VChlcleS, and 111 ay COlltalll 1'ol'mLllatOry agents SLICK aS
SLiSpellCllllg, Stablllllllg and/or dispersing agents.
The therapeutic agents may also be formulated in rectal or vaginal compositions such as suppositories o1° retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glyccrides.
In addition to the formulations described previously, the therapeutic agents play also be formulated as a depot preparation. Such long-acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
The therapeutic agents also may comprise suitable solid or gel phase carriers or 1.0 eXGlpleIltS. ~XanlpleS ofSLlGh Garrler5 oY eXC1p1e11tS 111G1LIde, bLlt art IlOt llllllted t0, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
Suitable Liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleatGd, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be sarafched into the skin. 'the pharmaceutical compositions also include granules, powders, tablets, coated tablets, micro) capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose pl°eparation excipients and additives andlor auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The therapeutic agents are suitable for use in a variety of dru g delivery systems. llor a brief review of methods for drug delivery, see Langer, ~,S'c~iencv 2~19:1527-1533, (1990), which is incorporated herein by reference.
Other delivery systems Gan include time-release, delayed release or sustained release delivery systems. Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer based systems such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactonc;
nonpolymer systems that are lipids includin g sterols such as cholesterol, cholesterol esters and Fatty acids or neutral fats such as mono-, di and triglycerides; hydrogel release systems;
silastic systems; peptide based systems; wax coatings, compressed tablets using conventional binders and excipients, partially fused implants and the like.
Specific examples include, but are not limited to: (a) erosional systems in which the polysaccharide is contained in a Corm within a matrix, Fouled in U.S. Patent Nos,
4,452,775 (Kent); ~1,~67,O1~I (Nestor et al.); and 4,7~I8,034 and 5,239,660 (Leonard) and (b) difFusional systems in which an active component permeates at a controlled rate through a polymer, found in L1.S. PatentNos. 3,832,253 (I-Iiguchi et al.) and 3,854,80 (ZafFaroni). In addition, a pump-based hardware delivery system can be used, some oI~
which are adapted for implantation.
When administered to a pafient undergoing cancer treatment, the polysaccharides may be administered in cocktails containing other anti-cancer agents. The polysaccharide compositions may also be administered in cocktails containing agents that treat the side-effects of radiation therapy, such as anti-emetics, radiation protectants, etc.
Anti-cancer drugs that can be co-administered with the compounds of the invention include, but are not limited to Acivicin; Aclarubicin; Acodazole hydrochloride; Acronine; Adriamycin; Adozelesin; Aldesleulcin; Altretamine;
Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastcozole;
Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin;
Batimastat;
Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate;
Bizelesin;
Bleomycin Sulfate; Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin;
Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin; Cisplatin;
Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine; Dacarbazine;
Dactinomycin; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin;
Dezaguanine;
Dezaguanine Mesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone Propionate;
Duazomycin; Edatrexate; Eflornithine Hydrochloride; Elsamitrucin; Enloplatin;
Enpromate; Epipropidin e; Epirubicin Hydrochloride; Erbulozole; Esorubicin I-Iydrochloride; Istramustine; Estramustine Phosphate Sodium; Etanidazole;
I>toposide;
Etoposide Phosphate; Etoprine; I~adrozole Hydrochloride; hazarabine;
I~enretinide;
hloxuridine; Fludarabine Phosphate; Fluorouracil; l; lurocitabine; Fosquidone;
Fostriecin SOdl11111; Gelllcltabllle; ~lenlCltab111e Hydrochloride; flydt'OxyLII'ea;
Iclal'LIbICIIl I-Iydrochloricfe; IFosfamide; Ilmofosine; In terferon Alfa-2a; Interferon Alfa-2b; InterFcron Alfa-nl ; Interferon Alfa-n3; Interferon Beta- I a; Interferon Gamma- I b;
Iproplatin;
Irinotecan Hydrochloride; Lanreotide Acetate; Letrozole; Leuprolidc Acetate;
I,iarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxaniron a I-Iydrochloride;
Masoprocol; Maytansine; Mechlorethamine I-Iydrochloride; Megestrol Acetafe;
Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate;
Methotrexate Sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin;
Mitocromin;
Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone I-Iydrochloride;
Mycophenolic Acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel;
Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfamide;
Pipobroman; Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane;
fortimer Sodium; Porfiromycin; Prednimustine; Procarbazine Hydrochloride; Puromycin;
Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safin got; Safin got Hydrochloride; Semustine; Simtrazene; Sparfosate Sodium; Sparsomycin;
Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Streptonigrin;
Streptozocin;
Sulofenur; Talisomycin; Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride;
Temoportin; Teniposide; Teroxirone; Testolactone; Thiamiprine; Thioguanine;
Thiotepa;
Tiazofurin; Tirapazamine; Topotecan Hydrochloride; Toremifene Citrate;
Trestolone Acetate; Triciribin a Phosphate; Trimefrexate; Trimetrexate Glucuronate;
Triptorelin;
Tubulozole Hydrochloride; L~racil Mustard; Uredepa; Vapreotide; Verteporfin;
Vinblastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine Sulfate;
Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate;
Vinrosidine Sulfate; Vin zolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; 7orubicin Hydrochloride.
The following description of experiments performed is exemplary and non-limiting to the scope of the claimed invention.
EDAM PLGS
W ample 1: Preparation and Pulmonary delivery of Unformulated Pol s~charide Particles Introduction 3b 'I o determine whether pulmonary inhalation ol=both U~hI-I and LMWI-I
generated pharmacol:inetics parameters are similar to that of s.c. injection far rats and 1'or rabhits, several parameters were investigated. To examine the ef'Cect oI~ multiple:
blood withdrawals and pulmonary inhalation on fihe hematology of circulation, blood samples were collected in the beginning and at fine end of the experiments. I~"or examination o1' the potential pafihological efFects oFinl7aled powder on the lung histology, the lungs o1_ rats and rabbits were harvested at th E end oFthe experiments. Anofiher parameter S investigated was whole-blood recalciftcation times (WBRT), which were used to indirectly determine the amount of unfractionafied heparins presen fi in the blood.
~latea~ials aoarlll~etho~ls:
.F'orzzzulallon of hepar~izzs. 100°~o heparin (UFH and ardeparin) particles were prepared by using a coffee grinder to a size of 1-500 11111. This powder was fihen subjected to size separation by sieving through the sieves of mesh sizes ?0.
53, 75, and 106 tlm. As a result, powder with sizes ranging from I -500, I -20, 20-53, 53-75, 75- I 06 and I-53 Ltm were obtained. Dry powders incorporating DPPC were prepared by combining ardeparin (93 IUlmg, anti-Xa) (Celcus, OH) with DPPC (Sigma Chemical Co., IVIO} using a standard single-sfiep spray-drying process and the particles were analyzed as described (Ben-Jebria, etc., Pharmaceutical Research, I 6: 555-561, 1999;
Wang, etc., Journal of aerosol medicine, 12: 27-36, 1999). Ifs lxilro and in ~~ioo activity assays showed no loss of activity of ardeparin due to the formulation processes.
~Ininzal ~~odela~:
Rats: For the rat model, male rats weighing 350-450 g (Charles River Laborafiories, Wilmington, MA) were housed for 5-7 days prior to experiments.
Rats were fed on rat chow and tap water ad libitum. After anesthetization with Ketamin a ($0 mglkg} and Xylazine (10 mglkg), right carotid artery was isolated and incubated with a Teflon catheter. A 3-way stopcock was connected to fine cafiheter for blood sample collection. The blood collection followed the procedures described by Bjornsson and Levy(Journal of pharmacology and experimental therapeutics, 210: 237-242, 1979.
Pulmonary inhalation was done with an insufflator (belong Distributors, h1.1) specially designed For powder inhalation in small animals. The device was weighed prior to and after the inhalation to determine the amount oFpowder inhaled. The inhalation was aCC0117pI1Shed by pLIShlllg the plllllge OF the Syrlllge COI7talnlllg 1 .~
1711 ail' two to tlll'CE
times. 0.? ml of blood was withdrawn 0, 15, 30 min., l , ?, 3, ~. 6, $, 10, 12, 16, ?() hours after treatment. Blood samples were collected in an adueous solution ol~
sodiun7 citrate (3.8°r'o; 1/9, vlv), centrifuged ?0 min at 2000 x g anct the rEsulting plasma was _~0_ ShOCIC froZell alld then SIOI'ed 111 a -80~1~ fl'eezel' Lllltll aSSay. Whole-blood samples 8'0111 UhI-I-treated fats were tested for whole-blood recalcilication tinges as described below.
Rabbits: hor the rabbit model, 2.5-3 lcg New Zealand male rabbits were used with ~-S rabbits per group. Rabbits were allowed to adapt for 7 days and free access to water and food. Ketamin E (40 mglkg) and Xylazine (5 mglkg) were usEd to anesthetize the rabbits. A-24 gauze Teflon catheter was inserted into the center auricular artery. The catheter was connecfed to a heparin cap filled with 0.9% saline solution.
'then a 15-cm tracheal tube was inserted into the trachea of the anesthetized rabbits via mouth.
Subsequently, the insufflator attached to a straight delivery tube of equal length to that of tracheal tube was in serted thraugh the tracheal tube. The penetration lEngth was controlled to be about 1 or ~ cm above the bifurcation point. LMWH was delivered at doses of 300 and 600 IUhcg, the amount of powder was derived by subtracting the weight of insufflator before and after delivery. 6-7 ml of air in a 10 ml syringe was pushed in with each puff. 0.2 ml of blood was withdrawn 0, 5, 10, 30 min, 1, 2, 3, ~I, 6, 8, 10, 12, 14, 18, 2~1 hours after the inhalation. The first 0.2 ml blood withdrawn was discarded with each withdraw. Blood samples were collected in an aqueous solution of sodium citrate (3.8°~'0; 119, v/v), centrifugEd at 2000 x g for 20 mill and the resulting plasma was shock frozen and stored in -80 °G freezer until assay.
Srrbcrttaneorts adr~7inistrcrlio>z acrd irzslillaliorz of the hepcrr'ir~s:
Ardeparin at doSeS of 300 and 600 IU/kg was also given by subcutaneous injection and by i.v. bolus injection via contralateral marginal ear vein. Blood samples were collected 0, 3, 5, 10, 15, 30 min, 1, 2, 3,4, G, 8, 12 holu-s after i.v. injection and processed as described above.
Ardeparin was also instilled through the trachea of the rabbits (n= 3) at 300 and 600 IU/Icg ill saline (1 ml/kg) via an intubated trachea tube. The plasma was collected at indicated times and analyzed for anti-Xa assay as described.
I'ulnZOrrcrry Icrvcr~~c sfrtcl~~: To determine the rate of disappearance of heparin l~ronl the lungs of rabbits after inhalation, lungs were harvested en bloc 0, 5, 30 min, 1, ?. ~, 6, 8 hours after either inhalation or instillation ofardeparin with two rabbits used for each tune point. ThE trachea was cannulated with an 18G animal feeding needle and lavaf~cd with five sequen tial aliquots of 6 ml normal saline, Lavage fluid was centrilvged at ?000 x g far 10 min. Th a supernatant was shock frozen immediately and transferred to -80 CSC
until assay. 'The resulting cell pellets were resuspended in salill~, homogcniled, and centrifuged. The supernatant was tested For anti-Xa activity. The lavaged lungs were homogenized in saline (I g in 5 ml saline) with a polytron device. The homogenate was centrifuged at 12,000 x g for 10 min. and the supernatant was tested for anti-Xa activity as described below.
~lclioitv assays: Anti-Xa assay was used to monitor plasma LMWI-1 level. Anti-Xa assay was performed by modification of the amidolytic method of Teien and Lie (Thrombosis res. 10: 399-410, 1977) with Coatest heparin test lcit by using S-2222 as the chromogenic substrate (Diapharma Group, II1G. OI-I). The detailed procedure was described elsewhere (Liu, etc., PNAS, 94: 1739-1744, 1997). The concentration of ardeparin in unknown samples was calculated by comparing to the calibration curve which was linear in the range of 0.1 - 0.7 IUlml. In selected groups, anti-IIa activity was also assayed with S-2238 as substrate according to manufacture's instruction (Diapharma Group, Ins. OH). The results were expressed in anti-Xa IU and then in lIg/ml.
CalcZrlation ofpharr~iacokir2etic par~ar~aelens: Experimental data, expressed in llglml, was utilized for non-linear regression curves based on one-conlpartmental model (Cornelli and Fareed, Semin thromb Hemost, 25: 57-61, 1999) by using SigmaPlot program with the method of extended least squares. From the kinetic curves.
the following parameters wet°e calculated: the area under curve (AUC
expressed in L~g.h.ml-I), the time corresponding to the peals of maximum concentration (t",,,,~
expressed in h);
the highest concentration (Cr"~,,~, expressed in llglml); absorption rate constant (Ka expressed in h-1); absorption hall=life (tl~~ expressed in h); elimination rate constant (Ke express in ti I); half life of apparent Elimination (tl~2e expressed in h), The AUC (0-t) was calculated using the trapezoidal rule (Rowland and Tozer, Clinical Pharmacolcinetics.
Concepts and Applicatians. 459-461, Lea and Febiger, 1989) and extrapolated to infinity (AUC) by dividing the value of the last measured concentration by the elimination rate constant.
Results:
1. Physical properties of heparin particles:
GeonletrlC dldIlletel' IVIaSS ACI'od~'I1a1111CI hol'C)5lty I (~llll) dellSlty Cllallletel' (~llll) g/cm~
1-500, UFI-I ( 1 OOo,~o) 0.47 0. 1 - 350 Nonporous I
_ 42 _ ' I-53, UFH (1 DOr'o) 0.4G 0.1 I- 35 ' Nonporous 20-53, UFI-I (100,~'0) 0.~4D.I 13- 35 Nonporovs 1- 3, UFI-I (GD~) DPPC (40r'o)D.3 0.1 0.5- I .G Nooporous I
1- 53, ardeparin (100J) i 0.39 I 1- 33 ' Nonhorous 0.1 I 1-20, ardeparin ( 100fo) ~ 0.42 i 1- I 3 i Nonporous 0.1 I 20- 53, ardeparin (100~0)0,43 D.1 13- 35 i Nonporous 53-75, ardeparin (100>~0) ' 0.45 ' 35- SD Nonporous D.1 75- 1 DG, arcieparin (100l)~ 0,45 ' S0- 71 Nonporous D. I
1- 500, ardeparin (100r~o) ~ 0.41 ~ 1- 320 ~ Nonporous _ - D.1 3-7, ardeparin (40%) DPPO ' 0. I ' 1.2- 2.7 ~ Nonporous (GOr'o) 5 0.05 2. Heparin particles consisting of 100°Jo UFII were generated with a geometric mean diameter of I-500 lun by grinding. This powder was then inhaled to the lung of the rats via a tube directly inseued into the trachea. At different time intervals, either the blood was withdrawn or the lungs were lavaged for analysis of heparin level.
