CA2154913C - Magnetically responsive composition for carrying biologically active substances and methods of production and use - Google Patents
Magnetically responsive composition for carrying biologically active substances and methods of production and useInfo
- Publication number
- CA2154913C CA2154913C CA002154913A CA2154913A CA2154913C CA 2154913 C CA2154913 C CA 2154913C CA 002154913 A CA002154913 A CA 002154913A CA 2154913 A CA2154913 A CA 2154913A CA 2154913 C CA2154913 C CA 2154913C
- Authority
- CA
- Canada
- Prior art keywords
- particles
- carbon
- composition
- carrier
- iron
- 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 - Fee Related
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 93
- 238000000034 method Methods 0.000 title claims abstract description 52
- 239000013543 active substance Substances 0.000 title claims abstract description 25
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 20
- 239000002245 particle Substances 0.000 claims abstract description 181
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 128
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 94
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 89
- 229910052742 iron Inorganic materials 0.000 claims abstract description 63
- 230000005291 magnetic effect Effects 0.000 claims abstract description 41
- 229940088623 biologically active substance Drugs 0.000 claims abstract description 34
- 239000000843 powder Substances 0.000 claims abstract description 16
- 239000000126 substance Substances 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 26
- 201000010099 disease Diseases 0.000 claims description 25
- 238000001727 in vivo Methods 0.000 claims description 14
- 238000010521 absorption reaction Methods 0.000 claims description 13
- 238000002347 injection Methods 0.000 claims description 12
- 239000007924 injection Substances 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 9
- 238000003801 milling Methods 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000008280 blood Substances 0.000 claims description 7
- 210000004369 blood Anatomy 0.000 claims description 7
- 230000010102 embolization Effects 0.000 claims description 7
- 230000004043 responsiveness Effects 0.000 claims description 7
- 210000004872 soft tissue Anatomy 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 5
- 238000012545 processing Methods 0.000 claims description 5
- 230000000259 anti-tumor effect Effects 0.000 claims description 4
- 210000004204 blood vessel Anatomy 0.000 claims description 4
- 230000005484 gravity Effects 0.000 claims description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 230000004044 response Effects 0.000 claims description 3
- 239000011812 mixed powder Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- 230000036512 infertility Effects 0.000 claims 1
- 238000003780 insertion Methods 0.000 claims 1
- 230000037431 insertion Effects 0.000 claims 1
- 239000011860 particles by size Substances 0.000 claims 1
- 238000009736 wetting Methods 0.000 claims 1
- 239000000725 suspension Substances 0.000 abstract description 9
- 239000000320 mechanical mixture Substances 0.000 abstract description 7
- 239000002131 composite material Substances 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 description 22
- 239000006185 dispersion Substances 0.000 description 13
- 241000700159 Rattus Species 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 239000011246 composite particle Substances 0.000 description 8
- 230000005294 ferromagnetic effect Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 238000003860 storage Methods 0.000 description 6
- 239000000969 carrier Substances 0.000 description 5
- 230000001575 pathological effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 239000004005 microsphere Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- OKTJSMMVPCPJKN-YPZZEJLDSA-N carbon-10 atom Chemical compound [10C] OKTJSMMVPCPJKN-YPZZEJLDSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 210000005075 mammary gland Anatomy 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000009827 uniform distribution Methods 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 201000000274 Carcinosarcoma Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 108010092726 Gelatinol Proteins 0.000 description 1
- 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 1
- 241000440580 Mammaria Species 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 101150054830 S100A6 gene Proteins 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 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 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 238000003508 chemical denaturation Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000012829 chemotherapy agent Substances 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 239000003302 ferromagnetic material Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000696 magnetic material Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000005272 metallurgy Methods 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 229940053973 novocaine Drugs 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000006833 reintegration Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5094—Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
A magnetically controllable, or guided, carrier composition and methods of use and productions are disclosed, the composition for carrying biologically active substances to a treatment zone in a body under control of a magnetic field. The composition comprises composite, volume-compounded ferrocarbon particles of 0.2 to 5.0 .mu.m in size, and preferably between 1.0 and 4.0 .mu.m, containing 1.0 to 95.0% by volume of carbon, and preferably between about 20 and 50%. The particles are produced by a joint deformation of a mechanical mixture of iron and carbon powders. The obtained particles are placed in a solution of a biologically active substance to absorb the substance onto the particles. The combination is administered in suspension.
Description
MAGNETICALLY RESPONSIVE COMPOSITION FOR CARRYING
BIOLOGICALLY ACTIVE SUBSTANCES AND METHODS OF PRODUCTION
AND USE
Field of the Invention This invention relates to compositions and methods for delivery of medicament to a selected location in a body, and, more particularly, relates to carriers for drugs, their methods of production and use, which provide for targeted magnetic transport of the drugs and the maintenance of them in a predetermined place, the aim being exercise of local influence on pathological structures in the body.
Back~round of the Invention Metallic carrier compositions used in the treatment of various disorders have been heretofore suggested and/or utilized (see, for example, U.S. Patent Nos.
4,849,209 and 4,106,488), and have included such compositions which are guided or controlled in a body in response to external application of a magnetic field (see, for example, U.S. Patent Nos. 4,501,726, 4,652,257 and 4,690,130). Such compositions have not always proven practical and/or entirely effective, however, for example lacking adequate capacity for carriage of the desired biologically active agent to the treatment site, having less than desirable magnetic susceptibility and/or being difficult to manufacture, store and/or use.
