CA1239092A - Ultrasound contrast agents containing microparticles and gas micro-bubbles - Google Patents
Ultrasound contrast agents containing microparticles and gas micro-bubblesInfo
- Publication number
- CA1239092A CA1239092A CA000451730A CA451730A CA1239092A CA 1239092 A CA1239092 A CA 1239092A CA 000451730 A CA000451730 A CA 000451730A CA 451730 A CA451730 A CA 451730A CA 1239092 A CA1239092 A CA 1239092A
- Authority
- CA
- Canada
- Prior art keywords
- microparticles
- active substance
- contrast agent
- solid
- weight
- 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.)
- Expired
Links
- 239000011859 microparticle Substances 0.000 title claims abstract description 111
- 239000002961 echo contrast media Substances 0.000 title abstract description 25
- 239000007788 liquid Substances 0.000 claims abstract description 65
- 239000004094 surface-active agent Substances 0.000 claims abstract description 59
- 239000007787 solid Substances 0.000 claims abstract description 48
- 238000002604 ultrasonography Methods 0.000 claims abstract description 26
- 239000002872 contrast media Substances 0.000 claims description 50
- 238000002360 preparation method Methods 0.000 claims description 43
- 239000002245 particle Substances 0.000 claims description 41
- 239000000725 suspension Substances 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 32
- 239000000243 solution Substances 0.000 claims description 32
- 229930182830 galactose Natural products 0.000 claims description 25
- 238000002347 injection Methods 0.000 claims description 21
- 239000007924 injection Substances 0.000 claims description 21
- 239000011780 sodium chloride Substances 0.000 claims description 16
- -1 polyoxyethylene Polymers 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 13
- 238000009007 Diagnostic Kit Methods 0.000 claims description 11
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- 239000008101 lactose Substances 0.000 claims description 10
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- 239000007864 aqueous solution Substances 0.000 claims description 7
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- 235000011187 glycerol Nutrition 0.000 claims description 4
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- 229960003082 galactose Drugs 0.000 claims 7
- 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 claims 6
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- 235000013681 dietary sucrose Nutrition 0.000 claims 6
- 229960004793 sucrose Drugs 0.000 claims 6
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 claims 4
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims 4
- 235000010385 ascorbyl palmitate Nutrition 0.000 claims 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims 4
- 239000003708 ampul Substances 0.000 claims 2
- 235000019359 magnesium stearate Nutrition 0.000 claims 2
- ONAIRGOTKJCYEY-XXDXYRHBSA-N CCCCCCCCCCCCCCCCCC(O)=O.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 Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.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 ONAIRGOTKJCYEY-XXDXYRHBSA-N 0.000 claims 1
- 229920005862 polyol Polymers 0.000 claims 1
- 150000003077 polyols Chemical class 0.000 claims 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims 1
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- 210000002216 heart Anatomy 0.000 abstract description 20
- 210000000056 organ Anatomy 0.000 abstract description 5
- 210000004165 myocardium Anatomy 0.000 abstract description 4
- 210000003734 kidney Anatomy 0.000 abstract description 3
- 210000004185 liver Anatomy 0.000 abstract description 3
- 210000000952 spleen Anatomy 0.000 abstract description 3
- 238000001990 intravenous administration Methods 0.000 abstract description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 37
- 238000009826 distribution Methods 0.000 description 23
- 239000008280 blood Substances 0.000 description 15
- 210000004369 blood Anatomy 0.000 description 15
- 239000008215 water for injection Substances 0.000 description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 210000004072 lung Anatomy 0.000 description 5
- 230000002093 peripheral effect Effects 0.000 description 5
- 210000003462 vein Anatomy 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- 238000000227 grinding Methods 0.000 description 4
- 238000009877 rendering Methods 0.000 description 4
- 238000001665 trituration Methods 0.000 description 4
- 235000009434 Actinidia chinensis Nutrition 0.000 description 3
- 244000298697 Actinidia deliciosa Species 0.000 description 3
- 235000009436 Actinidia deliciosa Nutrition 0.000 description 3
- 208000005189 Embolism Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000002592 echocardiography Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000008227 sterile water for injection Substances 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 210000000709 aorta Anatomy 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Polymers OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- JNYAEWCLZODPBN-UHFFFAOYSA-N 2-(1,2-dihydroxyethyl)oxolane-3,4-diol Polymers OCC(O)C1OCC(O)C1O JNYAEWCLZODPBN-UHFFFAOYSA-N 0.000 description 1
- XLMXUUQMSMKFMH-UZRURVBFSA-N 2-hydroxyethyl (z,12r)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC(=O)OCCO XLMXUUQMSMKFMH-UZRURVBFSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 241001504519 Papio ursinus Species 0.000 description 1
- 244000236480 Podophyllum peltatum Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 238000004581 coalescence Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012084 conversion product Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940021013 electrolyte solution Drugs 0.000 description 1
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 210000005246 left atrium Anatomy 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 210000003492 pulmonary vein Anatomy 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 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 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- JNYAEWCLZODPBN-CTQIIAAMSA-N sorbitan Polymers OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
- A61B90/39—Markers, e.g. radio-opaque or breast lesions markers
- A61B2090/3925—Markers, e.g. radio-opaque or breast lesions markers ultrasonic
Abstract
ABSTRACT
An ultrasound contrast agent containing micro-particles and gaseous micro-bubbles is described which contains microparticles of a solid surface-active substance, and optionally microparticles of a solid non-surface-active substance, in a liquid carrier.
In the case of ultrasound images, after intra-venous administration it permits the contrasting of the left-hand side of the heart, the myocardium and other organs, such as the liver, the spleen, the kidneys and the right-hand side of the heart.
An ultrasound contrast agent containing micro-particles and gaseous micro-bubbles is described which contains microparticles of a solid surface-active substance, and optionally microparticles of a solid non-surface-active substance, in a liquid carrier.
In the case of ultrasound images, after intra-venous administration it permits the contrasting of the left-hand side of the heart, the myocardium and other organs, such as the liver, the spleen, the kidneys and the right-hand side of the heart.
Description
~LfJR 30~
The Invention relates to contrast agents for use In ultrasound diagnosis of the human or animal body.
The examination of organs using ultrasound (sonography) Is a diagnostic method which has been well established and pray-tlsed for some years. Ultrasound waves In the megahertz range (above 2 megahertz with wavelengths of between 1 and 0.2 mm) are reflected at the Interfaces of various types of tissue. The resulting echoes are amplified and rendered visible. Of partlcu-far Importance Is the examination of the heart by this method which Is known as echocardlography (Heft, Jar. et at.: Clinical echocardlography, Future, Mount Classic, New York 1978; Killer, E.
KlInlsche Echokardlographle, Eke, Stuttgart 1979; Stephen, G. et at.: Echokardlographle, Theme, Stuttgart-New York 1981; G.
Blamlno, L. Lange: Echokardlographle, Hoechst AGO 1983).
Since fluids, Including blood, produce ultrasound Image contrast only when there are differences In density with respect to the surroundings, posslbllltles were sought of rendering the blood and Its circulation visible for ultrasound examination and this may be effected by Injecting extremely fine gas bubbles Into I
the bloodstream.
Several methods of producing and stabilizing gas bubbles have been described in the literature. They can be produced, for example, before injection into the bloodstream, by vigorously shaking or stirring a liquid solution, such, for example, as sodium chloride solution, dye solution or previously removed blood.
Although ultrasound image contrast is achieved by these methods, they have serious disadvantages which are manifested in poor reproducibility, greatly fluctuating size of the gas bubbles and a certain risk of embolism due to a proportion of large visible bubbles. Some of these disadvantages have been eliminated by other production processes, such as, for example, by the process of US. Patent No. 3,640,271 in which bubbles of a reproducible size are produced by filtration or by the use of direct current electrode apparatus. Against the advantage of being able to produce gas bubbles of a reproducible size is the disadvantage of the considerable technical outlay involved.
US. Patent No. 4,276,885 describes the production of gas micro-bubbles of a specific size which are surrounded by a gelatin membrane which protects them from coalescence. The prepared bubbles can be stored only in the "frozen" state, for example by storing at refrigerator temperature, and they must ~;Lf'~3~0~
..
be raised to body temperature again before they can be used.
US. Patent No. 4,265,251 describes the production and use of gas micro-bubbles with a solid saccharine covering, which bubbles may be filled with a pressurized gas. If they are under normal pressure, they can be used as ultrasound image contrast agents;
when used at an elevated internal pressure, they can be used for measuring blood pressure. Although in this lo case the storage of the solid gas bubbles does not present any problem, the technical outlay involved in their production gives rise to high-costs as a result of the complex techniques.
- The risks involved with the hitherto known contrast agents for ultrasound diagnosis are caused by two factors: the size and number both of the particles of solid material and also of the gas bubbles.
The ultrasound contrast agents prepared by the previously described methods have, in all cases, possessed only some of the following properties that are required:-1. Exclusion of the risk of embolism (dependent on size and number of gas bubbles and size and number of particles of solid material).
The Invention relates to contrast agents for use In ultrasound diagnosis of the human or animal body.
The examination of organs using ultrasound (sonography) Is a diagnostic method which has been well established and pray-tlsed for some years. Ultrasound waves In the megahertz range (above 2 megahertz with wavelengths of between 1 and 0.2 mm) are reflected at the Interfaces of various types of tissue. The resulting echoes are amplified and rendered visible. Of partlcu-far Importance Is the examination of the heart by this method which Is known as echocardlography (Heft, Jar. et at.: Clinical echocardlography, Future, Mount Classic, New York 1978; Killer, E.