Once inhaled to the lung, heparin rapidly appeared in the blood circulation causing hypocoagulability of the blood (Figures 1 a and b). In the mean time, heparin quickly disappeared from the lung as revealed in the lavage fluid (Figure 1b). More than 70°f° of the UFH was removed from the lavage fluid in less than I hour. The absorption profile of the dry heparin pauticles was distinct fram that of intratrachea instillation of liquid heparin into the rat lungs. The appearance of heparin in the blood after instillation of liquid heparin was very much delayed (tmax > 3 hours) and moderate (30-50°l° increase in whole blood clotting time at 10 times higher doses) compared to that of heparin particle inhalation (tmax < 1 hour, 100-20D °~'o increase in whole blood clotting time).
3. To study ifLMWI-Ls could be similarly delivered, we ground 100°,~'o ardeparin with a grinder and sieved the generated particles ( 1-SOD L~IIl) with sieves oCdifferent mesh sizes (20, 53, 75, and lOG l.un cut oF~. Ardeparin particles ranges from 1-500, 1-20, 20-53, S3-75, 75-lOG and 1-S3 ltm were obtained. These particles were administered by inhalation to rabbits with an insuftlator at 300 and G00 IU/lcg via an incubated trachea tube. The same doses were alsa injected subcutaneously and intravenously for reference.
'fo our surprise, particles of all sizes tested showed significant, fast absorption as indicated by anti-Xa activity assay of the plasma samples (Figure 2a- (~ and ~I°able 1 ).
The characteristics shared by these particles have 1 ) an extremely short absorption hall=
life (1-10 min), compared to 1-2 hours after s.c. administration (tma~ was reached at - d3 -about 30 minutes after inhalation); 2) comparable elimination rates to s.c.
administration (the elimination halF lives oFthe tested particles range From about 2-3 hours, which is similar to that of s.c. administration); 3) si~niCcant bioavailability (depending on the relative bioavailability to s.c. administration ranges from about 15-50%), and 4) close dose-response relationship (the higher dose is associated with higher peals concentration (G",,,~) (30-60% of C",a,~ obtained for s.c. administration). It is important to note that these characteristics of dry aerosolized heparin particles are distinct from that pulmonary delivery of liquid heparin (Figure 2g). Finally, the mean residence time (MR°h) value of 100°°~o heparin particles was about the half of that of s.c.
administration (Table 1 ). A
close dose-response relationship was also observed for 100°~'°
ardeparin particles as shown in t~ figure 2c, d, a and Table 1.
Table 1 Pharmacolcinetic parameters of ardepacin after inhalation as dry aerosol pai°ticles o~F
di;Fferent size distribution and composition in comparison to s.c.
administration oj' ardeparin.
1 _ ~ 40 100l Ardeprin Ardeparin II With 100% I
Ardeparin 6001U/kg Inhalation IU/kg 600fU/k~ I
Inhalation S.C. S.C
i inhalation6001U/k300 I ~ IIU/kg g 1-53~mI 1-20ymI 20-53ym1-500 ~1-53l 3-7 ym ym rm0 stn, I_ I ~ ~ I I
I ~ 0475 16.59 1 11.1627.35215.68 2.39 9.19 2.86 0.35 7 K I 0.368 i I 0.23 0.28 1 0,39061 D 1 0.35 1 1 ~ 0.30 37 0.29 1 t,rza ~ ~-- --I
(min)2.8 1 3.7 1.5 7,3 7.4 4.5 14 4 120 87.4 - ._ -til2e , (h~
I 2.332.95 2.49 1 1.771 1.88 1 1.98 7 1 .14 1 1.88 2.3 AUC _ _ i I
(ug*h/ml)~ 19.40, 28.181_ 33.46 1 I_12~89I 43.1670.09~41.03I
27.37 8J4 Gmax 5.60 7.00 7.22 1 13.162.98 3.28 11.2$ 1 1 I 8.98 7.091 tmax I D.250.35 0.17 1 0.511 1 84 3.14 2 th) 0.76 0.60 0. 3$1 ''MRT2.50u 2.76u 2,83 2.52~ ~ 1e641_ ,~ 4.41 (h)l 1~86u _ 5.291 4. To investigate the potential absorption mechanism ol~ dry heparin aerosol, we lavaged the lungs of rabbits after inhalation of 1-53 Etm ardeparin particles at indicated time intervals and the heparin level in lavage fluid was determined. In contrast to pulmonary delivery o1' liquid heparin, the heparin (ardeparin) level in lavage i7uid _~r~_ decreased precipitously aFter inhalation of dry ardeparin particles (figure 21~. More than 90°~'0 of ardeparin disappeared from the Iavage fluid in about I hour and base line levels were reached in about 2 hours. Coupled with the rapid appearance ol~ardeparin in the blood circulation, it is apparent that inhaled dry unformulated heparin was quickly absorbed from the lung.
Small particles: Since we observed a significant absorption of heparin as 10D%
heparin particles, it led its to investigate whether modified pharmacokinetics could be achieved by combining heparin with exipients. I~laturally occurring lung surFactant DPPC
(dipalmitoylphosphatidylcholine) was used as the exipient during the formulation process. Dry ardeparin and UFH particles incorporating DPPC at difFerent percentages were generated by a spray drying procedure. Briefly, heparin dissolved in water was mixed with DPPC in ethanol prior to spray drying with a Buchi 190 spray dryer.
The inlet temperature was controlled to be about 1 10 - 120 °C, and the outlet temperature was conhalled to be about ~0-50 °C. This procedure produced particles sizes of 1-3 ~m for UFH and 3-7 ~m for ardeparin. The particles were then tested in rabbits at the doses indicated earlier. The pharmacokinetic parameters generated with these small heparin particles (1-3 ~m for UFH and 3-7 pm for ardeparin) with DPPC as exipien t showed comparable pharmacolcinetics to that of 100°lo UFH and ardeparin particles with a slightly increased absorption and elimination half lives (Fig, la and 3a;
Table I).
However, prolonged biological half lives, MRT, as well as, bioavailability was also noted for formulated ardeparin. (Figure 3a, Table 1).
Discztssion It is a generally accepted that a geometric diameter or aerodynamic diameter of 1-'?5 5 ~tm is required for deep lung deposition of the dry aerosol particles.
Particles with aerodynamic diameters of $-10 ltm are more likely to deposit in the tracheobronchial region. It is also assumed that the major site of absorption of compounds administered to the respiratory tract is often assumed to be the alveoli since a greater absorption surlacc and lack oCmueociliary clearance is found in the deep lung. Dry aerosol particles have:
been used to deliver various proteins, peptides and some small molecules.
°fhe bioavailability varies substantially depending on the particle properties, method of delivery and experimental protocols. Whoa delivered directly to the lung system via a trachea tube, some small molecules have shown bioavailability of more than 80%
and a Fast absorption was also observed. However, up to data, there have been no studies which to the inventors knowledge demonstrate that polysaccharides such as heparin (UI'I-I or I~MWI-Is) can be eFticiently delivered as dry aerosol particles.
Pulmonary delivery oChepai°in as liquid aerosol or intratracheal instillation failed to generate efficient absorption and the pharmacolcinetics have been unpredictable.
In the present study, we demonstrated the efficient absorption of heparin as dry aerosol particles, with or without exipient. The absorption rate of the inhaled heparin particles is surprisingly fast because heparin molecules are highly negatively charged macromolecules which is not expected to diffuse through the negatively charged/coated air-blood barrier of alveoli. Once absorbed, heparin is eliminated from the body in a manner akin to that of s.c. administration of heparin. A good bioavailability was observed for the unformulated heparin particles, which was Cunther improved by incorporating DPPC as exipient. The incorporation of DPPC into the particles also 1 S slowed dawn the absorption and elimination processes as reflected with prolonged absorption half life, MRT, and delayed t",~,~ (1"able 1).
What is extraordinary about the unfarmulated heparin particle pharmacokineties is that a significant absorption is observed for particles with aerodynamic or geometric diameters larger than 1-S Lrm and of any tested mass density. The mass density of the particles tested ranged from 0.1 S to Q.47 glcm~. Particles of different shape showed good absorption (Figure 7; Table 1). Significant absorption was observed for a wide range of particle size from 1 to S00 ym in geometric diameter. I~ or instance, ardeparin particles of 20-53 Ltm geometric diameter (aerodynamic diameter 13-3S E~m) showed comparable absorption to that of small particles with a geometric diameter of 3-7 lam ~S (aerodynamic diameter of l .?-2.7 Lam). This property of heparin particles is unique and unexpected. The significant absorption of large heparin particles suggest that absorlation of heparin after inhalation is likely to oncur at multiple levels of respiratory tract and deep lung is likely to be partially responsible for the absorption of heparin.
'this notion is Further supported by the results li~onl tile lavage study which showed fast disappearance of inhaled heparin after inhalation of heparin particles.
Another important conclusion drawn From this study is that the pharmacol:inetic pro Files of heparin can be adjusted by incorporating exipient materials such as DPPC' to meet the requirement of a specific clinical application. Far example. DPPC was shown here to prolong the biological half lives oCinhaled heparin particles, which generated a more comparable pharmacolcinetic profile to that ol~ s.c. administration (hig.
3a; 'I'ablc 1 ).
This would allow inhalation of heparin particles as a promising alternative for s.c.
administration of LMWHs, which is being widely used in the prevention and treatment of thromboembolic diseases in the clinic.
E~atrn~le 2: Prrlnzor7ary ir2lzalalior~ of cly3 crerosolizecl, foornulcrtccl /~olo,s°crcclranicle,s nesZrlled ire ~fficier7l aJ~sor~liorz and the bioavailahilily of irihcrlc~d holJ~,~~crcchcrride,s~ clo,~~c~ly reser~able lhal of s,c. irzjectiorn li?'etltods Heparin Fot~r~zatlaliorrs: Preweighed UFH (178 USP/mg) or >~MWH (93 IUlzng, anti-Xa) (Celcus, OH) was dissolved in water, and DPPC was dissolved in ethanol.
Then, two solutions were mixed at various ratios prior to spray drying. Irz nilr~o and in vivo activity assays showed no loss of activify of either UFH or IsMWI-I due to fhe formulation processes.
Phcrrnaacokiraetic Par~arnel~r~s:
Ilc~r~aatolo,~y: Blood samples were collected in the beginning and at the end of the experiment and submitted for analysis. Blood features measured included white cell. red blood cell, and platelet counts, hematocrit, and hemoglobin and all were measured using standard procedures.
His~lology: The lungs of rats and rabbits were harvested at the end oFthe experiments. The lungs were fixed with formalin, paraffin embedded, sectioned, and stained with hematoxylin and eosin staining using standard procedures. The stained sections were examined with a light microscope for pathological changes.
~lolivity asscz~~s: Whole-blood recalcification limes (WBRT) were used to indirectly determine the amount of unfractionated heparins present in the blood as described (Ameer, etc, (1999) l3iolc~chr~ol l3ioc~rrg 63, G 18-2~). 0.2m1 blood samples were collected into tubes containing 3.8% sodium citrate ( 119, vlv}. Initially, 0.2 ml oI~ citrated blood was added to I-Iemoeln-on AC~I" test tubes containing glass particles (CardioMedical Products, Roclcaway, 1<I~J). Next, 0.2 ml oi' 0.02 M CaCI~ was added to the test tube and the I-Iemochron-801 clot-timer machine (CardioMedical products, Roclcaway, NJ) was immediately started. ~fhe test tube was gently mixed Uor 10 sec., and 7_ inserted into the test well of the Hemochron 801. The time required l~or a clot to Dorm was recorded. The unknown samples were compared to a standard curve, which was linear in the range oC0-4 USP units heparin/ml blood.
C'crlcarlalior7 of/~hcrr~mcrcokir~etic pcrr~crrnL~lL~r,~; This was performed as described S above.
~L~SIi~~S
Pulmonary inhalation ofdry aerosolised heparins in rats and rabbits resulted in efficient absorption and the bioavailability of inhaled heparin closely resembled that of s.c. injection as described above. There are noticeable distinctions in pharmacolcinetics between s.c. injection and pulmonary inhalation. Lndependent of doses administered, inhaled heparin generally resulted in faster absorption (Figures 2; table 1 ).
The absorption hal~ lives of LMWH for inhalation in rabbits were less than 30 min.
compared to more than one hour for s.c. injection (table I). As a result, the rabbit and rat data generated pharmacolcinetic characteristics lies somewhere between i.v.
and s.c.
injection featuring very short absorption phase followed by exponential elimination phase.
)Example 3: 1)ry aerosol inhalation of heparin is superior to liquid aerosol or instillation of heparin To compare to the pulmonary inhalation of liquid heparin, liquid heparin was instilled to rabbits. To determine the rate of disappearance of heparin from the lungs of rats and rabbits after inhalation, plasma was collected and anti-Xa assays of the plasma samples was performed. In addition, lungs of rats were also harvested, lavaged. and tested for anti-Xa activity as described below.
Methods Ir~stillcrliorz of L~I~YI~H ire Rate. >,MWH was instilled through the trachea of~ the rats and rabbits at 600 IUllcg in 0.3 ml (rats) or 1 ml (rabbits] of saline.
~l rats or 2 rabbits per group were used. The plasma was collected at indicated times and analysed Ior anti-Xa assay as described below Pulmorzcn~a lcrva~r~: To determine the rate of disappearance of heparin prom the 3p lungs of rat and rabbits after inhalation, lungs were harvested en bloc 0, ~, 30 min, l . '', d, 6, 8 hours aFter inhalation with one rabbit per time point and lavage was perlortned as described above. The trachea was cannulated with an 18G animal Feeding needle and _~8_ lavaged with five sequential aliquots of 3 ml (rats) G ml (rabbits) normal saline, Ijavagc fluid was centrifuged at 2000 x g for 10 min. The supernatant was shock (i-ozen immediately and transferred to -80 t~C until assay.
~lj~li-.~'a~ls~,scry. Anti-Xa assay was performed by madil~ication ofthe amidolytic method of Teien and Lie as described above.