For example, one such known composition, deliverable by way of intravascular injection, includes microspheres made up of a ferromagnetic component covered with a biocompatible polymer (albumin, gelatine, polisaccharides) which also contains a drug (Driscol C.F.
et al. Prog. Am. Assoc. Cancer Res., 1980, p. 261).
It is possible to produce albumen microspheres up to 3.0 mcmm in size containing a magnetic material (magnetite Fe304) and anti-tumoral antibiotic doxorubine (Widder K. et al. J. Pharm. Sci. 1979, v.68, No. i, p.
BIOLOGICALLY ACTIVE SUBSTANCES AND METHODS OF PRODUCTION
AND USE
Field of the Invention This invention relates to compositions and methods for delivery of medicament to a selected location in a body, and, more particularly, relates to carriers for drugs, their methods of production and use, which provide for targeted magnetic transport of the drugs and the maintenance of them in a predetermined place, the aim being exercise of local influence on pathological structures in the body.
Back~round of the Invention Metallic carrier compositions used in the treatment of various disorders have been heretofore suggested and/or utilized (see, for example, U.S. Patent Nos.
4,849,209 and 4,106,488), and have included such compositions which are guided or controlled in a body in response to external application of a magnetic field (see, for example, U.S. Patent Nos. 4,501,726, 4,652,257 and 4,690,130). Such compositions have not always proven practical and/or entirely effective, however, for example lacking adequate capacity for carriage of the desired biologically active agent to the treatment site, having less than desirable magnetic susceptibility and/or being difficult to manufacture, store and/or use.
For example, one such known composition, deliverable by way of intravascular injection, includes microspheres made up of a ferromagnetic component covered with a biocompatible polymer (albumin, gelatine, polisaccharides) which also contains a drug (Driscol C.F.
et al. Prog. Am. Assoc. Cancer Res., 1980, p. 261).
It is possible to produce albumen microspheres up to 3.0 mcmm in size containing a magnetic material (magnetite Fe304) and anti-tumoral antibiotic doxorubine (Widder K. et al. J. Pharm. Sci. 1979, v.68, No. i, p.
79-82). Such microspheres are produced through thermal and/or chemical denaturation of albumin in an emulsion (water in oil), with the input phase containing a magnetite suspension in a medicinal solution. Similar technique has been used to produce magnetically controlled, or guided, microcapsules covered with ethylcellulose containing antibiotic mitimicine (Fujimoto S. et al., Cancer, 1985, v. 56, (10), p. 2404-2410).
Another method is to produce magnetically controlled to liposomes 200 to 800 nm in size carrying preparations which can dissolve atherosclerotic formations. This method is based on the ability of phospholipides to create closed membrane structures in the presence of water (Gregoriadis G., Ryman B.E., Biochem. J., 1971, v.124, p. 58).
The above compositions have a number of serious shortcomings which make their practical medical use difficult, including requirement of extremely high flux density magnetic fields for their control, the lack of technical ability to produce standard magnetically controlled microspheres or liposomes on an industrial scale and the inability to consistently sterilize and store such compositions without changing their designed properties.
To overcome these shortcomings a method for producing magnetically controlled dispersion has been suggested (See European Patent Office Publication No.
0 451 299 A1, by Kholodov L.E., Volkonsky V.A., Kolesnik N.F., et al.), the essence of which is that ferrocarbon particles be used as a ferromagnetic material. The ferrocarbon particles are produced by heating iron powder made up of particles 100 to 500 ~,m at temperatures of 800 to 1200°C in an oxygen containing atmosphere, with subsequent treatment by carbon monoxide at 400 to 700°C
until carbon particles in an amount of 10 to 90% mass begin emerging on the surface. A biologically active substance is then absorbed on them.
Another method is to produce magnetically controlled to liposomes 200 to 800 nm in size carrying preparations which can dissolve atherosclerotic formations. This method is based on the ability of phospholipides to create closed membrane structures in the presence of water (Gregoriadis G., Ryman B.E., Biochem. J., 1971, v.124, p. 58).
The above compositions have a number of serious shortcomings which make their practical medical use difficult, including requirement of extremely high flux density magnetic fields for their control, the lack of technical ability to produce standard magnetically controlled microspheres or liposomes on an industrial scale and the inability to consistently sterilize and store such compositions without changing their designed properties.
To overcome these shortcomings a method for producing magnetically controlled dispersion has been suggested (See European Patent Office Publication No.
0 451 299 A1, by Kholodov L.E., Volkonsky V.A., Kolesnik N.F., et al.), the essence of which is that ferrocarbon particles be used as a ferromagnetic material. The ferrocarbon particles are produced by heating iron powder made up of particles 100 to 500 ~,m at temperatures of 800 to 1200°C in an oxygen containing atmosphere, with subsequent treatment by carbon monoxide at 400 to 700°C
until carbon particles in an amount of 10 to 90% mass begin emerging on the surface. A biologically active substance is then absorbed on them.
(-- J 2154913 This technology of manufacturing ferrocarbon particles ~is rather complicated and requires a lot of power. The process is accompanied by oxidation of the ferromagnetic component due to the synthesis of ferrocarbon particles at a high temperature in an oxygen containing atmosphere which dramatically decreases magnetic susceptibility of the dispersion obtained in this way (a 2 times decrease on the average as compared with metallic iron). The magnetically controlled dispersion produced by this technology has relatively low absorption capacity (2.0 to 2.5% of the mass of a ferromagnetic particle is the typical upper limit of absorption of a biologically active substance on such particles).