KlInlsche Echokardlographle, Eke, Stuttgart 1979; Stephen, G. et at.: Echokardlographle, Theme, Stuttgart-New York 1981; G.
Blamlno, L. Lange: Echokardlographle, Hoechst AGO 1983).
Since fluids, Including blood, produce ultrasound Image contrast only when there are differences In density with respect to the surroundings, posslbllltles were sought of rendering the blood and Its circulation visible for ultrasound examination and this may be effected by Injecting extremely fine gas bubbles Into I
the bloodstream.
Several methods of producing and stabilizing gas bubbles have been described in the literature. They can be produced, for example, before injection into the bloodstream, by vigorously shaking or stirring a liquid solution, such, for example, as sodium chloride solution, dye solution or previously removed blood.
Although ultrasound image contrast is achieved by these methods, they have serious disadvantages which are manifested in poor reproducibility, greatly fluctuating size of the gas bubbles and a certain risk of embolism due to a proportion of large visible bubbles. Some of these disadvantages have been eliminated by other production processes, such as, for example, by the process of US. Patent No. 3,640,271 in which bubbles of a reproducible size are produced by filtration or by the use of direct current electrode apparatus. Against the advantage of being able to produce gas bubbles of a reproducible size is the disadvantage of the considerable technical outlay involved.
US. Patent No. 4,276,885 describes the production of gas micro-bubbles of a specific size which are surrounded by a gelatin membrane which protects them from coalescence. The prepared bubbles can be stored only in the "frozen" state, for example by storing at refrigerator temperature, and they must ~;Lf'~3~0~
..
be raised to body temperature again before they can be used.
US. Patent No. 4,265,251 describes the production and use of gas micro-bubbles with a solid saccharine covering, which bubbles may be filled with a pressurized gas. If they are under normal pressure, they can be used as ultrasound image contrast agents;
when used at an elevated internal pressure, they can be used for measuring blood pressure. Although in this lo case the storage of the solid gas bubbles does not present any problem, the technical outlay involved in their production gives rise to high-costs as a result of the complex techniques.
- The risks involved with the hitherto known contrast agents for ultrasound diagnosis are caused by two factors: the size and number both of the particles of solid material and also of the gas bubbles.
The ultrasound contrast agents prepared by the previously described methods have, in all cases, possessed only some of the following properties that are required:-1. Exclusion of the risk of embolism (dependent on size and number of gas bubbles and size and number of particles of solid material).
2. Reproducibility.
3. Sufficiently long stability.
I I
I I
4. Ability to pass through the lungs, for example In order to obtain ultrasound Image contrast of the left-hand side of the heart.
5. Ability to pass through the capillaries.
6. Sterility and freedom from pyrogens.
7. Easy production at reasonable cost.
8. Easy storage.
European Patent Application No. 52575 published May 26, 1982 to Ultrasound Inc. describes the production of ultrasound contrast agents containing gas bubbles that are supposed to posy sews these necessary properties. However, In order to produce them, mlcropartlcles of a solid crystalline substance, such as, for example, galactose, are suspended In a liquid carrier, and the gas, which Is adsorbed at the particle surface and Is enclosed In cavities between the particles or In Intercrystalllne cavities, forms the gas bubbles. The resulting suspension of gas bubbles and mlcropartlcles Is Injected over a period of 10 men-vies. Although according to European Patent SpeclfIcatlon 52575 the suspension prepared by the described method Is capable, after Injection Into a peripheral vein, of appearing both on the fight-hand side of the heart and also, after passing through the lungs, on the left-hand side of the heart and of rendering visible the blood there and Its circulation during ultrasound examination, It was found when checked that the contrast medium prepared by the method 'I
391~9~
described in European Application No. 52575 and injected into a peripheral vein did not in fact produce ultrasound echoes in the left-hand side of the heart.
An object of the present invention is to provide a contrast agent for ultrasound diagnosis which is capable, after being administered intravenously, of rendering visible for ultrasound the blood and its circulation conditions not only on the right-hand side of the heart but also, after passing through the capillary bed of the lungs, on the left-hand side of the heart. In addition, it should also permit the representation of the circulation of blood through other organs, such as the myocardium, the liver, the spleen and the kidneys.
The present invention provides a contrast agent for use in the ultrasound diagnosis of the human or animal body, which comprises micro particles of a solid surface-active substance and micro-bubbles of a gas in - a liquid carrier. If desired, the liquid carrier also contains micro particles of a solid non-surface active agent.
It will be understood that the constituents of the contrast agents of the invention must be physiologically tolerable, and this, of course, equally applies to the liquid media and diagnostic kits described below.
The ultrasound contrast agents of the present kiwi invention possess all the above-mentioned properties that are expected of such a contrast agent.
The invention also provides a liquid medium for use in making up the ultrasound contrast agent, which comprises a suspension of micro particles of a solid surface-active substance, and, if desired, micro-particles of a solid non-surface active substance, in a liquid carrier.
Surprisingly, we have found that, by suspending micro particles of a solid surface-active substance, optionally in conjunction with micro particles of a solid non-surface-active substance, in a liquid carrier, an ultrasound contrast agent is obtained - which, after being injected into a peripheral vein, permits reproducible ultrasound images even of blood in the arterial left-hand side of the heart. Since the left-hand side of the heart can be reached with the ultrasound contrast agent of the invention after intravenous administration, ultrasound contrasts of other organs supplied with blood from the aorta, such as the myocardium, the liver, the spleen, the kidneys, inter alias are therefore also possible after venous administration. The ultrasound contrast agent of the invention is, of course, also suitable for contrasts on the right-hand side of the heart and for all other uses as an ultrasound image contrast medium.
All substances that are physiologically tolerable in the quantities used, that is, that have a low toxicity and/or are biologically degradable and the melting point of which is higher than room temperature, are suitable as the surface-active substance for the production of micro particles. Especially suitable are lecithins, lecithin fractions and their conversion products, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, polyoxyethylated sorbitan fatty acid esters, glycerine polyethylene - 10 glycol oxystearate, glycerine polyethylene glycol ricinoleate, ethoxylated soya strolls, ethoxylated castor oils and their hydrogenated derivatives, cholesterol, polyoxyethylene fatty acid struts and polyoxyethylenepolyoxypropylene polymers 15 having a molecular weight of from 6800 to 8975, 13300 and 16250, succors esters, such, for example, as sugar esters, for example succors dipalmitate and succors monolaurate or succors glycerides and xyloglycerides, saturated or unsaturated (C4-C20)-fatty alcohols or (C4-C20)-fatty acids or their metal salts, moo-, dip and triglycerides, sorbitan fatty acid esters, fatty acid esters of succors or fatty acid esters such, for example, as bottle Stewart and acquirable palpitate; calcium Stewart, the succors esters of Laurie acid Starkey acid and palmitic acid, and acquirable palpitate are preferred.
The rate at which the micro particles of the surface-active substance dissolve in the liquid carrier should be slower than the rate at which these micro particles dissolve in the blood. Advantageously, the volubility of the micro particles of the surface-active substance in the liquid carrier is such that when they are introduced into it they do not start to dissolve in it to a substantial extent for at least 10 minutes. It will be appreciated that upon administration of the contrast agent the micro particles - of the surface-active substance will start to dissolve in the blood.
The solid surface-active substance of the contrast agent is used in a concentration of from 0.01 to 5 %, preferably from 0.Q4 to 0.5 %, by weight of the contrast agent.
If desired, the micro particles of the surface-active substance can be used in conjunction with micro particles of a physiologically tolerable non-surface-active crystalline solid. Organic and inorganic substances can be used as the crystalline solid, for example salts such, for example, as sodium chloride, sodium citrate, sodium acetate or sodium tart rate, monosaccharides such, for example, as glucose, fructose or galactose; disaccharides such, for example, as succors, lactose or maltose; pentoses such, for example, as Arabians, Zulus or rubs; or Jo kiwi go cyclodextrines such, for example, as a-, B- or-y-cyclo-dextrine; galactose, lactose and -cyclodextrine are preferred. They are contained in the contrast agent of the invention in a concentration of from 5 to 50 %, 5 preferably from 9 to 40 %, by weight.
The micro particles may be produced by recrystallizing the surface-active substances and, if desired, non-surface-active substances under sterile conditions. They are then commented under sterile conditions, for example, by grinding in an air-jet mill, until the desired particle size is obtained.
Preferably the micro particles should have a median particle size of less than 10 em, advantageously less than 8 em, more especially within the range of from 1 to 3 em. The particle size is determined in a suitable measuring apparatus. The micro particles produced comprise either the commented surface-active substance alone or a mixture of the micro particles of the surface-active substance and a solid non-surface-active substance. In the latter case the ratio by weight of solid surface-active substance to solid non-surface-active substance is preferably from 0.01 to 5:100.
Both-the micro particle size achieved by the comminution process and also the size of the micro-bubbles containing a physiologically tolerable gas contained in the contrast agent of the invention ensure safe passage through the capillary system and the 3'~)9.~
capillary bed of the lungs and preclude the occurrence of embolism.
Some of the micro-bubbles required to produce image contrast are transported by the suspended micro-S particles, adsorbed at the surface of the micro-particles and enclosed in the cavities between the micro particles or enclosed in an inter crystalline manner.
The volume of gas transported by the micro particles in the form of gas micro-bubbles is from 0.02 to 0.6 ml per gram of micro particles.