Results Instilled heparin only generated mild increase in plasma anti-Xa activity (F
figure 2g). At 600 IUhcg, the absorption was relatively slow and lasted a much longer time compared to s.c. or dry aerosol inhalation. At 300 IU/lcg, the appearance of anti-Xa activity in plasma is minimal and very brief. It has been well documented that 8 to I 0 times higher doses of heparin is required to produce moderate anticoagulant state of the blood when instilled or inhaled as liquid heparin. Therefore, dry aerosol heparin inhalation drastically improved absorption of inhaled heparin.
hxamp~le 4: Inhaled dry aerosolized heparin is c~uickly absorbed into the blood circulation.
To investigate the mechanism of absorption for dry aerosolized heparin, the disappearance of hMWH from the lavage fluid from the rabbit lung was examined.
Results At G00 IUII<g, the amount of heparin found in the lavage fluid decreased precipitously in the first hour with an elimination half life of about G
minutes (Figure 2~I').
More than 90°,~° of the inhaled heparin has disappeared from the lavage Iluid after 1 hour of inhalation, while the lung tissue and alveolar macrophage examined consistently shawed very low level of heparin. Coupled with the rapid appearance of LMWI-I
in plasma (Figure 2f) and high bioavailability of inhaled heparin (about 20-GO°~o), the heparin particles deposited on the alveolar surface, may dissolve instantaneously resulting in the release of the heparin content and rapid absorption into the bland circulation, This is consistent with the hydrophilic nature ohthe heparin anti high permeability of the respiratory membrane. Because a majority of the inhaled heparin appeared in the blood, phagocytosis by alveolar macrophage may be insignificant. 'hhis is again in sharp contrast to the late of instilled heparin where a signil°icant amount of heparin was phagocytosized and sequestered. Morn than 50°~'0 of instilled heparin _q.9_ remained in the lavage fluid 1 ll2 hour after instillation, which is also observed in the rat instillation model. A significant amount of heparin remained in the lavage fluid even at 8 hour after instillation of the same dose as the inhalation in rabbits (figure 2g). In contrast, heparin level decreased sharply in both rabbit and rat studies (higure 1 b and 2 C).
The results suggests the absorption mechanism and deposition profile of the inhaled dry aerosolized heparin is distinct from that of inhaled liquid heparin.
Exarn~le 5; Inhaled he~arin~articles are effective in preventing human leucocyte elastase induced lung iniury.
>~Ieparin (both UFH and LMWHs) has been known to inhibit human leukocyte elastase and thereby is therapeutic in elastase induced emphysema. Since di°y aerosolized heparin particles have the advmfage of delivering the heparin directly to the site of elastase induced injury in the deep lung, the effect of inhaled dry heparin was tested in an acute emphysema model.
Methods L~nformulated ardeparin particles at 600 ILlllcg or formulated UFH at 12 mgh~g were administered by inhalation to the rats 1 hour prior to instillation of 250 yg of human sputum leukocyte elasfase via the trachea. The rats were kept head up at a 30 degree slope for 30 minutes. The incision was sutured and the rats were allowed to recover. 2~ hours later the rats were eud lanized; the lungs were harvested en bloc and lavaged. The level of hemoglobin in the lavage fluid was determined by a cholorimetric assay lcit from Sigma.
Results The inhalation of either heparin particle provided significant protection against the elastase induced acute injury as reflected by hemoglobin level in the lavage fluid (Fig. 6). Ardeparin particles appeared to be more effective, but a direct comparison with UFH was inappropriate due to the dosing difference. Gross examination of d le harvested lung also revealed consistent results with less hemorrhage on the lung surface found in ih a heparin treated group. furthermore, there was a trend that the distribution of hemorrhage was more limited to the upper lungs in the heparin treated rats.
ivrther a0 suggesting heparin particles exerted their protective effect by direct deposition to the site of~ injury (lower respiratory tract and deep lung).
We claim:
which are adapted for implantation.
When administered to a pafient undergoing cancer treatment, the polysaccharides may be administered in cocktails containing other anti-cancer agents. The polysaccharide compositions may also be administered in cocktails containing agents that treat the side-effects of radiation therapy, such as anti-emetics, radiation protectants, etc.
Anti-cancer drugs that can be co-administered with the compounds of the invention include, but are not limited to Acivicin; Aclarubicin; Acodazole hydrochloride; Acronine; Adriamycin; Adozelesin; Aldesleulcin; Altretamine;
Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastcozole;
Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin;
Batimastat;
Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate;
Bizelesin;
Bleomycin Sulfate; Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin;
Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin; Cisplatin;
Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine; Dacarbazine;
Dactinomycin; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin;
Dezaguanine;
Dezaguanine Mesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone Propionate;
Duazomycin; Edatrexate; Eflornithine Hydrochloride; Elsamitrucin; Enloplatin;
Enpromate; Epipropidin e; Epirubicin Hydrochloride; Erbulozole; Esorubicin I-Iydrochloride; Istramustine; Estramustine Phosphate Sodium; Etanidazole;
I>toposide;
Etoposide Phosphate; Etoprine; I~adrozole Hydrochloride; hazarabine;
I~enretinide;
hloxuridine; Fludarabine Phosphate; Fluorouracil; l; lurocitabine; Fosquidone;
Fostriecin SOdl11111; Gelllcltabllle; ~lenlCltab111e Hydrochloride; flydt'OxyLII'ea;
Iclal'LIbICIIl I-Iydrochloricfe; IFosfamide; Ilmofosine; In terferon Alfa-2a; Interferon Alfa-2b; InterFcron Alfa-nl ; Interferon Alfa-n3; Interferon Beta- I a; Interferon Gamma- I b;
Iproplatin;
Irinotecan Hydrochloride; Lanreotide Acetate; Letrozole; Leuprolidc Acetate;
I,iarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxaniron a I-Iydrochloride;
Masoprocol; Maytansine; Mechlorethamine I-Iydrochloride; Megestrol Acetafe;
Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate;
Methotrexate Sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin;
Mitocromin;
Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone I-Iydrochloride;
Mycophenolic Acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel;
Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfamide;
Pipobroman; Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane;
fortimer Sodium; Porfiromycin; Prednimustine; Procarbazine Hydrochloride; Puromycin;
Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safin got; Safin got Hydrochloride; Semustine; Simtrazene; Sparfosate Sodium; Sparsomycin;
Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Streptonigrin;
Streptozocin;
Sulofenur; Talisomycin; Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride;
Temoportin; Teniposide; Teroxirone; Testolactone; Thiamiprine; Thioguanine;
Thiotepa;
Tiazofurin; Tirapazamine; Topotecan Hydrochloride; Toremifene Citrate;
Trestolone Acetate; Triciribin a Phosphate; Trimefrexate; Trimetrexate Glucuronate;
Triptorelin;
Tubulozole Hydrochloride; L~racil Mustard; Uredepa; Vapreotide; Verteporfin;
Vinblastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine Sulfate;
Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate;
Vinrosidine Sulfate; Vin zolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; 7orubicin Hydrochloride.
The following description of experiments performed is exemplary and non-limiting to the scope of the claimed invention.
EDAM PLGS
W ample 1: Preparation and Pulmonary delivery of Unformulated Pol s~charide Particles Introduction 3b 'I o determine whether pulmonary inhalation ol=both U~hI-I and LMWI-I
generated pharmacol:inetics parameters are similar to that of s.c. injection far rats and 1'or rabhits, several parameters were investigated. To examine the ef'Cect oI~ multiple:
blood withdrawals and pulmonary inhalation on fihe hematology of circulation, blood samples were collected in the beginning and at fine end of the experiments. I~"or examination o1' the potential pafihological efFects oFinl7aled powder on the lung histology, the lungs o1_ rats and rabbits were harvested at th E end oFthe experiments. Anofiher parameter S investigated was whole-blood recalciftcation times (WBRT), which were used to indirectly determine the amount of unfractionafied heparins presen fi in the blood.
~latea~ials aoarlll~etho~ls:
.F'orzzzulallon of hepar~izzs. 100°~o heparin (UFH and ardeparin) particles were prepared by using a coffee grinder to a size of 1-500 11111. This powder was fihen subjected to size separation by sieving through the sieves of mesh sizes ?0.
53, 75, and 106 tlm. As a result, powder with sizes ranging from I -500, I -20, 20-53, 53-75, 75- I 06 and I-53 Ltm were obtained. Dry powders incorporating DPPC were prepared by combining ardeparin (93 IUlmg, anti-Xa) (Celcus, OH) with DPPC (Sigma Chemical Co., IVIO} using a standard single-sfiep spray-drying process and the particles were analyzed as described (Ben-Jebria, etc., Pharmaceutical Research, I 6: 555-561, 1999;
Wang, etc., Journal of aerosol medicine, 12: 27-36, 1999). Ifs lxilro and in ~~ioo activity assays showed no loss of activity of ardeparin due to the formulation processes.
~Ininzal ~~odela~:
Rats: For the rat model, male rats weighing 350-450 g (Charles River Laborafiories, Wilmington, MA) were housed for 5-7 days prior to experiments.
Rats were fed on rat chow and tap water ad libitum. After anesthetization with Ketamin a ($0 mglkg} and Xylazine (10 mglkg), right carotid artery was isolated and incubated with a Teflon catheter. A 3-way stopcock was connected to fine cafiheter for blood sample collection. The blood collection followed the procedures described by Bjornsson and Levy(Journal of pharmacology and experimental therapeutics, 210: 237-242, 1979.
Pulmonary inhalation was done with an insufflator (belong Distributors, h1.1) specially designed For powder inhalation in small animals. The device was weighed prior to and after the inhalation to determine the amount oFpowder inhaled. The inhalation was aCC0117pI1Shed by pLIShlllg the plllllge OF the Syrlllge COI7talnlllg 1 .~
1711 ail' two to tlll'CE
times. 0.? ml of blood was withdrawn 0, 15, 30 min., l , ?, 3, ~. 6, $, 10, 12, 16, ?() hours after treatment. Blood samples were collected in an adueous solution ol~
sodiun7 citrate (3.8°r'o; 1/9, vlv), centrifuged ?0 min at 2000 x g anct the rEsulting plasma was _~0_ ShOCIC froZell alld then SIOI'ed 111 a -80~1~ fl'eezel' Lllltll aSSay. Whole-blood samples 8'0111 UhI-I-treated fats were tested for whole-blood recalcilication tinges as described below.
Rabbits: hor the rabbit model, 2.5-3 lcg New Zealand male rabbits were used with ~-S rabbits per group. Rabbits were allowed to adapt for 7 days and free access to water and food. Ketamin E (40 mglkg) and Xylazine (5 mglkg) were usEd to anesthetize the rabbits. A-24 gauze Teflon catheter was inserted into the center auricular artery. The catheter was connecfed to a heparin cap filled with 0.9% saline solution.
'then a 15-cm tracheal tube was inserted into the trachea of the anesthetized rabbits via mouth.
Subsequently, the insufflator attached to a straight delivery tube of equal length to that of tracheal tube was in serted thraugh the tracheal tube. The penetration lEngth was controlled to be about 1 or ~ cm above the bifurcation point. LMWH was delivered at doses of 300 and 600 IUhcg, the amount of powder was derived by subtracting the weight of insufflator before and after delivery. 6-7 ml of air in a 10 ml syringe was pushed in with each puff. 0.2 ml of blood was withdrawn 0, 5, 10, 30 min, 1, 2, 3, ~I, 6, 8, 10, 12, 14, 18, 2~1 hours after the inhalation. The first 0.2 ml blood withdrawn was discarded with each withdraw. Blood samples were collected in an aqueous solution of sodium citrate (3.8°~'0; 119, v/v), centrifugEd at 2000 x g for 20 mill and the resulting plasma was shock frozen and stored in -80 °G freezer until assay.
Srrbcrttaneorts adr~7inistrcrlio>z acrd irzslillaliorz of the hepcrr'ir~s:
Ardeparin at doSeS of 300 and 600 IU/kg was also given by subcutaneous injection and by i.v. bolus injection via contralateral marginal ear vein. Blood samples were collected 0, 3, 5, 10, 15, 30 min, 1, 2, 3,4, G, 8, 12 holu-s after i.v. injection and processed as described above.
Ardeparin was also instilled through the trachea of the rabbits (n= 3) at 300 and 600 IU/Icg ill saline (1 ml/kg) via an intubated trachea tube. The plasma was collected at indicated times and analyzed for anti-Xa assay as described.
I'ulnZOrrcrry Icrvcr~~c sfrtcl~~: To determine the rate of disappearance of heparin l~ronl the lungs of rabbits after inhalation, lungs were harvested en bloc 0, 5, 30 min, 1, ?. ~, 6, 8 hours after either inhalation or instillation ofardeparin with two rabbits used for each tune point. ThE trachea was cannulated with an 18G animal feeding needle and lavaf~cd with five sequen tial aliquots of 6 ml normal saline, Lavage fluid was centrilvged at ?000 x g far 10 min. Th a supernatant was shock frozen immediately and transferred to -80 CSC
until assay. 'The resulting cell pellets were resuspended in salill~, homogcniled, and centrifuged. The supernatant was tested For anti-Xa activity. The lavaged lungs were homogenized in saline (I g in 5 ml saline) with a polytron device. The homogenate was centrifuged at 12,000 x g for 10 min. and the supernatant was tested for anti-Xa activity as described below.
~lclioitv assays: Anti-Xa assay was used to monitor plasma LMWI-1 level. Anti-Xa assay was performed by modification of the amidolytic method of Teien and Lie (Thrombosis res. 10: 399-410, 1977) with Coatest heparin test lcit by using S-2222 as the chromogenic substrate (Diapharma Group, II1G. OI-I). The detailed procedure was described elsewhere (Liu, etc., PNAS, 94: 1739-1744, 1997). The concentration of ardeparin in unknown samples was calculated by comparing to the calibration curve which was linear in the range of 0.1 - 0.7 IUlml. In selected groups, anti-IIa activity was also assayed with S-2238 as substrate according to manufacture's instruction (Diapharma Group, Ins. OH). The results were expressed in anti-Xa IU and then in lIg/ml.
CalcZrlation ofpharr~iacokir2etic par~ar~aelens: Experimental data, expressed in llglml, was utilized for non-linear regression curves based on one-conlpartmental model (Cornelli and Fareed, Semin thromb Hemost, 25: 57-61, 1999) by using SigmaPlot program with the method of extended least squares. From the kinetic curves.
the following parameters wet°e calculated: the area under curve (AUC
expressed in L~g.h.ml-I), the time corresponding to the peals of maximum concentration (t",,,,~
expressed in h);
the highest concentration (Cr"~,,~, expressed in llglml); absorption rate constant (Ka expressed in h-1); absorption hall=life (tl~~ expressed in h); elimination rate constant (Ke express in ti I); half life of apparent Elimination (tl~2e expressed in h), The AUC (0-t) was calculated using the trapezoidal rule (Rowland and Tozer, Clinical Pharmacolcinetics.