Furthermore, the magnetically controlled particle itself has a ferromagnetic component of a spheroidal form with a thread-like carbon chain extending from it. The overall size of such a composite particle is less than 2.0 ~cm. Such structure of the ferrocarbon particle predetermines its relatively low absorption capacity, and also leads to breaking of the fragile thread-like chains of carbon from the ferromagnetic component during storage and transportation as well as difficulties during packaging because of its looseness.
Further development in this field could thus still be utilized.
Summary of the Invention It is an object of the present invention is to provide magnetically responsive composition for carrying biologically active substances and methods of production and use. In accordance with an aspect of the present invention there is provided, a magnetically responsive composition comprising particles including carbon and iron with the carbon substantially uniformly distributed throughout the particle volume, wherein the cross-sectional size of each particle is less than 5 pm.
A
3a 2 1 5 4 9 1 3 In accordance with another aspect of the invention, there is provided a method for producing a magnetically responsive composition for carrying a biologically active substance comprising mixing iron and carbon powders and milling the mixed powders for a time suf~cient to bind said powders into particles having a diameter of less than 5 pm and containing 1% to 95% by volume of the carbon, each particle including carbon and iron with said carbon distributed throughout the volume of each said particle and at both particle surface and particle interior.
In accordance with yet another aspect of the invention, there is provided a method for producing a magnetically responsive composition for localized in vivo treatment of disease comprising:
providing a mixture of iron and carbon;
mechanically processing said mixture suf~ciently to bind said carbon and said iron into particles having a diameter of from 0.2 to 5.0 pm, a substantial portion of said particles including carbon and iron with 1.0 to 95% by volume of carbon distributed throughout the volume of each particle;
separating said particles to select particles of a size between about 1 pm and 4 pm from said substantial portion of said particles; and absorbing a biologically or therapeutically active substance, selected for its efficacy in treating the disease, onto said selected particles.
In accordance with a further aspect of the invention, there is provided the use of a magnetically responsive composition, for localized in vivo treatment of disease comprising:
a carrier including particles between about 0.2 pm and 5 pm in cross-sectional size, each particle comprising between 1% to 95% carbon and iron, with said carbon being distributed throughout the volume of each said particle; and a biologically or therapeutically active substance, selected for its ef~cacy in treating the disease, absorbed on the particles;
inserting delivery means in a blood vessel of a body being tieated to within a short distance from a site to be treated and at a branch to a network of vessels carrying blood at said site;
A
- 3b injecting said carrier through said delivery means; and establishing a magnetic field exterior to the body and adjacent to said site of sufficient field strength to guide a substantial quantity of said injected carner to, and retain said substantial quantity of said carrier at, said site and to draw said carrier at said site adjacent to soft tissue of said network of vessels thus avoiding substantial embolization of any said network of vessels.
In accordance with yet a fi~rther aspect of the invention, there is provided the use of a magnetically responsive composition for localized in vivo treatment of disease comprising:
a carrier including particles between about 0.2 um and S ~m in cross-sectional size, each particle comprising between 1 % to 95% carbon and iron, with said carbon being distributed throughout the volume of each said particle; and a biologically or therapeutically active substance, selected for its efficacy in treating the disease, absorbed on the particles.
injecting said carrier with said biologically active substance absorbed thereon into a body; and establishing a magnetic field exterior to the body and adjacent to a treatment site of sufficient field strength to guide a substantial quantity of said injected carrier to, and retain said substantial quantity of said carrier at, said site.
This invention provides a magnetically responsive composition for carrying biologically active substances (any soluted substance can be carried, many of which have been heretofore suggested, for example, without limitation, alkylating agents, antimetabolites, antitumor antibiotic chemotherapy agents or combinations thereof, and other therapeutic agents and drugs such as systemic toxicity inhibitors, hydrocortisone or the like) , and :~ethods of production and use thereof, :~hereir. the above-mentioned shortcomings are eli:~inated.
A
Furthermore, the magnetically controlled particle itself has a ferromagnetic component of a spheroidal form with a thread-like carbon chain extending from it. The overall size of such a composite particle is less than 2.0 ~cm. Such structure of the ferrocarbon particle predetermines its relatively low absorption capacity, and also leads to breaking of the fragile thread-like chains of carbon from the ferromagnetic component during storage and transportation as well as difficulties during packaging because of its looseness.
Further development in this field could thus still be utilized.
Summary of the Invention It is an object of the present invention is to provide magnetically responsive composition for carrying biologically active substances and methods of production and use. In accordance with an aspect of the present invention there is provided, a magnetically responsive composition comprising particles including carbon and iron with the carbon substantially uniformly distributed throughout the particle volume, wherein the cross-sectional size of each particle is less than 5 pm.
A
3a 2 1 5 4 9 1 3 In accordance with another aspect of the invention, there is provided a method for producing a magnetically responsive composition for carrying a biologically active substance comprising mixing iron and carbon powders and milling the mixed powders for a time suf~cient to bind said powders into particles having a diameter of less than 5 pm and containing 1% to 95% by volume of the carbon, each particle including carbon and iron with said carbon distributed throughout the volume of each said particle and at both particle surface and particle interior.