Apart from its transporting function, the carrier liquid also has the function of stabilizing the suspend soon comprising micro particles and gas micro-bubbles, for example of preventing the sedimentation of the micro particles and the coalescing of the gas micro-bubbles or of delaying the dissolving process of the micro particles.
There may be used as the liquid carrier, for example, water, aqueous solutions of one or more inorganic salts such, for example, as physiological sodium chloride solution and buffer solutions, aqueous solutions of moo- or disaccharides such, for example, as galactose, glucose or lactose, mandrake or polyhydric alcohols, in so far as they are physiologically tolerable such, for example, as ethanol, propanol, isopropyl alcohol, polyethylene kiwi glycol, ethylene glycol, glycerine, propylene glycol, propylene glycol methyl ester or their aqueous solutions.
Water and physiological electrolyte solutions, . 5 such, for example, as physiological sodium chloride solution, and aqueous solutions of galactose and lactose, are preferred. If solutions are used, the concentration of the dissolved substance should be from 0.1 to on % by weight, preferably from 0.5 to 25 % by weight, and, more especially there may be mentioned, 0.9 % aqueous sodium chloride solution or 20 % aqueous galactose~
The invention also provides a process for the preparation of the contrast agent of the invention, wherein micro particles of a physiologically tolerable solid surface-active substance and, if desired, micro particles of a solid non-surface-active substance, are mixed with a liquid carrier and agitated until a homogeneous suspension is formed.
In order to prepare the ultrasound contrast agent in a form ready for use, the sterile liquid carrier may be added to the sterile solid surface-active substance, which is in the form of micro particles and which is optionally in conjunction with micro particles of a sterile solid non-surface-active substance, and this mixture with the carrier liquid is shaken until a homogeneous suspension has formed, which takes 3 . d approximately from 5 to 10 seconds. Immediately after its preparation, and at the latest up to 5 minutes thereafter, the resulting suspension is injected in the form of a bonus into a peripheral vein or into a catheter which is already present, from 0.01 ml to 1 ml/kg body weight being administered.
For reasons of expediency, the components necessary for the preparation of the contrast agent of the invention such, for example, as carrier liquid and micro particles of the surface-active substance, optionally in conjunction with micro particles of the solid non-surface-active substance are stored under sterile conditions in two separate vessels (A) and (B) respectively in the quantity necessary to carry out an examination. The size of vessel (B) should be such that the contents of vessel (A) can be transferred to (B) by means of an injection syringe and the resulting mixture can be shaken.
The present invention also provides a diagnostic kit for use in the ultrasound diagnosis of the human or animal body, which comprises (A) a container which contains a liquid carrier, and (B) a second container which contains micro particles of a solid surface-active substance and, if desired, micro particles of a solid non-surface-active substance.
AL Ed The contents of the containers are in a form ready for mixing together immediately before use.
Preferably container (A) is provided with a closure permitting the removal of the contents under --s sterile conditions and container (B) is provided with a closure permitting, under sterile conditions, the addition of the contents of vessel (A) and the removal of the resulting contrast agent.
Advantageously the containers A and B both have a volume of from 5 to 10 ml. When the non-surface active substance is present, the ratio by weight of the micro-particles of the surface active substance to the micro-particles of the non-surface-active substance is preferably from 0.01 to 5:100.
The use of the contrast agent of the invention is demonstrated by an echocardiographic examination of a baboon weighing 10 kg. which will now be described.
5 ml of carrier liquid (prepared according to Example 1 below) are removed from a Phil using an 2-0 injection syringe and are added to 2 g of micro-particles (prepared according to Example 1 B below) which are in a second Phil, and the mixture is shaken for approximately from 5 to 10 seconds until a homogeneous suspension has formed. 2 ml of this suspension are injected into a peripheral vein (V.
jugulars, brachialis or siphon) via a three-way tap having an infusion speed of at least 1 ml/sec., preferably 2-3 mljsec. Immediately after injecting the contrast agent, 10 ml of physiological sodium chloride solution are injected at the same speed so that the contrast agent bonus is maintained as complete as possible until the right-hand side of the heart is reached. Before, during and after injection, a commercially available transducer for echo cardiography is held against the thorax of the experimental animal so that a typical cross-section is obtained through the right-hand side and the left-hand side of the heart.
- This test procedure is understood and well known to a person skilled in the art.
If the ultrasound contrast agent reaches the right-- hand side of the heart, it is possible to follow in a 2-D echo image or an M-mode echo image how the blood marked by the contrast agent first reaches the level of the right-hand atrium and then the level of the right-hand ventricle and the pulmonary artery, homogeneous filling occurring for approximately 10 seconds. While the cavities in the right-hand side of the heart in the ultrasound image empty again, the blood which is rendered visible with contrast agent, after passing through the lungs, appears again in the pulmonary veins and fills the left atrium, the left ventricle and the aorta homogeneously, the contrast image lasting from 2 to 3 times longer than on the right-hand side of the heart. In addition to the representation of the blood I
flow through the cavities of the left-hand side of the heart, there is also a representation of the myocardium showing the circulation of the blood.
The use of the ultrasound contrast agent of the invention is, however, not limited to rendering visible the circulation of blood in the arterial part of the heart after venous administration but is also used with outstanding success as a contrast agent for examining the right-hand side of the heart and other organs.
The invention still further provides a method of ultrasound diagnosis of the human or animal body, wherein a contrast agent of the invention containing a dispersion of micro-bubbles is injected into a part of the human or animal body, preferably intravascularly, and an ultrasound image of the micro-bubbles at a site in the body which it is desired to investigate is obtained.
do The following Examples illustrate the invention, the parts and percentages being by weight unless otherwise indicated.
Example 1 I) Preparation of the carrier liquid 80 g of galactose are dissolved in water for injection purposes, made up to a volume of 400 ml and forced through a 0.2 em filter; 5 ml phallus are each filled with 4 ml of this filtrate and sterilized for 20 lo minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, 198 g of galactose are mixed intensively with 2 g of magnesium Stewart by homoeopathic trituration, passed through a 0.8 mm sieve, mixed loosely and ground in an air-jet mill until the following distribution of the particle size is obtained:
Median: 1.9 em 99 % < 6 em < 3 em.
The particle size and the distribution thereof are determined in a particle-measuring apparatus after suspension in an hydrous isopropanol. 5 ml phallus are each filled with 2 9 of the micro particles.
I
.
C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier fluid (20 % galactose solution in water, A) are introduced by means of an injection syringe into a Phil containing micro-particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 2 A) Preparation of the carrier liquid-Water for injection purposes is used and 5 ml phallus are each filled with 4 ml of the water and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, 198 g of galactose are mixed intensively with 2 g of acquirable palpitate by homoeopathic trituration and further processed as described in Example 1 under B), the following distribution of the particle size being obtained:
Median: 1.9 em 100 % 6 em 90 % < 3 em.
The particle size is determined as described in Example 1 under B).
5 ml phallus are each filled with 1200 my of the micro particles.
I
C) For the preparation of 4.5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (water, A) are introduced by means of an injection syringe into a Phil containing micro particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 3 A) Preparation of the carrier liquid:
4.5 g of sodium chloride are dissolved in water to a volume of 500 ml and the solution is forced through a 0.2 em filter; 5 ml phallus are each filled with 4 ml of - this solution and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, 198 g of an hydrous lactose ( < 0.3 mm) are mixed intensively with 2 g of acquirable palpitate by homoeopathic trituration and the mixture is further processed as described in Example 1 under B), the following distribution of the particle size being obtained:
Median: . 2.8 em 100 % < 48 em 99 % < 12 em.
The particle size is determined as described in Example 1 under B).
C~)6~
5 ml phallus are each filled with 1.6 9 of the micro particles.
C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil (0.9 % sodium chloride solution in water, A) are introduced by means of an injection syringe into a Phil containing micro particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 4 A) Preparation of the carrier liquid:
In the same manner as described in Example 3 under A), Ox % aqueous sodium chloride solution is prepared, introduced in 4 ml portions into 5 ml phallus and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, 199 g of â-cyclodextrine are mixed intensively with 1 g of acquirable palpitate by homoeopathic trituration and the mixture is further processed as described in Example 1 under B), micro-particles having the following size distribution being obtained:
Median: 2 em.
99 < 6 em - 90 % < 4 em.
I
The particle size is determined as described in Example 1 under 8).
5 ml phallus are each filled with 400 my of the micro particles.
C) For the preparation of 4 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil (0.9 % aqueous sodium chloride solution, A) are introduced by means of an injection syringe into a Phil containing micro particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 5 A) Preparation of the carrier liquid:
50 g of lactose are dissolved in water for injection purposes, made up to a volume of 500 ml and forced through a 0.2 em filter; 5 ml phallus are each filled with 4 ml of the solution and sterilized for 20 minutes at 120C.-B) Preparation of the micro particles:
Acquirable palpitate is dissolved in methanol, filtered under sterile conditions through a 0.2 em filter, recrystallized under sterile conditions, dried and passed through a 0.8 mm sieve. The sterile acquirable palpitate is then ground under sterile clue conditions in an air-jet mill until the following size distribution of the particles is obtained:
Median value: 1.9 em 99 < 6 em 90 % < 3 em.
The particle size and the distribution thereof are determined in a particle-measuring apparatus after (a my suspension in cold aqueous 0.1 Pluronic F68 solution.
Sterile 5 ml phallus are each filled with 40 my of the micro particles.