Concepts and Applicatians. 459-461, Lea and Febiger, 1989) and extrapolated to infinity (AUC) by dividing the value of the last measured concentration by the elimination rate constant.
Results:
1. Physical properties of heparin particles:
GeonletrlC dldIlletel' IVIaSS ACI'od~'I1a1111CI hol'C)5lty I (~llll) dellSlty Cllallletel' (~llll) g/cm~
1-500, UFI-I ( 1 OOo,~o) 0.47 0. 1 - 350 Nonporous I
_ 42 _ ' I-53, UFH (1 DOr'o) 0.4G 0.1 I- 35 ' Nonporous 20-53, UFI-I (100,~'0) 0.~4D.I 13- 35 Nonporovs 1- 3, UFI-I (GD~) DPPC (40r'o)D.3 0.1 0.5- I .G Nooporous I
1- 53, ardeparin (100J) i 0.39 I 1- 33 ' Nonhorous 0.1 I 1-20, ardeparin ( 100fo) ~ 0.42 i 1- I 3 i Nonporous 0.1 I 20- 53, ardeparin (100~0)0,43 D.1 13- 35 i Nonporous 53-75, ardeparin (100>~0) ' 0.45 ' 35- SD Nonporous D.1 75- 1 DG, arcieparin (100l)~ 0,45 ' S0- 71 Nonporous D. I
1- 500, ardeparin (100r~o) ~ 0.41 ~ 1- 320 ~ Nonporous _ - D.1 3-7, ardeparin (40%) DPPO ' 0. I ' 1.2- 2.7 ~ Nonporous (GOr'o) 5 0.05 2. Heparin particles consisting of 100°Jo UFII were generated with a geometric mean diameter of I-500 lun by grinding. This powder was then inhaled to the lung of the rats via a tube directly inseued into the trachea. At different time intervals, either the blood was withdrawn or the lungs were lavaged for analysis of heparin level.
Once inhaled to the lung, heparin rapidly appeared in the blood circulation causing hypocoagulability of the blood (Figures 1 a and b). In the mean time, heparin quickly disappeared from the lung as revealed in the lavage fluid (Figure 1b). More than 70°f° of the UFH was removed from the lavage fluid in less than I hour. The absorption profile of the dry heparin pauticles was distinct fram that of intratrachea instillation of liquid heparin into the rat lungs. The appearance of heparin in the blood after instillation of liquid heparin was very much delayed (tmax > 3 hours) and moderate (30-50°l° increase in whole blood clotting time at 10 times higher doses) compared to that of heparin particle inhalation (tmax < 1 hour, 100-20D °~'o increase in whole blood clotting time).
3. To study ifLMWI-Ls could be similarly delivered, we ground 100°,~'o ardeparin with a grinder and sieved the generated particles ( 1-SOD L~IIl) with sieves oCdifferent mesh sizes (20, 53, 75, and lOG l.un cut oF~. Ardeparin particles ranges from 1-500, 1-20, 20-53, S3-75, 75-lOG and 1-S3 ltm were obtained. These particles were administered by inhalation to rabbits with an insuftlator at 300 and G00 IU/lcg via an incubated trachea tube. The same doses were alsa injected subcutaneously and intravenously for reference.
'fo our surprise, particles of all sizes tested showed significant, fast absorption as indicated by anti-Xa activity assay of the plasma samples (Figure 2a- (~ and ~I°able 1 ).
The characteristics shared by these particles have 1 ) an extremely short absorption hall=
life (1-10 min), compared to 1-2 hours after s.c. administration (tma~ was reached at - d3 -about 30 minutes after inhalation); 2) comparable elimination rates to s.c.
administration (the elimination halF lives oFthe tested particles range From about 2-3 hours, which is similar to that of s.c. administration); 3) si~niCcant bioavailability (depending on the relative bioavailability to s.c. administration ranges from about 15-50%), and 4) close dose-response relationship (the higher dose is associated with higher peals concentration (G",,,~) (30-60% of C",a,~ obtained for s.c. administration). It is important to note that these characteristics of dry aerosolized heparin particles are distinct from that pulmonary delivery of liquid heparin (Figure 2g). Finally, the mean residence time (MR°h) value of 100°°~o heparin particles was about the half of that of s.c.
administration (Table 1 ). A
close dose-response relationship was also observed for 100°~'°
ardeparin particles as shown in t~ figure 2c, d, a and Table 1.
Table 1 Pharmacolcinetic parameters of ardepacin after inhalation as dry aerosol pai°ticles o~F
di;Fferent size distribution and composition in comparison to s.c.
administration oj' ardeparin.
1 _ ~ 40 100l Ardeprin Ardeparin II With 100% I
Ardeparin 6001U/kg Inhalation IU/kg 600fU/k~ I
Inhalation S.C. S.C
i inhalation6001U/k300 I ~ IIU/kg g 1-53~mI 1-20ymI 20-53ym1-500 ~1-53l 3-7 ym ym rm0 stn, I_ I ~ ~ I I
I ~ 0475 16.59 1 11.1627.35215.68 2.39 9.19 2.86 0.35 7 K I 0.368 i I 0.23 0.28 1 0,39061 D 1 0.35 1 1 ~ 0.30 37 0.29 1 t,rza ~ ~-- --I
(min)2.8 1 3.7 1.5 7,3 7.4 4.5 14 4 120 87.4 - ._ -til2e , (h~
I 2.332.95 2.49 1 1.771 1.88 1 1.98 7 1 .14 1 1.88 2.3 AUC _ _ i I
(ug*h/ml)~ 19.40, 28.181_ 33.46 1 I_12~89I 43.1670.09~41.03I
27.37 8J4 Gmax 5.60 7.00 7.22 1 13.162.98 3.28 11.2$ 1 1 I 8.98 7.091 tmax I D.250.35 0.17 1 0.511 1 84 3.14 2 th) 0.76 0.60 0. 3$1 ''MRT2.50u 2.76u 2,83 2.52~ ~ 1e641_ ,~ 4.41 (h)l 1~86u _ 5.291 4. To investigate the potential absorption mechanism ol~ dry heparin aerosol, we lavaged the lungs of rabbits after inhalation of 1-53 Etm ardeparin particles at indicated time intervals and the heparin level in lavage fluid was determined. In contrast to pulmonary delivery o1' liquid heparin, the heparin (ardeparin) level in lavage i7uid _~r~_ decreased precipitously aFter inhalation of dry ardeparin particles (figure 21~. More than 90°~'0 of ardeparin disappeared from the Iavage fluid in about I hour and base line levels were reached in about 2 hours. Coupled with the rapid appearance ol~ardeparin in the blood circulation, it is apparent that inhaled dry unformulated heparin was quickly absorbed from the lung.
Small particles: Since we observed a significant absorption of heparin as 10D%
heparin particles, it led its to investigate whether modified pharmacokinetics could be achieved by combining heparin with exipients. I~laturally occurring lung surFactant DPPC
(dipalmitoylphosphatidylcholine) was used as the exipient during the formulation process. Dry ardeparin and UFH particles incorporating DPPC at difFerent percentages were generated by a spray drying procedure. Briefly, heparin dissolved in water was mixed with DPPC in ethanol prior to spray drying with a Buchi 190 spray dryer.
The inlet temperature was controlled to be about 1 10 - 120 °C, and the outlet temperature was conhalled to be about ~0-50 °C. This procedure produced particles sizes of 1-3 ~m for UFH and 3-7 ~m for ardeparin. The particles were then tested in rabbits at the doses indicated earlier. The pharmacokinetic parameters generated with these small heparin particles (1-3 ~m for UFH and 3-7 pm for ardeparin) with DPPC as exipien t showed comparable pharmacolcinetics to that of 100°lo UFH and ardeparin particles with a slightly increased absorption and elimination half lives (Fig, la and 3a;
Table I).
However, prolonged biological half lives, MRT, as well as, bioavailability was also noted for formulated ardeparin. (Figure 3a, Table 1).
Discztssion It is a generally accepted that a geometric diameter or aerodynamic diameter of 1-'?5 5 ~tm is required for deep lung deposition of the dry aerosol particles.
Particles with aerodynamic diameters of $-10 ltm are more likely to deposit in the tracheobronchial region. It is also assumed that the major site of absorption of compounds administered to the respiratory tract is often assumed to be the alveoli since a greater absorption surlacc and lack oCmueociliary clearance is found in the deep lung. Dry aerosol particles have:
been used to deliver various proteins, peptides and some small molecules.
°fhe bioavailability varies substantially depending on the particle properties, method of delivery and experimental protocols. Whoa delivered directly to the lung system via a trachea tube, some small molecules have shown bioavailability of more than 80%
and a Fast absorption was also observed. However, up to data, there have been no studies which to the inventors knowledge demonstrate that polysaccharides such as heparin (UI'I-I or I~MWI-Is) can be eFticiently delivered as dry aerosol particles.
Pulmonary delivery oChepai°in as liquid aerosol or intratracheal instillation failed to generate efficient absorption and the pharmacolcinetics have been unpredictable.
In the present study, we demonstrated the efficient absorption of heparin as dry aerosol particles, with or without exipient. The absorption rate of the inhaled heparin particles is surprisingly fast because heparin molecules are highly negatively charged macromolecules which is not expected to diffuse through the negatively charged/coated air-blood barrier of alveoli. Once absorbed, heparin is eliminated from the body in a manner akin to that of s.c. administration of heparin. A good bioavailability was observed for the unformulated heparin particles, which was Cunther improved by incorporating DPPC as exipient. The incorporation of DPPC into the particles also 1 S slowed dawn the absorption and elimination processes as reflected with prolonged absorption half life, MRT, and delayed t",~,~ (1"able 1).
What is extraordinary about the unfarmulated heparin particle pharmacokineties is that a significant absorption is observed for particles with aerodynamic or geometric diameters larger than 1-S Lrm and of any tested mass density. The mass density of the particles tested ranged from 0.1 S to Q.47 glcm~. Particles of different shape showed good absorption (Figure 7; Table 1). Significant absorption was observed for a wide range of particle size from 1 to S00 ym in geometric diameter. I~ or instance, ardeparin particles of 20-53 Ltm geometric diameter (aerodynamic diameter 13-3S E~m) showed comparable absorption to that of small particles with a geometric diameter of 3-7 lam ~S (aerodynamic diameter of l .?-2.7 Lam). This property of heparin particles is unique and unexpected. The significant absorption of large heparin particles suggest that absorlation of heparin after inhalation is likely to oncur at multiple levels of respiratory tract and deep lung is likely to be partially responsible for the absorption of heparin.
'this notion is Further supported by the results li~onl tile lavage study which showed fast disappearance of inhaled heparin after inhalation of heparin particles.
Another important conclusion drawn From this study is that the pharmacol:inetic pro Files of heparin can be adjusted by incorporating exipient materials such as DPPC' to meet the requirement of a specific clinical application. Far example. DPPC was shown here to prolong the biological half lives oCinhaled heparin particles, which generated a more comparable pharmacolcinetic profile to that ol~ s.c. administration (hig.
3a; 'I'ablc 1 ).
This would allow inhalation of heparin particles as a promising alternative for s.c.
administration of LMWHs, which is being widely used in the prevention and treatment of thromboembolic diseases in the clinic.
E~atrn~le 2: Prrlnzor7ary ir2lzalalior~ of cly3 crerosolizecl, foornulcrtccl /~olo,s°crcclranicle,s nesZrlled ire ~fficier7l aJ~sor~liorz and the bioavailahilily of irihcrlc~d holJ~,~~crcchcrride,s~ clo,~~c~ly reser~able lhal of s,c. irzjectiorn li?'etltods Heparin Fot~r~zatlaliorrs: Preweighed UFH (178 USP/mg) or >~MWH (93 IUlzng, anti-Xa) (Celcus, OH) was dissolved in water, and DPPC was dissolved in ethanol.
Then, two solutions were mixed at various ratios prior to spray drying. Irz nilr~o and in vivo activity assays showed no loss of activify of either UFH or IsMWI-I due to fhe formulation processes.
Phcrrnaacokiraetic Par~arnel~r~s:
Ilc~r~aatolo,~y: Blood samples were collected in the beginning and at the end of the experiment and submitted for analysis. Blood features measured included white cell. red blood cell, and platelet counts, hematocrit, and hemoglobin and all were measured using standard procedures.
His~lology: The lungs of rats and rabbits were harvested at the end oFthe experiments. The lungs were fixed with formalin, paraffin embedded, sectioned, and stained with hematoxylin and eosin staining using standard procedures. The stained sections were examined with a light microscope for pathological changes.
~lolivity asscz~~s: Whole-blood recalcification limes (WBRT) were used to indirectly determine the amount of unfractionated heparins present in the blood as described (Ameer, etc, (1999) l3iolc~chr~ol l3ioc~rrg 63, G 18-2~). 0.2m1 blood samples were collected into tubes containing 3.8% sodium citrate ( 119, vlv}. Initially, 0.2 ml oI~ citrated blood was added to I-Iemoeln-on AC~I" test tubes containing glass particles (CardioMedical Products, Roclcaway, 1<I~J). Next, 0.2 ml oi' 0.02 M CaCI~ was added to the test tube and the I-Iemochron-801 clot-timer machine (CardioMedical products, Roclcaway, NJ) was immediately started. ~fhe test tube was gently mixed Uor 10 sec., and 7_ inserted into the test well of the Hemochron 801. The time required l~or a clot to Dorm was recorded. The unknown samples were compared to a standard curve, which was linear in the range oC0-4 USP units heparin/ml blood.
C'crlcarlalior7 of/~hcrr~mcrcokir~etic pcrr~crrnL~lL~r,~; This was performed as described S above.
~L~SIi~~S
Pulmonary inhalation ofdry aerosolised heparins in rats and rabbits resulted in efficient absorption and the bioavailability of inhaled heparin closely resembled that of s.c. injection as described above. There are noticeable distinctions in pharmacolcinetics between s.c. injection and pulmonary inhalation. Lndependent of doses administered, inhaled heparin generally resulted in faster absorption (Figures 2; table 1 ).
The absorption hal~ lives of LMWH for inhalation in rabbits were less than 30 min.
compared to more than one hour for s.c. injection (table I). As a result, the rabbit and rat data generated pharmacolcinetic characteristics lies somewhere between i.v.
and s.c.
injection featuring very short absorption phase followed by exponential elimination phase.