In accordance with yet another aspect of the invention, there is provided a method for producing a magnetically responsive composition for localized in vivo treatment of disease comprising:
providing a mixture of iron and carbon;
mechanically processing said mixture suf~ciently to bind said carbon and said iron into particles having a diameter of from 0.2 to 5.0 pm, a substantial portion of said particles including carbon and iron with 1.0 to 95% by volume of carbon distributed throughout the volume of each particle;
separating said particles to select particles of a size between about 1 pm and 4 pm from said substantial portion of said particles; and absorbing a biologically or therapeutically active substance, selected for its efficacy in treating the disease, onto said selected particles.
In accordance with a further aspect of the invention, there is provided the use of a magnetically responsive composition, for localized in vivo treatment of disease comprising:
a carrier including particles between about 0.2 pm and 5 pm in cross-sectional size, each particle comprising between 1% to 95% carbon and iron, with said carbon being distributed throughout the volume of each said particle; and a biologically or therapeutically active substance, selected for its ef~cacy in treating the disease, absorbed on the particles;
inserting delivery means in a blood vessel of a body being tieated to within a short distance from a site to be treated and at a branch to a network of vessels carrying blood at said site;
A
- 3b injecting said carrier through said delivery means; and establishing a magnetic field exterior to the body and adjacent to said site of sufficient field strength to guide a substantial quantity of said injected carner to, and retain said substantial quantity of said carrier at, said site and to draw said carrier at said site adjacent to soft tissue of said network of vessels thus avoiding substantial embolization of any said network of vessels.
In accordance with yet a fi~rther aspect of the invention, there is provided the use of a magnetically responsive composition for localized in vivo treatment of disease comprising:
a carrier including particles between about 0.2 um and S ~m in cross-sectional size, each particle comprising between 1 % to 95% carbon and iron, with said carbon being distributed throughout the volume of each said particle; and a biologically or therapeutically active substance, selected for its efficacy in treating the disease, absorbed on the particles.
injecting said carrier with said biologically active substance absorbed thereon into a body; and establishing a magnetic field exterior to the body and adjacent to a treatment site of sufficient field strength to guide a substantial quantity of said injected carrier to, and retain said substantial quantity of said carrier at, said site.
This invention provides a magnetically responsive composition for carrying biologically active substances (any soluted substance can be carried, many of which have been heretofore suggested, for example, without limitation, alkylating agents, antimetabolites, antitumor antibiotic chemotherapy agents or combinations thereof, and other therapeutic agents and drugs such as systemic toxicity inhibitors, hydrocortisone or the like) , and :~ethods of production and use thereof, :~hereir. the above-mentioned shortcomings are eli:~inated.
A
The aim of this invention is to improve some parameters of magnetically controlled compositions used for the targeted transport of biologically active substances, including increasing relative absorption capacity, increasing magnetic susceptibilizy, intensifying therapeutic effect and easiness of use, as well as simpli~fying the technology of manufacturing the magnetically controlled composition and ensuring its guaranteed long storage without changing its desired characteristics.
This is achieved by using composite, volume-compounded ferrocarbon particles as a magnetically susceptible material for a magnetically controlled composition. These particles have a size of 0.2 to 5.0/Cm (and preferably from 1.0 to 4.0 ~m) and contain from 1.0 to 95.Oo (by volume) of carbon relatively uniformly distributed throughout the volume of a composite particle and strongly connected with iron, the particles being obtained by a joint deformation of a mechanical mixture of iron and carbon powders.
The composition utilized for localized in vivo treatment of disease includes a carrier including particles between about lum and 4~,m in size, each particle including carbon and iron with the carbon distributed throughout the volume of the particle, and a biologically active substance selected for its efficacy in treating the disease absorbed on the particles.
The method of producing the composition includes the step of jointly deforming a mechanical mixture of iron and carbon powders for a time sufficient to bind the powders into particles less than 5 ~cm in size, each particle including carbon and iron with the carbon distributed throughout the volume of each of the particles. The particles are preferably separated to select particles of a size of between about lum and 4~,m, after whi.ch a biologically active substance can be absorbed onto the selected particles.
a ~ 5~9 ~ 3 The methods of use include methods for localized in vivo treatment of disease comprising providing a magnetically responsive ferrocarbon carrier (such as the carrier of this invention) having a biologically active 5 substance selected for its efficacy in treating the disease absorbed thereon, injecting the carrier into the body of a patient, for example by inserting delivery means in a blood vessel to within a short distance from a site to be treated and at a branch or branches (preferably the most immediate) to a network of vessels carrying blood at the site and injecting the carrier through the delivery means, and establishing a magnetic field exterior to the body and adjacent to the site of sufficient field strength to guide a substantial quantity of the injected carrier to, and retain the substantial quantity of the carrier at, the site. Preferably, the magnetic field is of sufficient field strength to draw the carrier at the site adjacent to soft tissue of the network of vessels thus avoiding substantial embolization of any of the network of vessels.
It is therefore an object of this invention to provide an improved magneticaily responsive carrier composition for carrying biologically active substances and methods of production and use thereof.
It is another object of this invention to provide a magnetically responsive carrier for biologically active substances which has improved magnetic responsiveness, is capable of greater absorption of the biologically active substance, and which is durable during storage and use.
It is another object of this invention to provide a magnetically responsive composition for carrying a biologically active substance comprising particles less than 5 ~,m in size, each particle including carbon and iron with the carbon distributed throughout the volume of each particle.