C) For the preparation of 4 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (10 lactose solution, A) are introduced by means of an injection syringe into a Phil containing the micro particles and shaken until a homogeneous suspension is formed.
- Example 6 A) Preparation of the carrier liquid:
4.5 g of sodium chloride are dissolved in water to a volume of 500 ml and the solution is forced through a 0.2 em filter; 5 ml phallus are each filled with 4 ml of this solution and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, a solution, filtered ~3C~
I
under sterile conditions, of OHS g of acquirable palpitate in 40 g of isopropanol is absorbed on 199.5 g of sterile galactose particles, the isopropanol is removed by drying at 40 and 200 torn and comminution is carried out in an air-jet mill until the following size distribution of the particles is obtained:
Median value: 1.9 em 99 % < 6 em 90 % < 3 em.
The particle size and the distribution thereof are determined in a particle-measuring apparatus, for example after suspension in isopropanol. 2 g portions of the micro particles are each packed into 5 ml phallus.
C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (0.9 % sodium chloride solution in water, A) are introduced by means of an injection syringe into a Phil containing micro-particles (B) and-shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 7 A) Preparation of the carrier liquid:
4.5 g of sodium chloride are dissolved in water and made up to a volume of 500 ml; the solution is forced through a 0.2 em filter and 5 ml falser each cut filled with 4 ml of this solution and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles: -Under sterile conditions, 199.5 g of galactose are triturated with 0.5 g of acquirable palpitate, mixed intensively, passed through a 0.8 mm sieve and commented in an air-jet mill until the following size distribution of the particles is obtained:
Median value: 1.9 em 99 % 6 em 90 % 3 em.
.
The particle size and the distribution thereof are determined in a particle-measuring apparatus, for example after suspension in isopropanol. 2 g portions of the micro particles are each packed into 5 ml phallus.
- C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (0.9 % sodium chloride solution in water, A) are introduced by means of an injection syringe into a Phil containing micro-particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Jo ~24-Example 8 A) Preparation of the carrier liquid:
Water for injection purposes is used and 5 ml phallus are each filled with 4 ml of the water and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, 0.5 g of succors monopalmitate is triturated with 199.5 g of galactose, mixed intensively, passed through a 0.8 mm sieve and ground in an air-jet mill until the following size distribution of the particles is obtained:
Median value: 1.9 em at least 99 % 6 em at least 90 % < 3 em.
The particle size and the distribution thereof are determined in a particle-measuring apparatus, for example after suspension in isopropanol. 2 g portions of the micro particles are each packed into 5 ml phallus.
C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (sterile water for injection purposes, A) are introduced by means of an injection syringe into a Phil containing micro-particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
I
Example 9 A) Preparation of the carrier liquid:
5 ml phallus are each filled with 4 ml of water used for injection purposes and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, a solution, filtered under sterile conditions, of 0.5 g of succors monopalmitate in 40 g of isopropanol is absorbed on 199.5 g of sterile galactose particles, the isopropanol is removed by drying at 40C and 200 torn and - grinding is carried out in an air-jet mill until the following size distribution of the particles is obtained:
Median value: 1.9 em at least 99 % 6 em at least 90 % < 3 em.
- The particle size and the distribution thereof are - determined in a particle-measuring apparatus after suspension in isopropanol. 2 g portions of the micro particles are each packed into 5 ml phallus.
C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents - of a Phil containing carrier liquid (water for injection purposes, A) are introduced by means of an do to injection syringe into a Phil containing micro-particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 10 A) Preparation of the carrier liquid:
5 ml phallus are each filled with 4 ml of water used for injection purposes and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, a solution, filtered under sterile conditions, of 0.5 g of succors - menstruate in 40 g of isopropanol is absorbed on 199.5 g of sterile galactose particles, the isopropanol is removed by drying at 40C and 200 torn and grinding is carried out in an air-jet mill until the following size distribution of the particle is obtained:
Median value: 1.9 em at least 99 % < 6 em at least 90 % < 3 em.
The particle size and the distribution thereof are determined in a particle-measuring apparatus after suspension in isopropanol. 2 g portions of the micro particles are each packed into 5 ml phallus.
I
C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (water for injection purposes, A) are introduced by means of an injection syringe into a Phil containing micro-particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 11 A) Preparation of the carrier liquid:
Water for injection purposes is used and 5 ml phallus are each filled with 4 ml of the water and sterilized for 20 minutes at 120C.
B) Preparation of the_microparticles:
under sterile conditions, 0.5 g of succors menstruate is triturated with 199.5 g of galactose, mixed intensively, passed through a 0.8 mm sieve and ground in an air-jet mill until the following size distribution of the particles is obtained:
Median value: 1.9 em at least 99 % < 6 em at least 90 % < 3 em.
The particle size and the distribution thereof are determined in a particle-measurinq apparatus after suspension in isopropanol. 2 g portions of the micro particles are each packed into 5 ml phallus.
C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (sterile water for injection purposes, A) are introduced by means of an injection syringe into a Phil containing micro-particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 12 A) Preparation of the carrier liquid:
5 ml phallus are each filled with 4 ml of water for injection purposes and sterilized for 20 minutes at 120C.
B) Preparation of the-microparticles:
Under sterile conditions, a solution, filtered under sterile conditions, of 0.5 9 of succors distrait in 40 9 of isopropanol is absorbed on 199.5 9 of sterile galactose particles, the isopropanol is removed by drying at 40C and 200 torn and grinding is carried out in an air-jet mill until the following size distribution of the particles is obtained:
Median value: 1.9 em at least 99 % 6 em at least 90 % < 3 em.
The particle size and the distribution thereof are ~L~3'~)9 determined in a particle-measuring apparatus after suspension in isopropanol. 2 g portions of the micro particles are each packed into 5 ml phallus.
C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (water for injection purposes, A) are introduced by means of an injection syringe into a Phil containing micro-particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 13 A) Preparation of the carrier liquid:
Water for injection purposes is used and 5 ml phallus are each filled with 4 ml of the water and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, 0.5 g of succors distrait is triturated with 199.5 g of galactose, mixed intensively, passed through a 0.8 mm sieve and ground in an air-jet mill until the following size distribution of the particles is obtained:
Median value: 1.9 em at least 99 % < 6 em at least 90 < 3 em.
The particle size and the distribution thereof are determined in a particle-measuring apparatus after suspension in isopropanol. 2 g portions of the micro particles are each packed into 5 ml phallus. --C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (sterile water for injection purposes, A) are introduced by means of an injection syringe into a Phil containing micro-- 10 particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
European Patent Application No. 52575 published May 26, 1982 to Ultrasound Inc. describes the production of ultrasound contrast agents containing gas bubbles that are supposed to posy sews these necessary properties. However, In order to produce them, mlcropartlcles of a solid crystalline substance, such as, for example, galactose, are suspended In a liquid carrier, and the gas, which Is adsorbed at the particle surface and Is enclosed In cavities between the particles or In Intercrystalllne cavities, forms the gas bubbles. The resulting suspension of gas bubbles and mlcropartlcles Is Injected over a period of 10 men-vies. Although according to European Patent SpeclfIcatlon 52575 the suspension prepared by the described method Is capable, after Injection Into a peripheral vein, of appearing both on the fight-hand side of the heart and also, after passing through the lungs, on the left-hand side of the heart and of rendering visible the blood there and Its circulation during ultrasound examination, It was found when checked that the contrast medium prepared by the method 'I
391~9~
described in European Application No. 52575 and injected into a peripheral vein did not in fact produce ultrasound echoes in the left-hand side of the heart.
An object of the present invention is to provide a contrast agent for ultrasound diagnosis which is capable, after being administered intravenously, of rendering visible for ultrasound the blood and its circulation conditions not only on the right-hand side of the heart but also, after passing through the capillary bed of the lungs, on the left-hand side of the heart. In addition, it should also permit the representation of the circulation of blood through other organs, such as the myocardium, the liver, the spleen and the kidneys.
The present invention provides a contrast agent for use in the ultrasound diagnosis of the human or animal body, which comprises micro particles of a solid surface-active substance and micro-bubbles of a gas in - a liquid carrier. If desired, the liquid carrier also contains micro particles of a solid non-surface active agent.
It will be understood that the constituents of the contrast agents of the invention must be physiologically tolerable, and this, of course, equally applies to the liquid media and diagnostic kits described below.
The ultrasound contrast agents of the present kiwi invention possess all the above-mentioned properties that are expected of such a contrast agent.
The invention also provides a liquid medium for use in making up the ultrasound contrast agent, which comprises a suspension of micro particles of a solid surface-active substance, and, if desired, micro-particles of a solid non-surface active substance, in a liquid carrier.
Surprisingly, we have found that, by suspending micro particles of a solid surface-active substance, optionally in conjunction with micro particles of a solid non-surface-active substance, in a liquid carrier, an ultrasound contrast agent is obtained - which, after being injected into a peripheral vein, permits reproducible ultrasound images even of blood in the arterial left-hand side of the heart. Since the left-hand side of the heart can be reached with the ultrasound contrast agent of the invention after intravenous administration, ultrasound contrasts of other organs supplied with blood from the aorta, such as the myocardium, the liver, the spleen, the kidneys, inter alias are therefore also possible after venous administration. The ultrasound contrast agent of the invention is, of course, also suitable for contrasts on the right-hand side of the heart and for all other uses as an ultrasound image contrast medium.