)Example 3: 1)ry aerosol inhalation of heparin is superior to liquid aerosol or instillation of heparin To compare to the pulmonary inhalation of liquid heparin, liquid heparin was instilled to rabbits. To determine the rate of disappearance of heparin from the lungs of rats and rabbits after inhalation, plasma was collected and anti-Xa assays of the plasma samples was performed. In addition, lungs of rats were also harvested, lavaged. and tested for anti-Xa activity as described below.
Methods Ir~stillcrliorz of L~I~YI~H ire Rate. >,MWH was instilled through the trachea of~ the rats and rabbits at 600 IUllcg in 0.3 ml (rats) or 1 ml (rabbits] of saline.
~l rats or 2 rabbits per group were used. The plasma was collected at indicated times and analysed Ior anti-Xa assay as described below Pulmorzcn~a lcrva~r~: To determine the rate of disappearance of heparin prom the 3p lungs of rat and rabbits after inhalation, lungs were harvested en bloc 0, ~, 30 min, l . '', d, 6, 8 hours aFter inhalation with one rabbit per time point and lavage was perlortned as described above. The trachea was cannulated with an 18G animal Feeding needle and _~8_ lavaged with five sequential aliquots of 3 ml (rats) G ml (rabbits) normal saline, Ijavagc fluid was centrifuged at 2000 x g for 10 min. The supernatant was shock (i-ozen immediately and transferred to -80 t~C until assay.
~lj~li-.~'a~ls~,scry. Anti-Xa assay was performed by madil~ication ofthe amidolytic method of Teien and Lie as described above.
Results Instilled heparin only generated mild increase in plasma anti-Xa activity (F
figure 2g). At 600 IUhcg, the absorption was relatively slow and lasted a much longer time compared to s.c. or dry aerosol inhalation. At 300 IU/lcg, the appearance of anti-Xa activity in plasma is minimal and very brief. It has been well documented that 8 to I 0 times higher doses of heparin is required to produce moderate anticoagulant state of the blood when instilled or inhaled as liquid heparin. Therefore, dry aerosol heparin inhalation drastically improved absorption of inhaled heparin.
hxamp~le 4: Inhaled dry aerosolized heparin is c~uickly absorbed into the blood circulation.
To investigate the mechanism of absorption for dry aerosolized heparin, the disappearance of hMWH from the lavage fluid from the rabbit lung was examined.
Results At G00 IUII<g, the amount of heparin found in the lavage fluid decreased precipitously in the first hour with an elimination half life of about G
minutes (Figure 2~I').
More than 90°,~° of the inhaled heparin has disappeared from the lavage Iluid after 1 hour of inhalation, while the lung tissue and alveolar macrophage examined consistently shawed very low level of heparin. Coupled with the rapid appearance of LMWI-I
in plasma (Figure 2f) and high bioavailability of inhaled heparin (about 20-GO°~o), the heparin particles deposited on the alveolar surface, may dissolve instantaneously resulting in the release of the heparin content and rapid absorption into the bland circulation, This is consistent with the hydrophilic nature ohthe heparin anti high permeability of the respiratory membrane. Because a majority of the inhaled heparin appeared in the blood, phagocytosis by alveolar macrophage may be insignificant. 'hhis is again in sharp contrast to the late of instilled heparin where a signil°icant amount of heparin was phagocytosized and sequestered. Morn than 50°~'0 of instilled heparin _q.9_ remained in the lavage fluid 1 ll2 hour after instillation, which is also observed in the rat instillation model. A significant amount of heparin remained in the lavage fluid even at 8 hour after instillation of the same dose as the inhalation in rabbits (figure 2g). In contrast, heparin level decreased sharply in both rabbit and rat studies (higure 1 b and 2 C).
The results suggests the absorption mechanism and deposition profile of the inhaled dry aerosolized heparin is distinct from that of inhaled liquid heparin.
Exarn~le 5; Inhaled he~arin~articles are effective in preventing human leucocyte elastase induced lung iniury.
>~Ieparin (both UFH and LMWHs) has been known to inhibit human leukocyte elastase and thereby is therapeutic in elastase induced emphysema. Since di°y aerosolized heparin particles have the advmfage of delivering the heparin directly to the site of elastase induced injury in the deep lung, the effect of inhaled dry heparin was tested in an acute emphysema model.
Methods L~nformulated ardeparin particles at 600 ILlllcg or formulated UFH at 12 mgh~g were administered by inhalation to the rats 1 hour prior to instillation of 250 yg of human sputum leukocyte elasfase via the trachea. The rats were kept head up at a 30 degree slope for 30 minutes. The incision was sutured and the rats were allowed to recover. 2~ hours later the rats were eud lanized; the lungs were harvested en bloc and lavaged. The level of hemoglobin in the lavage fluid was determined by a cholorimetric assay lcit from Sigma.
Results The inhalation of either heparin particle provided significant protection against the elastase induced acute injury as reflected by hemoglobin level in the lavage fluid (Fig. 6). Ardeparin particles appeared to be more effective, but a direct comparison with UFH was inappropriate due to the dosing difference. Gross examination of d le harvested lung also revealed consistent results with less hemorrhage on the lung surface found in ih a heparin treated group. furthermore, there was a trend that the distribution of hemorrhage was more limited to the upper lungs in the heparin treated rats.
ivrther a0 suggesting heparin particles exerted their protective effect by direct deposition to the site of~ injury (lower respiratory tract and deep lung).
We claim:
Claims (112)
1. A method for producing a therapeutic effect, comprising:
administering to a pulmonary tissue of a subject an unformulated dry polysaccharide particle in an effective amount for producing a therapeutic effect, wherein the unformulated dry polysaccharide particle has a mean geometric diameter of 1-500 microns.
administering to a pulmonary tissue of a subject an unformulated dry polysaccharide particle in an effective amount for producing a therapeutic effect, wherein the unformulated dry polysaccharide particle has a mean geometric diameter of 1-500 microns.
2. The method of claim 1, wherein the polysaccharide is a glycosaminoglycan.
3. The method of claim 2, wherein the glycosaminoglycan is a heparin.
4. The method of claim 2, wherein the glycosaminoglycan is a heparin sulfate.
5. The method of claim 2, wherein the glycosaminoglycan is a low molecular weight heparin.
6. The method of claim 3, wherein the heparin is a biotechnology derived heparin.
7. The method of claim 3, wherein the heparin is a chemically modified heparin.
8. The method of claim 2, wherein the glycosaminoglycan is a heparin analogue.
9. The method of claim 8, wherein the heparin analogue is selected from the group consisting of an oligosaccharide and an AT-III binding pentasaccharide.
10. The method of claim 2, wherein the glycosaminoglycan is an unfractionated heparin preparation.
11. The method of claim 1, wherein the unformulated dry polysaccharide particle has a mean geometric diameter of 1 -200 microns.
12. The method at claim 1, whererin the unformulated dry polysaccharide particle has a mean geometric diameter of 1-53 microns.
13. The method of claim 1, wherein the unformulated dry polysaccharide particle has a moan geometric diameter of 53-106 microns.
14. The method of claim 1, wherein the unformulated dry polysaccharide particle has a mean geometric diameter of 1-5 microns.
I 5. The method of claim 1, wherein the unformulated dry polysaccharide particle has a mean aerodynamic diameter of 1-5 microns.
-5l -
-5l -
16. The method of claim 1, wherein the unformulated dry polysaccharide particle has a meals aerodynamic diameter selected from the group consisting of 5-35 and 35-75 microns.
17. The method of claim 2, wherein the subject has or is at risk of a coagulation disorder and the therapeutic effect of the glycosaminoglycan is anti-coagulation or antithrombosis.
18. The method of claim 17, wherein the coagulation disorder is selected from the group consisting of thrombosis associated with cardiovascular disease and vascular conditions.
19. The method of claim 18, wherein the cardiovascular disease is selected from the group consisting of acute myocardial infraction, unstable angina, and atrial fibrillation.
20. The method of claim 18, wherein the vascular condition is selected from the group consisting of deep venous thrombosis, stroke, and pulmonary embolism.
21. The method of claim 17, wherein the glycosaminoglycan is administered in an amount effective to produce a minimum therapeutic level of approximately 0.2 IU/ml anti-factor Xa activity.
22. The method of claim 2, wherein the subject is preparing to undergo, is undergoing or is recovering from a surgical procedure.
23. The method of claim 22, wherein the surgical procedure is selected from the group consisting of cardiac-pulmonary by-pass surgery, coronary revascularization surgery, orthopedic surgery, and prosthesis replacement surgery.
24. The method of claim 2, wherein the subject has or is at risk of atherosclerosis.
25. The method of claim 2, wherein the subject has or is at risk of a respiratory disorder.
26. The method of claim 25, wherein the respiratory disorder is selected from the group consisting of asthma, emphysema, adult respiratory distress syndrome (ARDS), and lung reperfusion injury.
27. The method of claim 2, wherein the subject has or is at risk of developing a cancer or metastasis.
28. The method of claim 2, wherein the subject has or is at risk of developing an inflammatory disorder.
29. The method of claim 2, wherein the subject has or is at risk of developing an allergy.
30. The method of claim 2, wherein the subject has or is at risk of developing an angiogenic disorder and the glycosaminoglycan is administered in an effective amount for preventing angiogenesis.
31. The method of claim 2, wherein the angiogenic disorder is selected from the group consisting of neovascular disorders of the eye, osteoporosis, psoriasis, and arthritis.
32. The method of claim 1, wherein the polysaccharide is selected from the group consisting of chondroitin sulfate, dermatan sulfate, hyaluronic acid, Pectin, pectin derivatives, oligosaccharides and pentasaccharides that bind to AT-III.
33. The method of claim 1, wherein the unformulated dry polysaccharide is self administered by the subject.
34. The method of claim 1, wherein the unformulated dry polysaccharide is administered through a tracheal tube.
35. The method of claim 2, wherein the subject is undergoing a tissue or organ transplant.
36. The method of claim 1, wherein the unformulated dry polysaccharide has a tap density of 0.01 - 0.4 g/cm3.
37. The method of claim 1, wherein the unformulated dry polysaccharide has a tap density of greater than 0.4 g/cm3.
38. A method for delivering at least 5% of a polysaccharide to lower respiratory tract, comprising:
administering to a pulmonary tissue of a subject an unformulated dry polysaccharide particle, wherein the unformulated dry polysaccharide particle has a mean geometric diameter of 1-500 microns, and wherein at least 5% of the polysaccharide administered is delivered to the lower respiratory tract.
administering to a pulmonary tissue of a subject an unformulated dry polysaccharide particle, wherein the unformulated dry polysaccharide particle has a mean geometric diameter of 1-500 microns, and wherein at least 5% of the polysaccharide administered is delivered to the lower respiratory tract.
39. The method of claim 38, wherein at least 10% of the polysaccharide administered is delivered to the lower respiratory tract.
40. The method of claim 38, wherein at least 30% of the polysaccharide administered is delivered to the lower respiratory tract.
41. The method of claim 38, wherein at least 50% the polysaccharide administered is delivered to the lower respiratory tract.
42. A method for systemically delivering a polysaccharide to a subject, comprising:
administering to a pulmonary tissue of the subject an un formulated dry polysaccharide particle, wherein the unformulated dry polysaccharide particle has a mean geometric diameter of 1-500 microns.
administering to a pulmonary tissue of the subject an un formulated dry polysaccharide particle, wherein the unformulated dry polysaccharide particle has a mean geometric diameter of 1-500 microns.
43. A composition consisting of unformulated dry glycosaminoglycan having a mean geometric diameter of 1-500 microns.
44. The composition of claim 43, wherein the unformulated dry glycosaminoglycan has a mean geometric diameter of 1-200 microns.
45. The composition of claim 43, wherein the unformulated dry glycosaminoglycan has a mean geometric diameter of 1-53 microns.
46. The composition of claim 43, wherein the unformulated dry glycosaminoglycan has a mean geometric diameter of 1-5 microns.
47. The composition of claim 43, wherein the unformulated dry glycosaminoglycan has a mean geometric diameter of 5-53 microns.
48. The composition of claim 43, wherein the unformulated dry glycosaminoglycan has a mean geometric diameter of 53-106 microns.
49. The composition of claim 43, wherein the glycosaminoglycan is selected from the group consisting of a heparin, a heparin sulfate, a low molecular weight heparin, a biotechnology derived heparin, a chemically modified heparin, a heparin analogue, and an unfractionated heparin preparation.
50. The composition of claim 43, further comprising a formulated dry glycosaminoglycan preparation.
51. The composition of claim 50, wherein the glycosaminoglycan of the formulated dry glycosaminoglycan preparation is selected from the group consisting of a heparin, a heparin sulfate, a low molecular weight heparin, a biotechnology derived heparin, a chemically modified heparin, a heparin analogue, and an unfractionated heparin preparation.
52. The composition of claim 50, wherein the glycosaminoglycan of the formulated dry glycosaminoglycan preparation is the salve as the glycosaminoglycan of the unformulated dry glycosaminoglycan preparation.
53. The composition of claim 50, wherein the glycosaminoglycan of the formulated dry glycosaminoglycan preparation is different than the glycosaminoglycan of the unformulated dry glycosaminoglycan preparation.
54. The composition of claim 50, wherein the formulated dry glycosaminoglycan preparation includes a polymer to effect slow release of the glycosaminoglycan.
55. The composition of claim 50, wherein the polymer is selected from the group consisting of PLA, PGA, and PLGA.
56. The composition o~claim 50, wherein the formulated dry glycosaminoglycan preparation includes a surfactant.
57. The composition of claim 56, wherein the surfactant is DPPC.
58. A method for delivering a glycosaminoglycan to a subject, comprising, administering to a pulmonary tissue of a subject the composition of any one of claims 43-57.
59. A method o~ rapidly delivering a polysaccharide to a subject comprising:
administering a dry aerosol containing a polysaccharide to a pulmonary tissue of a subject in an effective amount to produce a peak plasma concentration of polysaccharide within two hours.
administering a dry aerosol containing a polysaccharide to a pulmonary tissue of a subject in an effective amount to produce a peak plasma concentration of polysaccharide within two hours.
60. The method of claim 59, wherein dry aerosol containing a polysaccharide is administered in an effective amount to produce the peak concentration or activity of polysaccharide within one and one half hours.
61. The method of claim 59, wherein dry aerosol containing a polysaccharide is administered in an effective amount to produce the peak concentration or activity of polysaccharide within one hour.
62. The method of claim 59, wherein dry aerosol containing a polysaccharide is administered in an effective amount to produce the peak concentration or activity of polysaccharide within one hall hour.