It is still another object of this invention to provide a composition utilized for localiz~d in vivo treatment of disease including a carrier with particles i i between about l~,m and 4~m in size, each particle including carbon and iron with the carbon distributed throughout the volume of the particle, and a biologically active substance selected for its efficacy in treating the disease absorbed on the particles.
It is yet another object of this invention to provide a method of producing a magnetically responsive carrier composition including the step of jointly deforming a mechanical mixture of iron and carbon powders for a time sufficient to bind the powders into particles less than 5 ~,m in size, each particle including carbon and iron with the carbon distributed throughout the volume of each of the particles.
It is still another object of this invention to provide a method for producing a magnetically responsive composition for localized in vivo treatment of disease including the steps of providing a mixture of iron and carbon, mechanically processing the mixture sufficiently to bind the carbon and the iron into particles, a substantial portion of the particles including carbon and iron with the carbon distributed throughout the volume of each particle, separating the particles to select particles of a size of between about l~,m and 4~cm from the substantial portion of the particles, and absorbing a biologically active substance onto the selected particles.
It is yet another object of this invention to provide a method for localized in vivo treatment of disease in a body comprising providing a magnetically responsive ferrocarbon carrier having a biologically active substance selected for its efficacy in treating the disease absorbed thereon, inserting delivery means in a blood vessel to within a short distance from a site to be treated and at a branch or branches to a network of vessels carrying blood at the site, injecting the carrier through the delivery means, and establishing a magnetic field exterior to the body and adjacent to the site of sufficient field strength to guide a substantial quantity of the injected carrier to, and retain the substantial quantity of the carrier at, the site and to draw the carrier at the site adjacent to soft tissue of the network of vessels thus avoiding substantial embolization of any of the network of vessels.
It is still another object of this invention to provide a method for localized in vivo treatment of disease in a body comprising absorbing a biologically active substance onto a magnetically responsive carrier l0 composition including particles less than 5 ~.m in size, each particle including carbon and iron with the carbon distributed throughout the volume of each particle, injecting the carrier with the biologically active substance absorbed thereon into the body, and establishing a magnetic field exterior to the body and adjacent to a treatment site of sufficient field strength to guide a substantial quantity of the injected carrier to, and retain the substantial quantity of the carrier at, the site.
With these and other objects in view, which will become apparent to one skilled in the art as the description proceeds, this invention resides in the novel construction, combination, arrangement of parts and methods substantially as hereinafter described, and more particularly defined by the appended claims, it being understood that changes in the precise embodiment of the herein disclosed invention are meant to be included as come within the scope of the claims.
Brief Description of the Drawings The accompanying drawings illustrate a complete embodiment of the invention according to the best mode so far devised for the practical application of the principles thereof, and in which:
FIGURE 1 is a magnified photograph (12000x) of particles of the carrier composition of this invention;
FIGURE 2a is a magnified photograph (30,OOOx) of a particle of the carrier composition of this invention;
WO 94/16683 "~ PCT/US94/00892 FIGURE 2b is a sectional illustration of the particle of FIGURE 2a;
FIGURES 3a through 3h are illustrations of a tumor during periods of treatment utilizing drugs absorbed on the carrier composition and delivered to, and maintained at, the tumor site utilizing one method of this invention;
FIGURE 4 is a diagram illustrating one example of application and magnetic targeting of the carrier composition; and FIGURE 5 is a diagram illustrating the carrier composition (having a drug absorbed thereon) at a pathological structure.
Description of the Invention The magnetically controllable, or guided, carrier composition of this invention comprises composite, volume-compounded ferrocarbon particles of 0.2 to 5.0 ~,m in size, and preferably between 1.0 and 4.0 ~.m, containing 1.0 to 95.0% by volume of carbon, and preferably between about 20 and 50% (about 40% carbon having been found to exhibit characteristics useful in many applications). The particles are produced by a joint deformation of a mechanical mixture of iron and carbon powders, after which the obtained particles are placed in a solution of a biologically active substance, the finished product then being separated (it being understood that separation could occur before exposure to the biologically active substance).
As shown in FIGURES 1 and 2a, ferrocarbon particles 8 manufactured by the method of this invention are of a generally spheroidal shape, with the inclusions of carbon deposits 10 being located throughout the whole volume of each particle (both at the surface and the interior of each particle). Uniform distribution of carbon 10 throughout the whole volume of each composite particle provides for a strong connection between the components (iron 12 and carbon 10) cahich is not broken during -- WO 94/16683 ~~~/ PCT/US94/00892 prolonged storage of the magnetically controlled composition, its transportation, strewing, packing and direct use.
The choice of the particles' size is determined in part by the constraints imposed by technological capabilities on producing particles under 0.2 ~,m. With regard to the preferred particle size range, for particles less than 1.O~,m carrying capacity is needlessly reduced. With particle sizes exceeding 4.0 ~,m an undesired degree of embolization of vessels becomes possible, coagulation of dispersion may take place (which makes injections more difficult) and the speed of discharging biologically active substances from the particles in the targeted pathological zones slows.