All substances that are physiologically tolerable in the quantities used, that is, that have a low toxicity and/or are biologically degradable and the melting point of which is higher than room temperature, are suitable as the surface-active substance for the production of micro particles. Especially suitable are lecithins, lecithin fractions and their conversion products, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, polyoxyethylated sorbitan fatty acid esters, glycerine polyethylene - 10 glycol oxystearate, glycerine polyethylene glycol ricinoleate, ethoxylated soya strolls, ethoxylated castor oils and their hydrogenated derivatives, cholesterol, polyoxyethylene fatty acid struts and polyoxyethylenepolyoxypropylene polymers 15 having a molecular weight of from 6800 to 8975, 13300 and 16250, succors esters, such, for example, as sugar esters, for example succors dipalmitate and succors monolaurate or succors glycerides and xyloglycerides, saturated or unsaturated (C4-C20)-fatty alcohols or (C4-C20)-fatty acids or their metal salts, moo-, dip and triglycerides, sorbitan fatty acid esters, fatty acid esters of succors or fatty acid esters such, for example, as bottle Stewart and acquirable palpitate; calcium Stewart, the succors esters of Laurie acid Starkey acid and palmitic acid, and acquirable palpitate are preferred.
The rate at which the micro particles of the surface-active substance dissolve in the liquid carrier should be slower than the rate at which these micro particles dissolve in the blood. Advantageously, the volubility of the micro particles of the surface-active substance in the liquid carrier is such that when they are introduced into it they do not start to dissolve in it to a substantial extent for at least 10 minutes. It will be appreciated that upon administration of the contrast agent the micro particles - of the surface-active substance will start to dissolve in the blood.
The solid surface-active substance of the contrast agent is used in a concentration of from 0.01 to 5 %, preferably from 0.Q4 to 0.5 %, by weight of the contrast agent.
If desired, the micro particles of the surface-active substance can be used in conjunction with micro particles of a physiologically tolerable non-surface-active crystalline solid. Organic and inorganic substances can be used as the crystalline solid, for example salts such, for example, as sodium chloride, sodium citrate, sodium acetate or sodium tart rate, monosaccharides such, for example, as glucose, fructose or galactose; disaccharides such, for example, as succors, lactose or maltose; pentoses such, for example, as Arabians, Zulus or rubs; or Jo kiwi go cyclodextrines such, for example, as a-, B- or-y-cyclo-dextrine; galactose, lactose and -cyclodextrine are preferred. They are contained in the contrast agent of the invention in a concentration of from 5 to 50 %, 5 preferably from 9 to 40 %, by weight.
The micro particles may be produced by recrystallizing the surface-active substances and, if desired, non-surface-active substances under sterile conditions. They are then commented under sterile conditions, for example, by grinding in an air-jet mill, until the desired particle size is obtained.
Preferably the micro particles should have a median particle size of less than 10 em, advantageously less than 8 em, more especially within the range of from 1 to 3 em. The particle size is determined in a suitable measuring apparatus. The micro particles produced comprise either the commented surface-active substance alone or a mixture of the micro particles of the surface-active substance and a solid non-surface-active substance. In the latter case the ratio by weight of solid surface-active substance to solid non-surface-active substance is preferably from 0.01 to 5:100.
Both-the micro particle size achieved by the comminution process and also the size of the micro-bubbles containing a physiologically tolerable gas contained in the contrast agent of the invention ensure safe passage through the capillary system and the 3'~)9.~
capillary bed of the lungs and preclude the occurrence of embolism.
Some of the micro-bubbles required to produce image contrast are transported by the suspended micro-S particles, adsorbed at the surface of the micro-particles and enclosed in the cavities between the micro particles or enclosed in an inter crystalline manner.
The volume of gas transported by the micro particles in the form of gas micro-bubbles is from 0.02 to 0.6 ml per gram of micro particles.
Apart from its transporting function, the carrier liquid also has the function of stabilizing the suspend soon comprising micro particles and gas micro-bubbles, for example of preventing the sedimentation of the micro particles and the coalescing of the gas micro-bubbles or of delaying the dissolving process of the micro particles.
There may be used as the liquid carrier, for example, water, aqueous solutions of one or more inorganic salts such, for example, as physiological sodium chloride solution and buffer solutions, aqueous solutions of moo- or disaccharides such, for example, as galactose, glucose or lactose, mandrake or polyhydric alcohols, in so far as they are physiologically tolerable such, for example, as ethanol, propanol, isopropyl alcohol, polyethylene kiwi glycol, ethylene glycol, glycerine, propylene glycol, propylene glycol methyl ester or their aqueous solutions.
Water and physiological electrolyte solutions, . 5 such, for example, as physiological sodium chloride solution, and aqueous solutions of galactose and lactose, are preferred. If solutions are used, the concentration of the dissolved substance should be from 0.1 to on % by weight, preferably from 0.5 to 25 % by weight, and, more especially there may be mentioned, 0.9 % aqueous sodium chloride solution or 20 % aqueous galactose~
The invention also provides a process for the preparation of the contrast agent of the invention, wherein micro particles of a physiologically tolerable solid surface-active substance and, if desired, micro particles of a solid non-surface-active substance, are mixed with a liquid carrier and agitated until a homogeneous suspension is formed.
In order to prepare the ultrasound contrast agent in a form ready for use, the sterile liquid carrier may be added to the sterile solid surface-active substance, which is in the form of micro particles and which is optionally in conjunction with micro particles of a sterile solid non-surface-active substance, and this mixture with the carrier liquid is shaken until a homogeneous suspension has formed, which takes 3 . d approximately from 5 to 10 seconds. Immediately after its preparation, and at the latest up to 5 minutes thereafter, the resulting suspension is injected in the form of a bonus into a peripheral vein or into a catheter which is already present, from 0.01 ml to 1 ml/kg body weight being administered.
For reasons of expediency, the components necessary for the preparation of the contrast agent of the invention such, for example, as carrier liquid and micro particles of the surface-active substance, optionally in conjunction with micro particles of the solid non-surface-active substance are stored under sterile conditions in two separate vessels (A) and (B) respectively in the quantity necessary to carry out an examination. The size of vessel (B) should be such that the contents of vessel (A) can be transferred to (B) by means of an injection syringe and the resulting mixture can be shaken.
The present invention also provides a diagnostic kit for use in the ultrasound diagnosis of the human or animal body, which comprises (A) a container which contains a liquid carrier, and (B) a second container which contains micro particles of a solid surface-active substance and, if desired, micro particles of a solid non-surface-active substance.
AL Ed The contents of the containers are in a form ready for mixing together immediately before use.
Preferably container (A) is provided with a closure permitting the removal of the contents under --s sterile conditions and container (B) is provided with a closure permitting, under sterile conditions, the addition of the contents of vessel (A) and the removal of the resulting contrast agent.
Advantageously the containers A and B both have a volume of from 5 to 10 ml. When the non-surface active substance is present, the ratio by weight of the micro-particles of the surface active substance to the micro-particles of the non-surface-active substance is preferably from 0.01 to 5:100.
The use of the contrast agent of the invention is demonstrated by an echocardiographic examination of a baboon weighing 10 kg. which will now be described.
5 ml of carrier liquid (prepared according to Example 1 below) are removed from a Phil using an 2-0 injection syringe and are added to 2 g of micro-particles (prepared according to Example 1 B below) which are in a second Phil, and the mixture is shaken for approximately from 5 to 10 seconds until a homogeneous suspension has formed. 2 ml of this suspension are injected into a peripheral vein (V.
jugulars, brachialis or siphon) via a three-way tap having an infusion speed of at least 1 ml/sec., preferably 2-3 mljsec. Immediately after injecting the contrast agent, 10 ml of physiological sodium chloride solution are injected at the same speed so that the contrast agent bonus is maintained as complete as possible until the right-hand side of the heart is reached. Before, during and after injection, a commercially available transducer for echo cardiography is held against the thorax of the experimental animal so that a typical cross-section is obtained through the right-hand side and the left-hand side of the heart.
- This test procedure is understood and well known to a person skilled in the art.
If the ultrasound contrast agent reaches the right-- hand side of the heart, it is possible to follow in a 2-D echo image or an M-mode echo image how the blood marked by the contrast agent first reaches the level of the right-hand atrium and then the level of the right-hand ventricle and the pulmonary artery, homogeneous filling occurring for approximately 10 seconds. While the cavities in the right-hand side of the heart in the ultrasound image empty again, the blood which is rendered visible with contrast agent, after passing through the lungs, appears again in the pulmonary veins and fills the left atrium, the left ventricle and the aorta homogeneously, the contrast image lasting from 2 to 3 times longer than on the right-hand side of the heart. In addition to the representation of the blood I
flow through the cavities of the left-hand side of the heart, there is also a representation of the myocardium showing the circulation of the blood.
The use of the ultrasound contrast agent of the invention is, however, not limited to rendering visible the circulation of blood in the arterial part of the heart after venous administration but is also used with outstanding success as a contrast agent for examining the right-hand side of the heart and other organs.
The invention still further provides a method of ultrasound diagnosis of the human or animal body, wherein a contrast agent of the invention containing a dispersion of micro-bubbles is injected into a part of the human or animal body, preferably intravascularly, and an ultrasound image of the micro-bubbles at a site in the body which it is desired to investigate is obtained.
do The following Examples illustrate the invention, the parts and percentages being by weight unless otherwise indicated.