63. The method of claim 59, wherein the polysaccharide is a glycosaminoglycan.
64. The method of claim 63, wherein the glycosaminoglycan is selected from the group consisting of a low-molecular-weight heparin, heparin, heparin sulfate.
biotechnology derived heparin, chemically modified heparin, heparin analogue, and unfractionated heparin preparation.
biotechnology derived heparin, chemically modified heparin, heparin analogue, and unfractionated heparin preparation.
65. The method of claim 59, wherein the dry aerosol contains an unformulated dry polysaccharide.
66. The method of claim 59, wherein the dry aerosol contains a dry polysaccharide formulated in a surfactant.
67. The method of claim 66, wherein the surfactant is DPPC.
68. The method of claim 66, wherein the surfactant is coated on the particle surface.
69. The method of claim 66, wherein the surfactant is incorporated into the formulation.
70. The method of claim 59 further comprising administering an additional therapeutic agent.
77. The method of claim 70, wherein the additional therapeutic agent is selected from the group consisting of proteins, peptides, nucleic acids, and small organic molecules.
72. The method of claim 59, wherein the dry aerosol containing a polysaccharide includes both a formulated and an unformulated dry polysaccharide.
73. A method of rapidly delivering a polysaccharide to a subject comprising:
administering a dry aerosol containing a polysaccharide to a pulmonary tissue of a subject in an effective amount to deliver at least 5% of the polysaccharide to the blood within one hour.
administering a dry aerosol containing a polysaccharide to a pulmonary tissue of a subject in an effective amount to deliver at least 5% of the polysaccharide to the blood within one hour.
74. A method of claim 73, wherein at least 10% of the polysaccharide is delivered to the blood within one hour.
75. The method of claim 73, wherein at least 20% of the polysaccharide is delivered to the blood within one hour.
76. The method of claim 73, wherein at least 40% of the polysaccharide is delivered to the blood within one hour.
77. The method of claim 73, wherein at least 50% of the polysaccharide is delivered to the blood within one hour.
78. A method of claim 73, wherein at least 10% of the polysaccharide is detectable in the blood within one hour.
79. A method for producing a rapid therapeutic effect, comprising:
administering a dry aerosol containing a polysaccharide to a pulmonary tissue:
of a subject in an effective amount for producing a therapeutic effect within 1 hour of administration.
administering a dry aerosol containing a polysaccharide to a pulmonary tissue:
of a subject in an effective amount for producing a therapeutic effect within 1 hour of administration.
80. The method of 79, wherein the dry aerosol is administered in an effective amount for producing a therapeutic effect within 15 minutes of administration.
81. The method of 79, wherein the dry aerosol is administered in an effective amount for producing a therapeutic effect within 10 minutes of administration.
82. A composition comprising a dry aerosol formulation of particles containing a heparin-like glycosaminoglycan, wherein the particles have a mean geometric diameter of greater than 30 microns.
83. The composition of claim 82, wherein the particles are spherical.
84. The composition of claim 82, wherein the particles are non-spherical.
85. The composition of claim 82, wherein the particles are porous.
86. The composition of claim 82, wherein the particles are non-porous.
87. The composition of claim 82, further comprising a surfactant.
88. The composition of claim 82, further comprising a polymer to effect slow release of the heparin-like glycosaminoglycan.
89. A composition comprising a dry aerosol formulation of particles containing a heparin-like glycosaminoglycan, wherein the particles have a mean aerodynamic diameter of greater than 5 microns.
90. A composition comprising a dry aerosol formulation of particles containing a heparin-like glycosaminoglycan, wherein the particles have a tap density of greater than 0.4 g/cm3.
91. A kit for administering a dry aerosol containing a polysaccharide to the respiratory tract of a subject comprising:
an inhalation apparatus, polysaccharide dry aerosol particle formulation, wherein the polysaccharide dry aerosol particle is formulated to release at least 5% of the polysaccharide within 2 hours and a detection system.
an inhalation apparatus, polysaccharide dry aerosol particle formulation, wherein the polysaccharide dry aerosol particle is formulated to release at least 5% of the polysaccharide within 2 hours and a detection system.
92. The kit of claim 91, wherein the polysaccharide is a glycosaminoglycan.
93. The kit of claim 92, wherein the glycosaminoglycan is selected from the group consisting of a low-molecular-weight heparin, heparin, heparin sulfate, biotechnology derived heparin, chemically modified heparin, heparin analogue and unfractionated heparin preparation.
94. The kit of claim 91, wherein the mean geometric diameter of the particles is between 1 and 500 µm.
95. The kit of claim 91, wherein the mean geometric diameter of the particles is between 1 and 106 µm.
96. The kit of claim 91, wherein the mean geometric diameter of the particles is between 5 and 53 µm.
97. The kit of claim 91, wherein the aerodynamic diameter of the particles is between 1 and 5 µm.
98. The kit of claim 91, wherein the aerodynamic diameter o~ the particles is selected from the group consisting of 5-35 and 35-75 microns..
99. A method for delivering a polysaccharide to a subject, comprising:
administering to a pulmonary tissue of the subject a dry aerosol formulation comprising an unformulated dry glycosaminoglycan preparation and a formulated dry glycosaminoglycan preparation to deliver the polysaccharide to the subject.
administering to a pulmonary tissue of the subject a dry aerosol formulation comprising an unformulated dry glycosaminoglycan preparation and a formulated dry glycosaminoglycan preparation to deliver the polysaccharide to the subject.
100. The method of claim 99, wherein the ratio of unformulated preparation to formulated preparation is 90:10.
101. The method of claim 99, wherein the ratio of unformulated preparation to formulated preparation is 70:30.
102. The method of claim 99, wherein the ratio of unformulated preparation to formulated preparation is 50:50.
103. The method of claim 99, wherein the ratio of unformulated preparation to formulated preparation is 30:70.
104. The method of claim 99, wherein the ratio of unformulated preparation to formulated preparation is 10:90.
105. The method of claim 99, wherein the polysaccharide, is a glycosaminoglycan and the glycosaminoglycan is selected from the group consisting of a heparin, a heparin sulfate, a low molecular weight heparin, a biotechnology derived heparin, a chemically modified heparin, a heparin analogue, and an unfractionated heparin preparation.
106. The method of claim 105, wherein the glycosaminoglycan of the formulated dry glycosaminoglycan preparation is the same as the glycosaminoglycan of the unformulated dry glycosaminoglycan preparation.
107. The method of claim 105, wherein the glycosaminoglycan of the formulated dry glycosaminoglycan preparation is different than the glycosaminoglycan of the unformulated dry glycosaminoglycan preparation.
108. The method of claim 99, wherein the formulated dry glycosaminoglycan preparation includes a polymer to effect slow release of the glycosaminoglycan.
109. The method of claim 108, wherein the polymer is selected from the group consisting of PLA, PGA, and PLGA.
110. The method of claim 99, wherein the formulated dry glycosaminoglycan preparation includes a surfactant.
111. The method of claim 110, wherein the surfactant is DPPC.
112. The method of claim 99, wherein the relative ratio of formulated to unformulated preparation is selected from the group consisting of 10:90, 20:80, 30:70.
40:60, 50:50, 60:40, 70:30, 80:20, and 90:10.
40:60, 50:50, 60:40, 70:30, 80:20, and 90:10.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US24155900P | 2000-10-18 | 2000-10-18 | |
US60/241,559 | 2000-10-18 | ||
PCT/US2001/032444 WO2002032406A2 (en) | 2000-10-18 | 2001-10-18 | Methods and products related to pulmonary delivery of polysaccharides |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2423469A1 true CA2423469A1 (en) | 2002-04-25 |
Family
ID=22911183
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002423469A Abandoned CA2423469A1 (en) | 2000-10-18 | 2001-10-18 | Methods and products related to pulmonary delivery of polysaccharides |
Country Status (6)
Country | Link |
---|---|
US (1) | US7709461B2 (en) |
EP (1) | EP1328260A2 (en) |
JP (1) | JP2004523479A (en) |
AU (2) | AU2440802A (en) |
CA (1) | CA2423469A1 (en) |
WO (1) | WO2002032406A2 (en) |
Families Citing this family (70)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1109919A2 (en) * | 1998-08-27 | 2001-06-27 | Massachusetts Institute Of Technology | Rationally designed heparinases derived from heparinase i and ii |
CA2370539C (en) * | 1999-04-23 | 2009-01-06 | Massachusetts Institute Of Technology | System and method for notating polymers |
CA2402160C (en) * | 2000-03-08 | 2012-02-14 | Massachusetts Institute Of Technology | Heparinase iii and uses thereof |
AU2001292618A1 (en) * | 2000-09-12 | 2002-03-26 | Massachusetts Institute Of Technology | Methods and products related to low molecular weight heparin |
AU2440802A (en) | 2000-10-18 | 2002-04-29 | Massachusetts Inst Technology | Methods and products related to pulmonary delivery of polysaccharides |
ES2238383T3 (en) * | 2000-12-16 | 2005-09-01 | Aventis Pharma Deutschland Gmbh | USE OF LOW MOLECULAR HEPARINE FOR THE TREATMENT OF OSTEOARTROSIS. |
WO2003068187A1 (en) * | 2002-02-18 | 2003-08-21 | University Of Southampton | Use of glycosaminoglycans such as e.g. heparin for the treatment of respiratory disorders such as copd |
ES2565028T3 (en) * | 2002-02-18 | 2016-03-30 | Ockham Biotech Limited | Combination therapy for respiratory disorders |
EP2284535A1 (en) | 2002-03-11 | 2011-02-16 | Momenta Pharmaceuticals, Inc. | Low molecular weight heparins |
EP1494696A4 (en) * | 2002-04-01 | 2006-01-25 | Gtc Biotherapeutics Inc | Treatment of lung disorder |
CA2483271A1 (en) * | 2002-04-25 | 2003-11-06 | Momenta Pharmaceuticals, Inc. | Methods and products for mucosal delivery |
EP1575534B1 (en) * | 2002-05-03 | 2013-04-10 | Massachusetts Institute Of Technology | D4,5 glycuronidase and uses thereof |
WO2004055491A2 (en) | 2002-05-20 | 2004-07-01 | Massachusetts Institute Of Technology | Novel method for sequence determination using nmr |
CA2493509C (en) * | 2002-06-03 | 2010-03-09 | Massachusetts Institute Of Technology | Rationally designed polysaccharide lyases derived from chondroitinase b |
AU2003245595A1 (en) * | 2002-07-03 | 2004-01-23 | Glycomimetics, Inc. | Compositions and methods for diagnosis and therapy of medical conditions involving angiogenesis |
JP4606712B2 (en) * | 2003-01-08 | 2011-01-05 | マサチューセッツ インスティテュート オブ テクノロジー | 2-O sulfatase compositions and related methods |
US7638138B2 (en) | 2003-02-21 | 2009-12-29 | Translational Research, Ltd. | Compositions for nasal administration of pharmaceuticals |
EP1607117A4 (en) | 2003-03-27 | 2007-10-24 | Bioactis Ltd | Powder medicine applicator for nasal cavity |
JP4851185B2 (en) | 2003-05-16 | 2012-01-11 | ジェレックスインターナショナル株式会社 | Allergy symptom suppressant and air filtration filter |
GB0327723D0 (en) | 2003-09-15 | 2003-12-31 | Vectura Ltd | Pharmaceutical compositions |
EP1667633A4 (en) * | 2003-10-01 | 2008-10-08 | Momenta Pharmaceuticals Inc | Polysaccharides for pulmonary delivery of active agents |
US7932365B2 (en) | 2003-11-08 | 2011-04-26 | Pro Thera Biologics, Llc | Preparation and composition of inter-alpha inhibitor proteins from human plasma for therapeutic use |
DE10356346A1 (en) * | 2003-11-28 | 2005-06-23 | TransMIT Gesellschaft für Technologietransfer mbH | Invention relating to the prophylaxis and therapy of diseases caused by or caused by thrombus formation |
US20050192226A1 (en) * | 2004-02-20 | 2005-09-01 | Perenlei Enkhbaatar | Method of preventing fibrin clots in pulmonary tissue through the use of aerosolized anticoagulants |
CA2557216A1 (en) * | 2004-02-26 | 2005-09-09 | Advanced Ocular Systems Limited | Heparin for the treatment of ocular pathologies |
EP1737954A2 (en) | 2004-03-10 | 2007-01-03 | The Massachusetts Institute Of Technology | Recombinant chondroitinase abc i and uses thereof |
US20060127950A1 (en) * | 2004-04-15 | 2006-06-15 | Massachusetts Institute Of Technology | Methods and products related to the improved analysis of carbohydrates |
WO2005111627A2 (en) * | 2004-04-15 | 2005-11-24 | Massachusetts Institute Of Technology | Methods and products related to the improved analysis of carbohydrates |
CA2614068A1 (en) * | 2004-06-29 | 2006-08-24 | Massachusetts Institute Of Technology | Methods and compositions related to the modulation of intercellular junctions |
WO2006083328A2 (en) * | 2004-09-15 | 2006-08-10 | Massachusetts Institute Of Technology | Biologically active surfaces and methods of their use |
TW200621794A (en) * | 2004-10-06 | 2006-07-01 | Akzo Nobel Nv | Pulmonary administration of an antithrombotic compound |