Regarding the justification for the chosen range of volume content of carbon in composite particles 8, while with carbon content less than 1.00% by volume specific absorption capacity of the magnetically controlled particles 8 (in dispersion) is enough for the transport of the required amount of biologically active substance towards the pathologic zone, it takes a greater quanity of the carrier, either by increased dosage or by increased number of injections, to reach the required concentration of biologically active substance in the damaged tissues. With carbon content exceeding 95.00% by volume, the susceptibility, cr responsiveness, of composite particles 8 to a magnetic field decreases, and thus conditions for their control in the body worsen (although absorption capacity increases). In addition, the particles become rather friable at carbon content levels exceeding 95%, lacking in such case strong connection between the iron and carbon components, thus achieving less desirable technical characteristics and making their destruction (separation into constituent components) possible during storage and/or direct use.
The utilization of a method (such as is described below) which jointly deforms a mechanical mixture of iron and activated carbon powders enables achievement of a I
WO 94/16683 ~ PCT/US94/00892 substantially uniform distribution of carbon throughout the volume of each composite particle, ensures their spheroidal form and achieves a share of 0.2 to 4.0 ~m size composite particles of 50.00 to 95.00% or more of 5 production volume.
Due to the fact that it is metallic (i.e., substantially elemental) iron and not its oxides (as is the~case in previously known magnetically controlled dispersions) which is the ferromagnetic component in the 10 produced composite particles of this invention, the magnetic susceptibility, or responsiveness, of ferrocarbon particles 8 is considerably higher.
In addition, intensive mechanical deformation and/or reintegration of iron particles 12 and the resulting formation within the particles of a well-developed substructure (see FIGURE 2b), a connected network of iron forming a network of voids having carbon deposits 10 captured therein, which takes place during the process of joint deformation of the mechanical mixture of iron and carbon particles, also leads to an increase in the magnetic susceptibility of iron inclusions in ferrocarbon particles 8 as compared with non-deformed iron particles.
Thus, the composite ferrocarbon particles produced by the herein suggested method have, for example, from 2.5 to 4.0 times greater magnetic susceptibility than the particles of the previously known magnetically controlled dispersion shown in European Patent Office Publication No. 0 451 299 A1, though ferromagnetic content in both is about the same. This improved responsiveness of ferrocarbon particles 8 makes it possible, in some cases, to decrease if desired the intensity of the magnetic field or fields utilized to guide the particles, and thereby lessen its effect on the human organism subjected to the therapy.
Because of a larger surface of carbon deposits 10 in particles 8 in comparison with other previously known ferrocarbon carriers described above, specific absorption capacity is increased (from about 2.5% of the absorbed -- WO 94/16683 2 1 5 ~ g ~ 3 : ~ PCT/LJS94/00892 biologically active substance out of the mass of a previously known magnetically controlled particle to up to about 7.5% in the case of particles 8; or, in different terms, from 25 mg of biologically active substance per gram of the previously known magnetically controlled dispersion up to about 75 mg of absorbed biologically active substance per gram of particles 8).
This allows, in use, for injection of much less of the carrier to achieve a given dose of the biologically active substance or, alternatively, for higher dosage of the biologically active substance per injection over some previously known carriers.
The following describes a method of production of the carrier composition of this invention utilized to produce small quantities of the carrier, it being understood that other means and mechanisms could be conceived of for the joint deformation of iron and carbon powders which comprise the essential starting elements for production of the carrier. The procedure utilized exerts mechanical pressure on iron particles (normally spherical) to deform the iron particles and develop a substantial substructure which captures the carbon. It is felt that no molecular bonding is involved. The formation of the carrier particles is accomplished without the addition of heat in the process, and is conducted in the presence of a liquid, for example 96% ethanol, to inhibit oxidation of the iron and to assure that the carrier particles produced are clean (sterile). The liquid may also serve as a lubricant during the joint deformation of the iron and carbon particles, and it is felt that use of ethanol reduces compacting of carbon during processing resulting in less dense carbon deposits in the carrier composition, thereby providing greater absorption capacity.
For example, to produce carrier composition having a 60%/40% iron/carbon makeup, one part of substantially pure iron particles form l~,m to 300~cm (preferable 2/cm to 10~m) in size are mixed with 0.3 to 0.6 parts of s substantially pure activated carbon granules (typically about 50~,m to 600~Cm in size). The iron particles and carbon granules are mixed vigorously to achieve good distribution throughout the volume.
The mixture is put into a standard laboratory planetary ball, or attrition, mill of the type used in powdered metallurgy, for example having 6mm diameter balls (any other device capable of mechanically processing the mixture to its desired state could be utilized), with a ball spacing adequate for deformation of the iron and carbon (and depending on the size of the particles of iron and granules of carbon initially, ball spacing being adjusted during milling until the space between balls is ultimately about 2 to 3 ~,m at the end of the process). A liquid (for example, by volume, 1 part ethanol to one part of the iron/carbon mixture initially) is added and the mixture is milled for between 4 and 12 hours (or for the time necessary to produce the particles as heretofore described) with liquid being added periodically to maintain wetness of the mixture.
Depending on the mill used, the mill may be run at anywhere from 120 RPM to 1000 RPM, the process not being overly sensitive to the speed of the mill (it being felt that speeds over 1000 RPM could create an undesirable quantity of overly small particles).
After milling, the resulting particles are moved to a sterile environment (for example, an ultra-violet chamber) and are ambiently air dried (i.e., to evaporate the liquid).