Example 1 I) Preparation of the carrier liquid 80 g of galactose are dissolved in water for injection purposes, made up to a volume of 400 ml and forced through a 0.2 em filter; 5 ml phallus are each filled with 4 ml of this filtrate and sterilized for 20 lo minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, 198 g of galactose are mixed intensively with 2 g of magnesium Stewart by homoeopathic trituration, passed through a 0.8 mm sieve, mixed loosely and ground in an air-jet mill until the following distribution of the particle size is obtained:
Median: 1.9 em 99 % < 6 em < 3 em.
The particle size and the distribution thereof are determined in a particle-measuring apparatus after suspension in an hydrous isopropanol. 5 ml phallus are each filled with 2 9 of the micro particles.
I
.
C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier fluid (20 % galactose solution in water, A) are introduced by means of an injection syringe into a Phil containing micro-particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 2 A) Preparation of the carrier liquid-Water for injection purposes is used and 5 ml phallus are each filled with 4 ml of the water and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, 198 g of galactose are mixed intensively with 2 g of acquirable palpitate by homoeopathic trituration and further processed as described in Example 1 under B), the following distribution of the particle size being obtained:
Median: 1.9 em 100 % 6 em 90 % < 3 em.
The particle size is determined as described in Example 1 under B).
5 ml phallus are each filled with 1200 my of the micro particles.
I
C) For the preparation of 4.5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (water, A) are introduced by means of an injection syringe into a Phil containing micro particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 3 A) Preparation of the carrier liquid:
4.5 g of sodium chloride are dissolved in water to a volume of 500 ml and the solution is forced through a 0.2 em filter; 5 ml phallus are each filled with 4 ml of - this solution and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, 198 g of an hydrous lactose ( < 0.3 mm) are mixed intensively with 2 g of acquirable palpitate by homoeopathic trituration and the mixture is further processed as described in Example 1 under B), the following distribution of the particle size being obtained:
Median: . 2.8 em 100 % < 48 em 99 % < 12 em.
The particle size is determined as described in Example 1 under B).
C~)6~
5 ml phallus are each filled with 1.6 9 of the micro particles.
C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil (0.9 % sodium chloride solution in water, A) are introduced by means of an injection syringe into a Phil containing micro particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 4 A) Preparation of the carrier liquid:
In the same manner as described in Example 3 under A), Ox % aqueous sodium chloride solution is prepared, introduced in 4 ml portions into 5 ml phallus and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, 199 g of â-cyclodextrine are mixed intensively with 1 g of acquirable palpitate by homoeopathic trituration and the mixture is further processed as described in Example 1 under B), micro-particles having the following size distribution being obtained:
Median: 2 em.
99 < 6 em - 90 % < 4 em.
I
The particle size is determined as described in Example 1 under 8).
5 ml phallus are each filled with 400 my of the micro particles.
C) For the preparation of 4 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil (0.9 % aqueous sodium chloride solution, A) are introduced by means of an injection syringe into a Phil containing micro particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 5 A) Preparation of the carrier liquid:
50 g of lactose are dissolved in water for injection purposes, made up to a volume of 500 ml and forced through a 0.2 em filter; 5 ml phallus are each filled with 4 ml of the solution and sterilized for 20 minutes at 120C.-B) Preparation of the micro particles:
Acquirable palpitate is dissolved in methanol, filtered under sterile conditions through a 0.2 em filter, recrystallized under sterile conditions, dried and passed through a 0.8 mm sieve. The sterile acquirable palpitate is then ground under sterile clue conditions in an air-jet mill until the following size distribution of the particles is obtained:
Median value: 1.9 em 99 < 6 em 90 % < 3 em.
The particle size and the distribution thereof are determined in a particle-measuring apparatus after (a my suspension in cold aqueous 0.1 Pluronic F68 solution.
Sterile 5 ml phallus are each filled with 40 my of the micro particles.
C) For the preparation of 4 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (10 lactose solution, A) are introduced by means of an injection syringe into a Phil containing the micro particles and shaken until a homogeneous suspension is formed.
- Example 6 A) Preparation of the carrier liquid:
4.5 g of sodium chloride are dissolved in water to a volume of 500 ml and the solution is forced through a 0.2 em filter; 5 ml phallus are each filled with 4 ml of this solution and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, a solution, filtered ~3C~
I
under sterile conditions, of OHS g of acquirable palpitate in 40 g of isopropanol is absorbed on 199.5 g of sterile galactose particles, the isopropanol is removed by drying at 40 and 200 torn and comminution is carried out in an air-jet mill until the following size distribution of the particles is obtained:
Median value: 1.9 em 99 % < 6 em 90 % < 3 em.
The particle size and the distribution thereof are determined in a particle-measuring apparatus, for example after suspension in isopropanol. 2 g portions of the micro particles are each packed into 5 ml phallus.
C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (0.9 % sodium chloride solution in water, A) are introduced by means of an injection syringe into a Phil containing micro-particles (B) and-shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 7 A) Preparation of the carrier liquid:
4.5 g of sodium chloride are dissolved in water and made up to a volume of 500 ml; the solution is forced through a 0.2 em filter and 5 ml falser each cut filled with 4 ml of this solution and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles: -Under sterile conditions, 199.5 g of galactose are triturated with 0.5 g of acquirable palpitate, mixed intensively, passed through a 0.8 mm sieve and commented in an air-jet mill until the following size distribution of the particles is obtained:
Median value: 1.9 em 99 % 6 em 90 % 3 em.
.
The particle size and the distribution thereof are determined in a particle-measuring apparatus, for example after suspension in isopropanol. 2 g portions of the micro particles are each packed into 5 ml phallus.
- C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (0.9 % sodium chloride solution in water, A) are introduced by means of an injection syringe into a Phil containing micro-particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Jo ~24-Example 8 A) Preparation of the carrier liquid:
Water for injection purposes is used and 5 ml phallus are each filled with 4 ml of the water and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, 0.5 g of succors monopalmitate is triturated with 199.5 g of galactose, mixed intensively, passed through a 0.8 mm sieve and ground in an air-jet mill until the following size distribution of the particles is obtained:
Median value: 1.9 em at least 99 % 6 em at least 90 % < 3 em.
The particle size and the distribution thereof are determined in a particle-measuring apparatus, for example after suspension in isopropanol. 2 g portions of the micro particles are each packed into 5 ml phallus.
C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (sterile water for injection purposes, A) are introduced by means of an injection syringe into a Phil containing micro-particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
I
Example 9 A) Preparation of the carrier liquid:
5 ml phallus are each filled with 4 ml of water used for injection purposes and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, a solution, filtered under sterile conditions, of 0.5 g of succors monopalmitate in 40 g of isopropanol is absorbed on 199.5 g of sterile galactose particles, the isopropanol is removed by drying at 40C and 200 torn and - grinding is carried out in an air-jet mill until the following size distribution of the particles is obtained:
Median value: 1.9 em at least 99 % 6 em at least 90 % < 3 em.
- The particle size and the distribution thereof are - determined in a particle-measuring apparatus after suspension in isopropanol. 2 g portions of the micro particles are each packed into 5 ml phallus.
C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents - of a Phil containing carrier liquid (water for injection purposes, A) are introduced by means of an do to injection syringe into a Phil containing micro-particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 10 A) Preparation of the carrier liquid:
5 ml phallus are each filled with 4 ml of water used for injection purposes and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, a solution, filtered under sterile conditions, of 0.5 g of succors - menstruate in 40 g of isopropanol is absorbed on 199.5 g of sterile galactose particles, the isopropanol is removed by drying at 40C and 200 torn and grinding is carried out in an air-jet mill until the following size distribution of the particle is obtained:
Median value: 1.9 em at least 99 % < 6 em at least 90 % < 3 em.
The particle size and the distribution thereof are determined in a particle-measuring apparatus after suspension in isopropanol. 2 g portions of the micro particles are each packed into 5 ml phallus.
I
C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (water for injection purposes, A) are introduced by means of an injection syringe into a Phil containing micro-particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 11 A) Preparation of the carrier liquid:
Water for injection purposes is used and 5 ml phallus are each filled with 4 ml of the water and sterilized for 20 minutes at 120C.
B) Preparation of the_microparticles:
under sterile conditions, 0.5 g of succors menstruate is triturated with 199.5 g of galactose, mixed intensively, passed through a 0.8 mm sieve and ground in an air-jet mill until the following size distribution of the particles is obtained:
Median value: 1.9 em at least 99 % < 6 em at least 90 % < 3 em.
The particle size and the distribution thereof are determined in a particle-measurinq apparatus after suspension in isopropanol. 2 g portions of the micro particles are each packed into 5 ml phallus.
C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (sterile water for injection purposes, A) are introduced by means of an injection syringe into a Phil containing micro-particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 12 A) Preparation of the carrier liquid:
5 ml phallus are each filled with 4 ml of water for injection purposes and sterilized for 20 minutes at 120C.
B) Preparation of the-microparticles:
Under sterile conditions, a solution, filtered under sterile conditions, of 0.5 9 of succors distrait in 40 9 of isopropanol is absorbed on 199.5 9 of sterile galactose particles, the isopropanol is removed by drying at 40C and 200 torn and grinding is carried out in an air-jet mill until the following size distribution of the particles is obtained:
Median value: 1.9 em at least 99 % 6 em at least 90 % < 3 em.
The particle size and the distribution thereof are ~L~3'~)9 determined in a particle-measuring apparatus after suspension in isopropanol. 2 g portions of the micro particles are each packed into 5 ml phallus.