WO2007053610A2 (en) * | 2005-11-01 | 2007-05-10 | The Regents Of The University Of California | Methods of treating atrial fibrillation wtih pirfenidone |
WO2007075388A2 (en) * | 2005-12-15 | 2007-07-05 | X-Cell Medical Incorporated | Methods of locally treating and preventing cardiac disorders |
US20070154546A1 (en) * | 2005-12-30 | 2007-07-05 | Zhang Jack Y | Sustained release pharmaceutical compositions |
WO2007120478A2 (en) * | 2006-04-03 | 2007-10-25 | Massachusetts Institute Of Technology | Glycomic patterns for the detection of disease |
CA2652205A1 (en) | 2006-05-25 | 2007-12-06 | Mallik Sundaram | Low molecular weight heparin composition and uses thereof |
CA2660519A1 (en) | 2006-08-10 | 2008-02-21 | Roy C. Levitt | Localized therapy of lower airways inflammatory disorders with proinflammatory cytokine inhibitors |
JP5415769B2 (en) | 2006-12-26 | 2014-02-12 | 株式会社新日本科学 | Nasal formulation |
CA2674493C (en) | 2007-01-05 | 2017-05-09 | Massachusetts Institute Of Technology | Compositions of and methods of using sulfatases from flavobacterium heparinum |
US9139876B1 (en) | 2007-05-03 | 2015-09-22 | Momenta Pharmacueticals, Inc. | Method of analyzing a preparation of a low molecular weight heparin |
EP2291654B1 (en) | 2008-05-28 | 2018-04-11 | Prothera Biologics, Inc. | Preparation and composition of inter-alpha inhibitor proteins from blood |
US20110236381A1 (en) * | 2008-12-10 | 2011-09-29 | Stavros Garantziotis | Inhibition of inter-alpha trypsin inhibitor for the treatment of airway disease |
ES2458818T3 (en) | 2009-04-16 | 2014-05-07 | Momenta Pharmaceuticals, Inc. | Methods to evaluate the activity of a polysaccharide composition |
GB0908129D0 (en) * | 2009-05-12 | 2009-06-24 | Innovata Ltd | Composition |
US9101539B2 (en) | 2009-05-15 | 2015-08-11 | Shin Nippon Biomedical Laboratories, Ltd. | Intranasal pharmaceutical compositions with improved pharmacokinetics |
WO2011011797A2 (en) | 2009-07-24 | 2011-01-27 | The Board Of Trustees Of The Leland Stanford Junior University | Cytokine compositions and methods of use thereof |
WO2011013003A2 (en) | 2009-07-31 | 2011-02-03 | Shin Nippon Biomedical Laboratories, Ltd. | Intranasal granisetron and nasal applicator |
KR20120093932A (en) | 2009-10-10 | 2012-08-23 | 일레븐 바이오테라피틱스, 아이엔씨. | Il-17 family cytokine compositions and uses |
CN102791742B (en) | 2010-01-19 | 2014-12-24 | 动量制药公司 | Evaluating heparin preparations |
US8921328B2 (en) | 2010-09-14 | 2014-12-30 | Glycomimetics, Inc. | E-selectin antagonists |
WO2012115952A1 (en) | 2011-02-21 | 2012-08-30 | Momenta Pharmaceuticals, Inc. | Evaluating heparin preparations |
WO2013096926A1 (en) | 2011-12-22 | 2013-06-27 | Glycomimetics, Inc. | E-selectin antagonist compounds, compositions, and methods of use |
US9717752B2 (en) | 2012-05-15 | 2017-08-01 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Uses of antagonists of hyaluronan signaling |
WO2014074186A2 (en) | 2012-08-09 | 2014-05-15 | The Board Of Trustees Of The Leland Stanford Junior University | Superkines and synthekines: repurposed cytokines with new and enhanced signaling activities |
CA2885604A1 (en) | 2012-09-09 | 2014-03-13 | Prothera Biologics, Inc. | Treatment of ischemia using inter-alpha inhibitor proteins |
US11497593B2 (en) * | 2014-04-13 | 2022-11-15 | R & M Butterworth Pty Ltd. | Livestock treatment method and apparatus |
ES2668045T3 (en) | 2012-12-07 | 2018-05-16 | Glycomimetics, Inc. | Compounds, compositions and methods that use E-selectin antagonists for the mobilization of hematopoietic cells |
US20150289962A1 (en) * | 2014-04-13 | 2015-10-15 | R & M Butterworth Pty Ltd. | Livestock Treatment Method and Apparatus |
SI3227310T1 (en) | 2014-12-03 | 2019-11-29 | Glycomimetics Inc | Heterobifunctional inhibitors of e-selectins and cxcr4 chemokine receptors |
US11291678B2 (en) | 2016-03-02 | 2022-04-05 | Glycomimetics, Inc | Methods for the treatment and/or prevention of cardiovascular disease by inhibition of E-selectin |
WO2018031445A1 (en) | 2016-08-08 | 2018-02-15 | Glycomimetics, Inc. | Combination of t-cell checkpoint inhibitors with inhibitors of e-selectin or cxcr4, or with heterobifunctional inhibitors of both e-selectin and cxcr4 |
CA3037850A1 (en) | 2016-10-07 | 2018-04-12 | Glycomimetics, Inc. | Highly potent multimeric e-selectin antagonists |
CA3054605A1 (en) | 2017-03-15 | 2018-09-20 | Glycomimetics, Inc. | Galactopyranosyl-cyclohexyl derivatives as e-selectin antagonists |
US11744967B2 (en) | 2017-09-26 | 2023-09-05 | Shin Nippon Biomedical Laboratories, Ltd. | Intranasal delivery devices |
WO2019108750A1 (en) | 2017-11-30 | 2019-06-06 | Glycomimetics, Inc. | Methods of mobilizing marrow infiltrating lymphocytes and uses thereof |
EP3732186A1 (en) | 2017-12-29 | 2020-11-04 | GlycoMimetics, Inc. | Heterobifunctional inhibitors of e-selectin and galectin-3 |
AU2019230013A1 (en) | 2018-03-05 | 2020-09-10 | Glycomimetics, Inc. | Methods for treating acute myeloid leukemia and related conditions |
US11845771B2 (en) | 2018-12-27 | 2023-12-19 | Glycomimetics, Inc. | Heterobifunctional inhibitors of E-selectin and galectin-3 |
IT202100001349A1 (en) * | 2021-01-25 | 2022-07-25 | Sofar Swiss Sa | COMPOSITION IN THE FORM OF DRY POWDER FOR INHALATION COMPRISING A HYALURONIC ACID AND A CHONDROITIN SULPHATE, USE OF THE COMPOSITION AND INHALER DEVICE CONTAINING THE COMPOSITION |
IT202100021602A1 (en) * | 2021-08-09 | 2023-02-09 | Sofar Spa | Composition in dry powder form for inhalation for use in a method of treatment of inflammation and/or oxidative stress of the respiratory system caused/or by air pollution |
Family Cites Families (118)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4281108A (en) | 1980-01-28 | 1981-07-28 | Hepar Industries, Inc. | Process for obtaining low molecular weight heparins endowed with elevated pharmacological properties, and product so obtained |
US4443545A (en) | 1980-08-25 | 1984-04-17 | Massachusetts Institute Of Technology | Process for producing heparinase |
US4341869A (en) | 1980-08-25 | 1982-07-27 | Massachusetts Institute Of Technology | Process for producing heparinase |
US4373023A (en) | 1980-10-14 | 1983-02-08 | Massachusetts Institute Of Technology | Process for neutralizing heparin |
US4396762A (en) | 1981-08-24 | 1983-08-02 | Massachusetts Institute Of Technology | Heparinase derived anticoagulants |
US4551296A (en) | 1982-03-19 | 1985-11-05 | Allied Corporation | Producing high tenacity, high modulus crystalline article such as fiber or film |
CA1226816A (en) | 1982-12-20 | 1987-09-15 | Moses J. Folkman | Inhibition of angiogenesis |
FR2553287B1 (en) | 1983-10-18 | 1986-09-12 | Choay Sa | COMPOSITIONS BASED ON MUCOPOLYSACCHARIDES OR OLIGOSACCHARIDES, ESPECIALLY BASED ON HEPARIN FRACTIONS OR FRAGMENTS, SUITABLE FOR THE TREATMENT OF CELL PROLIFERATION DISORDERS |
US4757056A (en) | 1984-03-05 | 1988-07-12 | Hepar Industries, Inc. | Method for tumor regression in rats, mice and hamsters using hexuronyl hexosaminoglycan-containing compositions |
US4679555A (en) * | 1984-08-07 | 1987-07-14 | Key Pharmaceuticals, Inc. | Method and apparatus for intrapulmonary delivery of heparin |
FR2584606A1 (en) * | 1985-07-12 | 1987-01-16 | Dropic | USE OF POLY- AND OLIGOSACCHARIDES FOR THE PRODUCTION OF ACTIVE MEDICAMENTS IN THE PATHOLOGIES OF CONNECTIVE TISSUE |
US5262403A (en) | 1986-03-10 | 1993-11-16 | Board Of Regents, The University Of Texas System | Glycosaminoglycan derivatives and their use as inhibitors of tumor invasiveness of metastatic profusion-II |
US5106734A (en) | 1986-04-30 | 1992-04-21 | Novo Nordisk A/S | Process of using light absorption to control enzymatic depolymerization of heparin to produce low molecular weight heparin |
DK196986D0 (en) | 1986-04-30 | 1986-04-30 | Novo Industri As | PREPARATION OF POLYSACCHARIDES |
US4745105A (en) | 1986-08-20 | 1988-05-17 | Griffin Charles C | Low molecular weight heparin derivatives with improved permeability |
US4942156A (en) | 1986-08-20 | 1990-07-17 | Hepar Industries, Inc. | Low molecular weight heparin derivatives having improved anti-Xa specificity |
US4830013A (en) | 1987-01-30 | 1989-05-16 | Minnesota Mining And Manufacturing Co. | Intravascular blood parameter measurement system |
FR2614026B1 (en) | 1987-04-16 | 1992-04-17 | Sanofi Sa | LOW MOLECULAR WEIGHT HEPARINS WITH REGULAR STRUCTURE, THEIR PREPARATION AND THEIR BIOLOGICAL APPLICATIONS |
SE8702254D0 (en) | 1987-05-29 | 1987-05-29 | Kabivitrum Ab | NOVEL HEPARIN DERIVATIVES |
US5217705A (en) | 1987-09-25 | 1993-06-08 | Neorx Corporation | Method of diagnosing blood clots using fibrin-binding proteins |
US5169772A (en) | 1988-06-06 | 1992-12-08 | Massachusetts Institute Of Technology | Large scale method for purification of high purity heparinase from flavobacterium heparinum |
IT1234508B (en) | 1988-06-10 | 1992-05-19 | Alfa Wassermann Spa | HEPARIN DERIVATIVES AND PROCEDURE FOR THEIR PREPARATION |
US5204323B1 (en) | 1988-10-06 | 1995-07-18 | Ciba Geigy Corp | Hirudin antidotal compositions and methods |
GB8826448D0 (en) | 1988-11-11 | 1988-12-14 | Thrombosis Res Inst | Improvements in/relating to organic compounds |
US5776434A (en) | 1988-12-06 | 1998-07-07 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
PT93847A (en) | 1989-04-24 | 1990-11-20 | Harvard College | PROCESS FOR THE PREPARATION OF OLIGOSACARIDES OF LOW MOLECULAR WEIGHT DERIVED FROM HEPARIN OR DESPOLYMENED HEPARAN SULFATE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM |
ATE99546T1 (en) * | 1989-05-01 | 1994-01-15 | Alkermes Inc | PROCESS FOR PRODUCTION OF SMALL PARTICLES OF BIOLOGICALLY ACTIVE MOLECULES. |
CA1340966C (en) | 1989-05-19 | 2000-04-18 | Thomas R. Covey | Method of protein analysis |
US5527532A (en) * | 1989-11-13 | 1996-06-18 | President And Fellows Of Harvard College | Extraluminal regulation of the growth and repair of tubular structures in vivo |
IT1237518B (en) | 1989-11-24 | 1993-06-08 | Renato Conti | SUPER-SULFATED HEPARINS |
GB8927546D0 (en) | 1989-12-06 | 1990-02-07 | Ciba Geigy | Process for the production of biologically active tgf-beta |
US5152784A (en) | 1989-12-14 | 1992-10-06 | Regents Of The University Of Minnesota | Prosthetic devices coated with a polypeptide with type IV collagen activity |
IT1245761B (en) | 1991-01-30 | 1994-10-14 | Alfa Wassermann Spa | PHARMACEUTICAL FORMULATIONS CONTAINING GLYCOSAMINOGLICANS ABSORBABLE ORALLY. |
JP3110064B2 (en) | 1991-03-06 | 2000-11-20 | 生化学工業株式会社 | Novel heparitinase, method for producing the same and bacteria producing the same |
US5262325A (en) | 1991-04-04 | 1993-11-16 | Ibex Technologies, Inc. | Method for the enzymatic neutralization of heparin |
CZ232593A3 (en) | 1991-05-02 | 1994-07-13 | Yeda Res & Dev | Pharmaceutical preparation for preventing and/or therapy of pathological states |
AU2561792A (en) | 1991-09-06 | 1993-04-05 | Children's Medical Center Corporation | Cell-type specific heparan sulfate proteoglycans and their uses |
US5714376A (en) | 1991-10-23 | 1998-02-03 | Massachusetts Institute Of Technology | Heparinase gene from flavobacterium heparinum |
AU3144993A (en) | 1991-11-21 | 1993-06-15 | Glyko, Inc. | Fluorophore-assisted therapeutic drug monitoring |
GB9202019D0 (en) | 1992-01-30 | 1992-03-18 | Imperial College | Methods and apparatus for assay of sulphated polysaccharides |
IT1254216B (en) | 1992-02-25 | 1995-09-14 | Opocrin Spa | POLYSACCHARIDIC DERIVATIVES OF HEPARIN, EPARAN SULPHATE, THEIR FRACTIONS AND FRAGMENTS, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
US5453171A (en) | 1992-03-10 | 1995-09-26 | The Board Of Regents Of The University Of Michigan | Heparin-selective polymeric membrane electrode |
GB9206291D0 (en) | 1992-03-23 | 1992-05-06 | Cancer Res Campaign Tech | Oligosaccharides having growth factor binding affinity |
AU3938093A (en) * | 1992-04-02 | 1993-11-08 | Baker Norton Pharmaceuticals, Inc. | Method and composition for treating antigen-induced and exercise-induced asthma |
US6582728B1 (en) | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
US6673335B1 (en) | 1992-07-08 | 2004-01-06 | Nektar Therapeutics | Compositions and methods for the pulmonary delivery of aerosolized medicaments |
DK1164145T3 (en) * | 1992-07-24 | 2008-04-14 | Thomas P Kennedy | Non-anticoagulant desulfated heparin as a drug |
US5389539A (en) | 1992-11-30 | 1995-02-14 | Massachusetts Institute Of Technology | Purification of heparinase I, II, and III from Flavobacterium heparinum |
US5696100A (en) | 1992-12-22 | 1997-12-09 | Glycomed Incorporated | Method for controlling O-desulfation of heparin and compositions produced thereby |
GB9306255D0 (en) | 1993-03-25 | 1993-05-19 | Cancer Res Campaign Tech | Heparan sulphate oligosaccharides having hepatocyte growth factor binding affinity |
FR2704861B1 (en) | 1993-05-07 | 1995-07-28 | Sanofi Elf | Purified heparin fractions, process for obtaining them and pharmaceutical compositions containing them. |
US5744155A (en) | 1993-08-13 | 1998-04-28 | Friedman; Doron | Bioadhesive emulsion preparations for enhanced drug delivery |
EP0726773A1 (en) | 1993-11-17 | 1996-08-21 | Massachusetts Institute Of Technology | Method for inhibiting angiogenesis using heparinase |
US6013628A (en) | 1994-02-28 | 2000-01-11 | Regents Of The University Of Minnesota | Method for treating conditions of the eye using polypeptides |
US6051256A (en) | 1994-03-07 | 2000-04-18 | Inhale Therapeutic Systems | Dispersible macromolecule compositions and methods for their preparation and use |