By a combined process of magnetic selection and sievi.ng (for example, blowing the particles through a 4~cm filter), the particles are separated to obtain particles of 1-4 microns in size which exhibit desired magnetic responsiveness. It has been found that, utilizing a carefully monitored milling process, typically less than 5% of production is not within the appropriate size range and/or is otherwise unusable. The particles are then sorted into dosages (typically one gram doses) and packaged, care being taken at each stage to maintain a sterile environment.
When ready for use (or, in the alternative, before packaging where a carrier is to be delivered with a preselected biologically active substance already absorbed thereon), up to 75mg (50mg is preferred to be absolutely assured of 100% absorption) of the biologically active substance in solution is added to 1 gram of the carrier. When ready for application to a patient, the combination is placed into suspension (for example, 5 to 10 ml) utilizing normal procedures.
Experimental evidence shows increased therapeutic efficiency of the use of the magnetically controlled carrier composition of this invention with an anti-tumorous preparation on a tumorous growth in comparison with previously known magnetically controlled dispersions.
Tests were carried out on male rats of the Vistor Line (bred at Stolbovaya Station of the USSR Academy of Medical Sciences). The rats were infused with carcinosarcoma Worker 256 under the tail's skin. When the tumorous volume averaged 986 + 98 mm3 the animals were divided into 4 groups, 10 rats in each. The first group (group I) was a control group, and groups II
through IV where experimental ones.
The animals in group II were given intravenous injections of a water solution of rubomicine in the amount of 2 mg/kg during 5 days (the model of traditional use of such anti-cancerous preparat.ions in clinics). The rats in group III were injected with a suspension of ferrocarbon dispersion produced by the previously known method described in European Patent Office Publication No. 0 451 299 A1. The dosage of ferrocarbon particles was 160 mg/kg, and the dosage of absorbed rubomicine thereon was 3.2 mg/kg. This suspension was injected into the tail vein after placing a permanent magnet with an intensity of the magnetic field of 6000 oersteds on the surface of the tumor. Magnetic localization of the magnetically controlled suspension in the tumorous growth zone was monitored by x-ray pictures.
The animals from group IV were given (using the same injection and magnetic control techniques, including placement of a permanent magnet with an intensity of the magnetic field of 600 oersteds on the surface of the tumor and x-ray monitoring) a one-time intravenous injection of the magnetically controlled dispersion produced in accord with the methods of this invention, the dosage being 160 mg/kg. The combination of components (iron/carbon) in each individual particle of the dispersion was 60/40, which was similar to the ratio in the dispersion produced by the previously known method used in experimental group III.
Due to the improved absorptive capability of particles 8, the dose of rubomicine absorbed on the magnetically controlled carrier particles of this invention was 9.96 mg/kg, which was 2.8 times more than the rubomicine absorbed by the previously known carrier particles in the experiment with the rats of group III.
This result was achieved solely due to the relative specific absorption capacities of the given carriers.
Observation of the animals gave the following results. The life span of animals in control group I
averaged 21 + 1.5 days. In group II, as a results of prescribed intravenous injections of the water solution of rubomicine (model of traditional use of antitumorous drugs), the rats' life span increased by an average of 4.5 days (P < 0.05). The animals from experimental group III lived during 46 ~ 4.3 days, which was 2.2 times more (P > 0.001) than the life span of control animals.
In group IV, 6 rats out of 10 (i.e., 60% of the cases) demonstrated complete dissolution of the tumor, which took place during 5 to 7 days after the one-time injection of the suspension of the magnetically controlled composition. Moreover, the remaining 4 rats from this group lived during 57.4 + 5.9 days, which exceeded the life span of the animals from group III by 25.0%, and is 2.7 times more as compared with the rats from control group I. The animals from group IV which showed complete regression of the tumors did not see any recurrence of tumorous growth during 157 days of 5 observation which testifies to a complete elimination of the tumors in these rats.
Further cl~inical observation has documented the effectiveness of this invention. FIGURES 4 and 5 illustrate use of this invention for treatment and 10 observation of a 61 year-old woman admitted on February 13, 1992 to the Zil Hospital in Moscow, Russia (CIS) and diagnosed with cancer of the left mammary gland T3NXMx.
The diagnosis was first made in 1989 when a biopsy was done. In December of 1991, focal radiation therapy 15 (10 grey) resulted in the tumor being partially reduced.
The decision was made to use the intra-arterial selective chemotherapy method of localized in vivo treatment of this invention utilizing the carrier of this invention wi th doxorubycin (Adriamycin) absorbed on the carrier.
Before the treatment, the dimensions of the tumor (illustrated in FIGURES 3a and 3b) were 44mm x 33mm x 37mm (65mm x 45mm, manual). On February 24, 1992 a puncture of the femoral artery (FIGURE 4) and injection of a vascular catheter into the aorta according to the Seldinger method were performed under local anaesthesia (0.5% novocaine, 30 ml). Under roentgenologic and contrast control, the catheter was placed at 25mm distance from the branch to the left intra-pectoral artery (a. mammaria interna sinisra). A newly prepared suspension of gelatinol with ferrocarbon particles 8 having 15 mg doxorubycin (Adriamycin) absorbed thereon was injected through the catheter. At this time, a magnet having a magnetic field intensity of 15,000 oersteds was placed over the tumor. As a result, the injected suspension was localized and was kept by the magnetic field in the zone of the tumor for 20 minutes (a time sufficient for full microembolization of the tumor feeding capillaries). The patient's condition was satisfactory at the time of therapy.