C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (water for injection purposes, A) are introduced by means of an injection syringe into a Phil containing micro-particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Example 13 A) Preparation of the carrier liquid:
Water for injection purposes is used and 5 ml phallus are each filled with 4 ml of the water and sterilized for 20 minutes at 120C.
B) Preparation of the micro particles:
Under sterile conditions, 0.5 g of succors distrait is triturated with 199.5 g of galactose, mixed intensively, passed through a 0.8 mm sieve and ground in an air-jet mill until the following size distribution of the particles is obtained:
Median value: 1.9 em at least 99 % < 6 em at least 90 < 3 em.
The particle size and the distribution thereof are determined in a particle-measuring apparatus after suspension in isopropanol. 2 g portions of the micro particles are each packed into 5 ml phallus. --C) For the preparation of 5 ml of the ultrasound contrast agent in a form ready for use, the contents of a Phil containing carrier liquid (sterile water for injection purposes, A) are introduced by means of an injection syringe into a Phil containing micro-- 10 particles (B) and shaken until a homogeneous suspension is formed (from 5 to 10 seconds).
Claims (47)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A contrast agent for use in the ultrasound diagno-sis of the human or animal body, which comprises microparticles of a solid surface-active substance and micro-bubbles of a gas in a liquid carrier.
2. A contrast agent as claimed in claim 1, wherein the liquid carrier also contains microparticles of a solid non-sur-face-active substance.
3. A contrast agent as claimed in claim 1, wherein the solid surface-active substance is a lecithin, a polyoxyethylene fatty acid ester, gylcerine polyethylene glycol ricinoieate, cholesterol, a polyoxyethylenepolyoxypropylene polymer, a saccha-rose ester, a xyloglyceride, a saturated or unsaturated (C4-C20)-fatty alcohol, a saturated or unsaturated (C4-C20)-fatty acid or a metal salt thereof, a mono- or di- or tri-glyceride or a fatty acid ester, or a mixture of any two or more of such substances.
4. A contrast agent as claimed in claim 3, wherein the solid surface active substance is magnesium stearate, ascorbyl palmitate, saccharose monopalmitate, saccharose monostearate or saccharose distearate, or a mixture of any two or more of such substances.
5. A contrast agent as claimed in claim 2, wherein the solid non-surface active substance is a cyclodextrine, a mono-saccharide, a disaccharide, a trisaccharide, a polyol or an inor-ganic or organic salt, or a mixture of any two or more of such substances.
6. A contrast agent as claimed in claim 2, wherein the solid non-surface-active substance is galactose, lactose or ? -cyclodextrine, or a mixture of two or more of such substances.
7. A contrast agent as claimed in claim 1, wherein the microparticles of the solid surface-active substance are present in a quantity of from 0.01 to 10% by weight.
8. A contrast agent as claimed in claim 7, wherein the microparticles of the solid surface-active substance are present in a quantity of from 0.01 to 5% by weight.
9. A contrast agent as claimed in claim 8, wherein the microparticles of the solid surface-active substance are present in a quantity of from 0.04 to 1% by weight.
10. A contrast agent as claimed in claim 2, wherein the microparticles of the solid non-surface-active substance are pre-sent in a quantity of from 5 to 50% by weight.
11. A contrast agent as claimed in claim 10, wherein the microparticles of the solid non-surface-active substance are present in a quantity of from 9 to 40% by weight.
12. A contrast agent as claimed in claim 2, 3 or 4, wherein the ratio by weight of the microparticles of the surface-active substance to the microparticles of the non-surface-active substance is from 0.01 to 5:100.
13. A contrast agent as claimed in claim 1, wherein the liquid carrier is water, a physiological electrolyte solution, an aqueous solution of a monohydric or polyhydric alcohol, or an aqueous solution of a mono- or di-saccharide.
14. A contrast agent as claimed in claim 13, wherein the liquid carrier is an aqueous solution of glycerine, polyethy-lene glycol or propylene glycol.
15. A contrast agent as claimed in claim 13, wherein the liquid carrier is physiological sodium chloride solution, 10%
aqueous lactose solution or 20% aqueous galactose solution.
aqueous lactose solution or 20% aqueous galactose solution.
16. A contrast agent as claimed in claim 1, 3 or 4, which comprises microparticles of magnesium stearate in a 20%
aqueous galactose solution.
aqueous galactose solution.
17. A contrast agent as claimed in claim 2, 3 or 4, which comprises microparticles of ascorbyl palmitate and galac-tose in water.
18. A contrast agent as claimed in claim 2, 3 or 4, which comprises microparticles of ascorbyl palmitate and ? -cyclodextrine in physiological sodium chloride solution.
19. A contrast agent as claimed in claim 1, 3 or 4, which comprises microparticles of ascorbyl palmitate in a 10%
aqueous lactose solution.
aqueous lactose solution.
20. A contrast agent as claimed in claim 2, 3 or 4, which comprises microparticles of saccharose monopalmitate and galactose in water.
21. A contrast agent as claimed in claim 2, 3 or 4, which comprises microparticles of saccharose monosterate and galactose in water.
22. A contrast agent as claimed in claim 2, 3 or 4, which comprises microparticles of saccharose distearate and galactose in water.
23. A contrast agent as claimed in claim 1, 2 or 3, wherein the microparticles have a median particle size of from 1 to 3µm.
24. A liquid medium for use in making up the contrast agent claimed in claim 1, which comprises a suspension of microparticles of a solid surface-active substance in a liquid carrier.
25. A liquid medium as claimed in claim 24, wherein the liquid carrier also contains microparticles of a solid non-sur-face active carrier.
26. A liquid medium as claimed in claim 24, which con-tains from 0.01 to 10% by weight of the microparticles of the solid surface-active substance.
27. A liquid medium as claimed in claim 26, which con-tains from 0.01 to 5% by weight of the microparticles of the solid surface-active substance.
28. A liquid medium as claimed in claim 27, which con-tains from 0.04 to 1% by weight of the microparticles of the solid surface-active substance.
29. A liquid medium as claimed in claim 25, which con-tains from 5 to 50% by weight of the microparticles of the solid non-surface-active solid substance.
30. A liquid medium as claimed in claim 29, which con-tains from 9 to 40% by weight of the microparticles of the solid non-surface-active substance.
31. A liquid medium as claimed in claim 24, wherein the surface-active substance is a substance(s) as claimed in claim 3 or 4.
32. A liquid medium as claimed in claim 25, wherein the non-surface-active substance is a substance(s) as claimed in claim 5 or 6.
33. A liquid medium as claimed in claim 24, wherein the liquid carrier is a liquid as claimed in claim 13 or 14.
34. A liquid medium as claimed in claim 24, 25 or 26, wherein the microparticles have a median particle size of from 1 to 3 µm.
35. A diagnostic kit for use in the ultrasound diagnosis of the human or animal body, which comprises (A) a container which contains a liquid carrier, and (B) a second container which contains microparticles of a solid surface-active substance, and a solid non-surface-active substance.
36. A kit as claimed in claim 35 in which the second container also contains microparticles of a solid non-surface-active substance.
37. A diagnostic kit as claimed in claim 35, wherein the containers A and B each has a volume of from 5 to 10 ml.
38. A diagnostic kit as claimed in claim 36, wherein the ratio by weight of the microparticles of the surface-active substance to the microparticles of the non-surface-active substance is from 0.01 to 5:100.
39. A diagnostic kit as claimed in claim 35, 36 or 37, wherein the surface-active substance is a substance(s) as claimed in claim 3 or 4.
40. A diagnostic kit as claimed in claim 36, wherein the non-surface-active substance is a substance(s) as claimed in claim 5 or 6.
41. A diagnostic kit as claimed in claim 35, wherein the liquid carrier is a liquid as claimed in claim 13 or 14.
42. A diagnostic kit as claimed in claim 35, 36 or 37 which also comprises an injection syringe for transfer-ring the contents of container (A) to container (B).
43. A diagnostic kit as claimed in claim 35, 36 or 37, wherein each of the containers (A) and (B) is a phial or ampoule.
44. A diagnostic kit as claimed in claim 35, 36 or 37, wherein the microparticles have a median particle size of from 1 to 3 µm.
45. A ampoule or phial for use in ultrasound diag-nosis of the human or animal body, which contains a contrast agent as claimed in claim 1, 2 or 3.
46. A process for the preparation of a contrast agent as claimed in claim 1, wherein microparticles of a solid surface-active substance are mixed with a liquid carrier and agitated until a homogeneous suspension is formed.