US5607859A (en) | 1994-03-28 | 1997-03-04 | Massachusetts Institute Of Technology | Methods and products for mass spectrometric molecular weight determination of polyionic analytes employing polyionic reagents |
US5753445A (en) | 1994-04-26 | 1998-05-19 | The Mount Sinai Medical Center Of The City University Of New York | Test for the detection of anti-heparin antibodies |
AU2435795A (en) | 1994-05-06 | 1995-11-29 | Glycomed Incorporated | O-desulfated heparin derivatives, methods of making and uses thereof |
ATE299892T1 (en) | 1994-05-18 | 2005-08-15 | Nektar Therapeutics | METHODS AND COMPOSITIONS FOR DRY POWDER MEDICATION FROM INTERFERONS |
US5681733A (en) | 1994-06-10 | 1997-10-28 | Ibex Technologies | Nucleic acid sequences and expression systems for heparinase II and heparinase III derived from Flavobacterium heparinum |
US5619421A (en) | 1994-06-17 | 1997-04-08 | Massachusetts Institute Of Technology | Computer-implemented process and computer system for estimating the three-dimensional shape of a ring-shaped molecule and of a portion of a molecule containing a ring-shaped structure |
US5997863A (en) | 1994-07-08 | 1999-12-07 | Ibex Technologies R And D, Inc. | Attenuation of wound healing processes |
US6309853B1 (en) | 1994-08-17 | 2001-10-30 | The Rockfeller University | Modulators of body weight, corresponding nucleic acids and proteins, and diagnostic and therapeutic uses thereof |
FR2723847A1 (en) | 1994-08-29 | 1996-03-01 | Debiopharm Sa | HEPARIN - BASED ANTITHROMBOTIC AND NON - HEMORRHAGIC COMPOSITIONS, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC APPLICATIONS. |
US5687090A (en) | 1994-09-01 | 1997-11-11 | Aspen Technology, Inc. | Polymer component characterization method and process simulation apparatus |
EP0785774B1 (en) | 1994-10-12 | 2001-01-31 | Focal, Inc. | Targeted delivery via biodegradable polymers |
US5569366A (en) | 1995-01-27 | 1996-10-29 | Beckman Instruments, Inc. | Fluorescent labelled carbohydrates and their analysis |
US5618917A (en) | 1995-02-15 | 1997-04-08 | Arch Development Corporation | Methods and compositions for detecting and treating kidney diseases associated with adhesion of crystals to kidney cells |
US5763427A (en) | 1995-03-31 | 1998-06-09 | Hamilton Civic Hospitals Research Development Inc. | Compositions and methods for inhibiting thrombogenesis |
US5597811A (en) * | 1995-04-10 | 1997-01-28 | Amerchol Corporation | Oxirane carboxylic acid derivatives of polyglucosamines |
US6165463A (en) | 1997-10-16 | 2000-12-26 | Inhale Therapeutic Systems, Inc. | Dispersible antibody compositions and methods for their preparation and use |
US5780014A (en) | 1995-04-14 | 1998-07-14 | Inhale Therapeutic Systems | Method and apparatus for pulmonary administration of dry powder alpha 1-antitrypsin |
US6019968A (en) | 1995-04-14 | 2000-02-01 | Inhale Therapeutic Systems, Inc. | Dispersible antibody compositions and methods for their preparation and use |
WO1996037165A1 (en) | 1995-05-26 | 1996-11-28 | Bsi Corporation | Method and implantable article for promoting endothelialization |
US5824299A (en) | 1995-06-22 | 1998-10-20 | President & Fellows Of Harvard College | Modulation of endothelial cell proliferation with IP-10 |
US5690910A (en) * | 1995-08-18 | 1997-11-25 | Baker Norton Pharmaceuticals, Inc. | Method for treating asthma |
ATE273020T1 (en) | 1995-09-29 | 2004-08-15 | Biomarin Pharm Inc | USE OF HEPARINASES TO REDUCE INFLAMMATORY REACTIONS |
US6217863B1 (en) | 1995-10-30 | 2001-04-17 | Massachusetts Institute Of Technology | Rationally designed polysaccharide lyases derived from heparinase I |
US5752019A (en) | 1995-12-22 | 1998-05-12 | International Business Machines Corporation | System and method for confirmationally-flexible molecular identification |
GB9606188D0 (en) * | 1996-03-23 | 1996-05-29 | Danbiosyst Uk | Pollysaccharide microspheres for the pulmonary delivery of drugs |
AU724503B2 (en) | 1996-04-29 | 2000-09-21 | Dura Pharmaceuticals, Inc. | Methods of dry powder inhalation |
US5985309A (en) | 1996-05-24 | 1999-11-16 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
US5874064A (en) | 1996-05-24 | 1999-02-23 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
US5855913A (en) | 1997-01-16 | 1999-01-05 | Massachusetts Instite Of Technology | Particles incorporating surfactants for pulmonary drug delivery |
USRE37053E1 (en) | 1996-05-24 | 2001-02-13 | Massachusetts Institute Of Technology | Particles incorporating surfactants for pulmonary drug delivery |
AU3892297A (en) | 1996-07-26 | 1998-02-20 | Ikonos Corporation | Sensor for detecting heparin and other analytes |
EP0918461B1 (en) | 1996-07-29 | 2004-10-27 | Paringenix, Inc. | Methods of treating asthma with o-desulfated heparin |
US5767269A (en) | 1996-10-01 | 1998-06-16 | Hamilton Civic Hospitals Research Development Inc. | Processes for the preparation of low-affinity, low molecular weight heparins useful as antithrombotics |
US5759767A (en) | 1996-10-11 | 1998-06-02 | Joseph R. Lakowicz | Two-photon and multi-photon measurement of analytes in animal and human tissues and fluids |
EP0954282B1 (en) * | 1997-01-16 | 2005-01-19 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
US6190875B1 (en) | 1997-09-02 | 2001-02-20 | Insight Strategy & Marketing Ltd. | Method of screening for potential anti-metastatic and anti-inflammatory agents using mammalian heparanase as a probe |
US5968822A (en) | 1997-09-02 | 1999-10-19 | Pecker; Iris | Polynucleotide encoding a polypeptide having heparanase activity and expression of same in transduced cells |
US6268146B1 (en) | 1998-03-13 | 2001-07-31 | Promega Corporation | Analytical methods and materials for nucleic acid detection |
US7056504B1 (en) | 1998-08-27 | 2006-06-06 | Massachusetts Institute Of Technology | Rationally designed heparinases derived from heparinase I and II |
EP1109919A2 (en) | 1998-08-27 | 2001-06-27 | Massachusetts Institute Of Technology | Rationally designed heparinases derived from heparinase i and ii |
US6291439B1 (en) | 1998-09-02 | 2001-09-18 | Biomarin Pharmaceuticals | Methods for diagnosing atherosclerosis by measuring endogenous heparin and methods for treating atherosclerosis using heparin |
US6333051B1 (en) | 1998-09-03 | 2001-12-25 | Supratek Pharma, Inc. | Nanogel networks and biological agent compositions thereof |
CA2370539C (en) | 1999-04-23 | 2009-01-06 | Massachusetts Institute Of Technology | System and method for notating polymers |
CA2402160C (en) | 2000-03-08 | 2012-02-14 | Massachusetts Institute Of Technology | Heparinase iii and uses thereof |
AU2001292618A1 (en) | 2000-09-12 | 2002-03-26 | Massachusetts Institute Of Technology | Methods and products related to low molecular weight heparin |
AU2440802A (en) | 2000-10-18 | 2002-04-29 | Massachusetts Inst Technology | Methods and products related to pulmonary delivery of polysaccharides |
JP2005503120A (en) | 2001-03-27 | 2005-02-03 | マサチューセッツ インスティテュート オブ テクノロジー | Methods and products for FGF dimerization |
ES2565028T3 (en) | 2002-02-18 | 2016-03-30 | Ockham Biotech Limited | Combination therapy for respiratory disorders |
WO2003068187A1 (en) | 2002-02-18 | 2003-08-21 | University Of Southampton | Use of glycosaminoglycans such as e.g. heparin for the treatment of respiratory disorders such as copd |
EP1575534B1 (en) | 2002-05-03 | 2013-04-10 | Massachusetts Institute Of Technology | D4,5 glycuronidase and uses thereof |
WO2004055491A2 (en) | 2002-05-20 | 2004-07-01 | Massachusetts Institute Of Technology | Novel method for sequence determination using nmr |
CA2493509C (en) | 2002-06-03 | 2010-03-09 | Massachusetts Institute Of Technology | Rationally designed polysaccharide lyases derived from chondroitinase b |
JP4606712B2 (en) | 2003-01-08 | 2011-01-05 | マサチューセッツ インスティテュート オブ テクノロジー | 2-O sulfatase compositions and related methods |
EP1737954A2 (en) | 2004-03-10 | 2007-01-03 | The Massachusetts Institute Of Technology | Recombinant chondroitinase abc i and uses thereof |
WO2005110438A2 (en) | 2004-04-15 | 2005-11-24 | Massachusetts Institute Of Technology | Methods and products related to the intracellular delivery of polysaccharides |
US20060127950A1 (en) | 2004-04-15 | 2006-06-15 | Massachusetts Institute Of Technology | Methods and products related to the improved analysis of carbohydrates |
WO2005111627A2 (en) | 2004-04-15 | 2005-11-24 | Massachusetts Institute Of Technology | Methods and products related to the improved analysis of carbohydrates |
CA2614068A1 (en) | 2004-06-29 | 2006-08-24 | Massachusetts Institute Of Technology | Methods and compositions related to the modulation of intercellular junctions |
WO2006083328A2 (en) | 2004-09-15 | 2006-08-10 | Massachusetts Institute Of Technology | Biologically active surfaces and methods of their use |
CA2594013A1 (en) | 2005-01-12 | 2006-07-20 | Massachusetts Institute Of Technology | Methods and compositions related to modulating the extracellular stem cell environment |
WO2006105313A2 (en) | 2005-03-29 | 2006-10-05 | Massachusetts Institute Of Technology | Compositions of and methods of using oversulfated glycosaminoglycans |
US20090156477A1 (en) | 2005-03-29 | 2009-06-18 | Massachusetts Institute Of Technology | Compositions and Methods for Regulating Inflammatory Responses |
WO2007120478A2 (en) | 2006-04-03 | 2007-10-25 | Massachusetts Institute Of Technology | Glycomic patterns for the detection of disease |
-
2001
- 2001-10-18 AU AU2440802A patent/AU2440802A/en active Pending
- 2001-10-18 EP EP01987662A patent/EP1328260A2/en not_active Withdrawn
- 2001-10-18 US US09/982,548 patent/US7709461B2/en not_active Expired - Fee Related
- 2001-10-18 JP JP2002535644A patent/JP2004523479A/en active Pending
- 2001-10-18 WO PCT/US2001/032444 patent/WO2002032406A2/en active Application Filing
- 2001-10-18 CA CA002423469A patent/CA2423469A1/en not_active Abandoned
- 2001-10-18 AU AU2002224408A patent/AU2002224408B2/en not_active Ceased
Also Published As
Publication number | Publication date |
---|---|
EP1328260A2 (en) | 2003-07-23 |
US7709461B2 (en) | 2010-05-04 |
WO2002032406A3 (en) | 2002-10-10 |
WO2002032406A2 (en) | 2002-04-25 |
AU2002224408B2 (en) | 2007-08-23 |
JP2004523479A (en) | 2004-08-05 |
AU2002224408B8 (en) | 2002-04-29 |
AU2440802A (en) | 2002-04-29 |
US20020128225A1 (en) | 2002-09-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2423469A1 (en) | Methods and products related to pulmonary delivery of polysaccharides | |
AU2002224408A1 (en) | Methods and products related to pulmonary delivery of polysaccharides | |
Cenni et al. | Biocompatibility of poly (D, L-lactide-co-glycolide) nanoparticles conjugated with alendronate | |
Chen et al. | The structure property and endothelial protective activity of fucoidan from Laminaria japonica | |
Bhat et al. | Drug diffusion through cystic fibrotic mucus: steady-state permeation, rheologic properties, and glycoprotein morphology | |
EP2786782B1 (en) | Sulphated hyaluronic acid for treating degenerative osteoarthritis | |
CA2856918C (en) | Use of chemically modified heparin derivates in sickle cell disease | |
Wu et al. | Rutin-loaded silver nanoparticles with antithrombotic function | |
AP1390A (en) | Pharmaceutical composition comprising a compound having anti-Xa activity and a platelet aggregation antagonist compound. | |
Ma et al. | In vitro and in vivo anticoagulant activity of heparin-like biomacromolecules and the mechanism analysis for heparin-mimicking activity | |
US20110200673A1 (en) | Oxidized heparin fractions and their use in inhibiting angiogenesis | |
CN101506272A (en) | Dendritic polyglycerol sulfates and sulfonates and their use for inflammatory diseases | |
JP2003526617A (en) | Synergistic effect of low molecular weight heparin and platelet aggregation inhibitor provides combination therapy for prevention and treatment of various thromboembolic disorders | |
Pomin | Marine medicinal glycomics | |
Du et al. | Enhanced biocompatibility of poly (l‑lactide‑co‑epsilon‑caprolactone) electrospun vascular grafts via self-assembly modification | |
EP1291362A1 (en) | A complex between folic acid and polysaccharides, its preparation method and a pharmaceutical composition comprising said complex as active component | |
JP6741277B2 (en) | Sulfated heparin-derived oligosaccharide and its preparation method and application | |
US9572831B2 (en) | Composition and method for sulfated non-anticoagulant low molecular weight heparins in cancer and tumor metastasis | |
Patel et al. | Low-molecular-weight heparin (LMWH)–loaded large porous PEG-PLGA particles for the treatment of asthma | |
Xiang et al. | A dynamic remodeling bio-mimic extracellular matrix to reduce thrombotic and inflammatory complications of vascular implants | |
JP6980018B2 (en) | Oligosaccharides that inhibit the endogenous tennase complex, their production methods and uses | |
AU2016274868B2 (en) | Medical devices, systems, and methods utilizing antithrombin-heparin compositions | |
Drozd et al. | Hemocompatibility of silver nanoparticles based on conjugate of quaternized chitosan with gallic acid in in vitro experiments | |
RU2366441C2 (en) | Anticoagulating biologically active complex made of siberian cedar bark | |
Hassan et al. | Development of plant based bioactive, anticoagulant and antioxidant surface coatings for medical implants |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
FZDE | Discontinued |