47. A process as claimed in claim 46 in which microparticles of a solid non-surface-active substance are also mixed with the liquid carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3313946.6 | 1983-04-15 | ||
| DE3313946A DE3313946A1 (en) | 1983-04-15 | 1983-04-15 | MICROPARTICLES AND GAS BUBBLES CONTAINING ULTRASONIC CONTRASTING AGENTS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1239092A true CA1239092A (en) | 1988-07-12 |
Family
ID=6196665
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000451730A Expired CA1239092A (en) | 1983-04-15 | 1984-04-11 | Ultrasound contrast agents containing microparticles and gas micro-bubbles |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0122624B1 (en) |
| JP (1) | JPS59205328A (en) |
| AT (1) | ATE36958T1 (en) |
| AU (1) | AU566928B2 (en) |
| CA (1) | CA1239092A (en) |
| DE (2) | DE3313946A1 (en) |
| DK (1) | DK165171C (en) |
| FI (1) | FI81264C (en) |
| IE (1) | IE57272B1 (en) |
| NO (1) | NO161356C (en) |
| NZ (1) | NZ207853A (en) |
| ZA (1) | ZA842801B (en) |
Cited By (21)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US5380411A (en) * | 1987-12-02 | 1995-01-10 | Schering Aktiengesellschaft | Ultrasound or shock wave work process and preparation for carrying out same |
| US5425366A (en) * | 1988-02-05 | 1995-06-20 | Schering Aktiengesellschaft | Ultrasonic contrast agents for color Doppler imaging |
| US5846518A (en) * | 1992-12-16 | 1998-12-08 | Bracco Research S.A. | Gas mixtures useful as ultrasound contrast media contrast agents containing the media and method |
| US5908610A (en) * | 1992-11-02 | 1999-06-01 | Bracco International B.V. | Stable microbubble suspensions comprising saturated phospholipios for ultrasonic echography |
| US5911972A (en) * | 1990-04-02 | 1999-06-15 | Bracco International B.V. | Stable microbubbles suspensions injectable into living organisms |
| US6071496A (en) * | 1988-02-05 | 2000-06-06 | Scharing Aktiengesellschaft | Polyalkylcyanoacrylate agents and methods for enhancing contrast in ultrasound imaging |
| US6585955B1 (en) | 1990-04-02 | 2003-07-01 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
| US6613306B1 (en) | 1990-04-02 | 2003-09-02 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
| US6881397B2 (en) | 1990-04-02 | 2005-04-19 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
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| USRE39146E1 (en) | 1990-04-02 | 2006-06-27 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
| US7083778B2 (en) | 1991-05-03 | 2006-08-01 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
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| DE3637926C1 (en) * | 1986-11-05 | 1987-11-26 | Schering Ag | Ultrasonic manometry in a liquid using microbubbles |
| DE3741199A1 (en) * | 1987-12-02 | 1989-08-17 | Schering Ag | USE OF ULTRASONIC CONTRASTING AGENTS FOR ULTRASONIC LITHOTRIPSY |
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| US4277367A (en) * | 1978-10-23 | 1981-07-07 | Wisconsin Alumni Research Foundation | Phantom material and method |
| US4265251A (en) * | 1979-06-28 | 1981-05-05 | Rasor Associates, Inc. | Method of determining pressure within liquid containing vessel |
| CA1170569A (en) * | 1980-11-17 | 1984-07-10 | Julia S. Rasor | Microbubble precursors and methods for their production and use |
| DE3141641A1 (en) * | 1981-10-16 | 1983-04-28 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | ULTRASONIC CONTRAST AGENTS AND THEIR PRODUCTION |
-
1983
- 1983-04-15 DE DE3313946A patent/DE3313946A1/en not_active Withdrawn
-
1984
- 1984-02-20 DK DK078984A patent/DK165171C/en not_active IP Right Cessation
- 1984-04-05 IE IE835/84A patent/IE57272B1/en not_active IP Right Cessation
- 1984-04-11 CA CA000451730A patent/CA1239092A/en not_active Expired
- 1984-04-12 FI FI841462A patent/FI81264C/en not_active IP Right Cessation
- 1984-04-12 JP JP59071939A patent/JPS59205328A/en active Granted
- 1984-04-13 DE DE8484104210T patent/DE3473828D1/en not_active Expired
- 1984-04-13 AT AT84104210T patent/ATE36958T1/en not_active IP Right Cessation
- 1984-04-13 NO NO841489A patent/NO161356C/en not_active IP Right Cessation
- 1984-04-13 AU AU26805/84A patent/AU566928B2/en not_active Ceased
- 1984-04-13 NZ NZ207853A patent/NZ207853A/en unknown
- 1984-04-13 EP EP84104210A patent/EP0122624B1/en not_active Expired
- 1984-04-13 ZA ZA842801A patent/ZA842801B/en unknown
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5380411A (en) * | 1987-12-02 | 1995-01-10 | Schering Aktiengesellschaft | Ultrasound or shock wave work process and preparation for carrying out same |
| US6071496A (en) * | 1988-02-05 | 2000-06-06 | Scharing Aktiengesellschaft | Polyalkylcyanoacrylate agents and methods for enhancing contrast in ultrasound imaging |
| US5425366A (en) * | 1988-02-05 | 1995-06-20 | Schering Aktiengesellschaft | Ultrasonic contrast agents for color Doppler imaging |
| US6177062B1 (en) | 1988-02-05 | 2001-01-23 | Schering Aktiengesellschaft | Agents and methods for enhancing contrast in ultrasound imaging |
| US7033574B1 (en) | 1990-04-02 | 2006-04-25 | Bracco International B.V. | Stable microbubbles suspensions injectable into living organisms |
| US5911972A (en) * | 1990-04-02 | 1999-06-15 | Bracco International B.V. | Stable microbubbles suspensions injectable into living organisms |
| US6136293A (en) * | 1990-04-02 | 2000-10-24 | Bracco International B.V. | Stable microbubbles suspensions containing saturated lamellar phospholipids |
| USRE39146E1 (en) | 1990-04-02 | 2006-06-27 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
| US6485705B1 (en) | 1990-04-02 | 2002-11-26 | Bracco International B.V. | Mixable combination for generating a suspension of stable microbubbles for ultrasonic imaging |
| US6585955B1 (en) | 1990-04-02 | 2003-07-01 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
| US6613306B1 (en) | 1990-04-02 | 2003-09-02 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
| US6881397B2 (en) | 1990-04-02 | 2005-04-19 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
| US6896875B2 (en) | 1990-04-02 | 2005-05-24 | Bracco International B.V. | Mixable combination for generating a suspension of stable microbubbles for ultrasonic imaging |
| US6989141B2 (en) | 1990-05-18 | 2006-01-24 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
| US7083778B2 (en) | 1991-05-03 | 2006-08-01 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
| US6592846B1 (en) | 1991-05-03 | 2003-07-15 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure resistant gas-filled microvesicles and methods for thereof preparation thereof |
| US6187288B1 (en) | 1992-02-11 | 2001-02-13 | Bracco International B.V. | Stable microbubble suspensions as enhancement agents for ultrasonic echography |
| US5908610A (en) * | 1992-11-02 | 1999-06-01 | Bracco International B.V. | Stable microbubble suspensions comprising saturated phospholipios for ultrasonic echography |
| US6183725B1 (en) | 1992-12-16 | 2001-02-06 | Bracco Research S.A. | Gas mixtures useful as ultrasound contrast media, contrast agents containing the media and method |
| US5846518A (en) * | 1992-12-16 | 1998-12-08 | Bracco Research S.A. | Gas mixtures useful as ultrasound contrast media contrast agents containing the media and method |
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| US9486274B2 (en) | 2005-09-07 | 2016-11-08 | Ulthera, Inc. | Dissection handpiece and method for reducing the appearance of cellulite |
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| US9510849B2 (en) | 2009-08-07 | 2016-12-06 | Ulthera, Inc. | Devices and methods for performing subcutaneous surgery |
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| US10271866B2 (en) | 2009-08-07 | 2019-04-30 | Ulthera, Inc. | Modular systems for treating tissue |
| US10485573B2 (en) | 2009-08-07 | 2019-11-26 | Ulthera, Inc. | Handpieces for tissue treatment |
| US10531888B2 (en) | 2009-08-07 | 2020-01-14 | Ulthera, Inc. | Methods for efficiently reducing the appearance of cellulite |
| US11096708B2 (en) | 2009-08-07 | 2021-08-24 | Ulthera, Inc. | Devices and methods for performing subcutaneous surgery |
| US11337725B2 (en) | 2009-08-07 | 2022-05-24 | Ulthera, Inc. | Handpieces for tissue treatment |
| US10603066B2 (en) | 2010-05-25 | 2020-03-31 | Ulthera, Inc. | Fluid-jet dissection system and method for reducing the appearance of cellulite |
| US8439940B2 (en) | 2010-12-22 | 2013-05-14 | Cabochon Aesthetics, Inc. | Dissection handpiece with aspiration means for reducing the appearance of cellulite |
| US11213618B2 (en) | 2010-12-22 | 2022-01-04 | Ulthera, Inc. | System for tissue dissection and aspiration |
Also Published As
| Publication number | Publication date |
|---|---|
| DK78984A (en) | 1984-10-16 |
| EP0122624A2 (en) | 1984-10-24 |
| DK165171C (en) | 1993-03-01 |
| JPH0425934B2 (en) | 1992-05-06 |
| DE3313946A1 (en) | 1984-10-18 |
| IE840835L (en) | 1984-10-15 |
| AU2680584A (en) | 1984-10-18 |
| NO841489L (en) | 1984-10-16 |
| IE57272B1 (en) | 1992-07-01 |
| JPS59205328A (en) | 1984-11-20 |
| EP0122624B1 (en) | 1988-09-07 |
| NO161356C (en) | 1989-08-09 |
| FI841462A (en) | 1984-10-16 |
| AU566928B2 (en) | 1987-11-05 |
| FI841462A0 (en) | 1984-04-12 |
| ZA842801B (en) | 1984-11-28 |
| ATE36958T1 (en) | 1988-09-15 |
| DK165171B (en) | 1992-10-19 |
| DE3473828D1 (en) | 1988-10-13 |
| EP0122624A3 (en) | 1986-11-20 |
| DK78984D0 (en) | 1984-02-20 |
| NO161356B (en) | 1989-05-02 |
| NZ207853A (en) | 1988-01-08 |
| FI81264C (en) | 1990-10-10 |
| FI81264B (en) | 1990-06-29 |
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