As shown in FIGURES 3c and 3d, by February 28, 1992 the patient's condition had improved, with an ultrasonic examination of the left mammary gland showing the dimensions of the tumor at 42mm x 33mm x 40mm. The tumor had a legible contour. By March 12, 1992, the dimensions of the tumor were found to have been reduced by 66.3% to 32mm x 27mm x 2lmm (FIGURES 3e and 3f), and by April 14 l0 to have been reduced by 99.22% to lOmm x 6mm x 7mm (FIGURES 3g and 3h).
It is felt that by releasing the carrier immediately upstream of the tumor (or other pathological) site, rather than penetrating the tumor, equally effective application of the biologically active substance occurs while potentially benefitting the patient by limiting spread of disease occasioned by puncture of the tumorous tissue. While a larger magnetic field was utilized in the above example of treatment, it has been found that the carrier composition of this invention begins to react in a field as small as 250 oersteds/cm (prior art carriers needing a field as large a 500 oersteds/cm before being influenced).
Figure 5 illustrates what is believed to occur under magnetic control at the treatment site. Under the influence of the applied magnetic field, the carrier particles are induced into the capillary network feeding the tumor. The particles are drawn closely adjacent to the soft tissue of the lumen of the capillaries (or perhaps even into the soft tissue) thereby reducing or eliminating the potential for embolization of the vessels. The biologically active substance is released from the carrier particles by a dynamic process of replacement of the substance in the carrier by materials produced by the body (for example the necrotic products of the tumor itself), such as proteins, glucose, lipids, peptides, or the like, thus literally pushing the ~r WO 94/16683 2 1 5 4 9 1 3 ' ~ PCTIUS94/00892 biologically active substance out of the carrier particles.
To replace the biologically active substance in the carrier particles, it is felt that the replacing substance must have a higher specific gravity than the biologically active substance, thus accounting for the low degree of washout of the biologically active substance in the blood stream (typically under 10%). Even fractions of the carrier not attracted to the treatment site by the magnetic field or escaping from the treatment site (typically around l00) are effective, as these fractions remain active against tumor cells in the blood and elsewhere (metastasis reduction has been observed in some cases). Since the carrier composition is formed of material which is readily processed or metabolized by the body, all carrier particles are excreted or metabolized within 30 days of application.
As may be appreciated, an improved magnetically responsive carrier for biologically active substances and methods for producing and using the same are provided by this invention, particles forming the carrier exhibiting improved responsiveness to magnetic fields, having improved absorptive capacity, and being durable during storage and use.
This is achieved by using composite, volume-compounded ferrocarbon particles as a magnetically susceptible material for a magnetically controlled composition. These particles have a size of 0.2 to 5.0/Cm (and preferably from 1.0 to 4.0 ~m) and contain from 1.0 to 95.Oo (by volume) of carbon relatively uniformly distributed throughout the volume of a composite particle and strongly connected with iron, the particles being obtained by a joint deformation of a mechanical mixture of iron and carbon powders.
The composition utilized for localized in vivo treatment of disease includes a carrier including particles between about lum and 4~,m in size, each particle including carbon and iron with the carbon distributed throughout the volume of the particle, and a biologically active substance selected for its efficacy in treating the disease absorbed on the particles.
The method of producing the composition includes the step of jointly deforming a mechanical mixture of iron and carbon powders for a time sufficient to bind the powders into particles less than 5 ~cm in size, each particle including carbon and iron with the carbon distributed throughout the volume of each of the particles. The particles are preferably separated to select particles of a size of between about lum and 4~,m, after whi.ch a biologically active substance can be absorbed onto the selected particles.
a ~ 5~9 ~ 3 The methods of use include methods for localized in vivo treatment of disease comprising providing a magnetically responsive ferrocarbon carrier (such as the carrier of this invention) having a biologically active 5 substance selected for its efficacy in treating the disease absorbed thereon, injecting the carrier into the body of a patient, for example by inserting delivery means in a blood vessel to within a short distance from a site to be treated and at a branch or branches (preferably the most immediate) to a network of vessels carrying blood at the site and injecting the carrier through the delivery means, and establishing a magnetic field exterior to the body and adjacent to the site of sufficient field strength to guide a substantial quantity of the injected carrier to, and retain the substantial quantity of the carrier at, the site. Preferably, the magnetic field is of sufficient field strength to draw the carrier at the site adjacent to soft tissue of the network of vessels thus avoiding substantial embolization of any of the network of vessels.
It is therefore an object of this invention to provide an improved magneticaily responsive carrier composition for carrying biologically active substances and methods of production and use thereof.
It is another object of this invention to provide a magnetically responsive carrier for biologically active substances which has improved magnetic responsiveness, is capable of greater absorption of the biologically active substance, and which is durable during storage and use.
It is another object of this invention to provide a magnetically responsive composition for carrying a biologically active substance comprising particles less than 5 ~,m in size, each particle including carbon and iron with the carbon distributed throughout the volume of each particle.
It is still another object of this invention to provide a composition utilized for localiz~d in vivo treatment of disease including a carrier with particles i i between about l~,m and 4~m in size, each particle including carbon and iron with the carbon distributed throughout the volume of the particle, and a biologically active substance selected for its efficacy in treating the disease absorbed on the particles.
It is yet another object of this invention to provide a method of producing a magnetically responsive carrier composition including the step of jointly deforming a mechanical mixture of iron and carbon powders for a time sufficient to bind the powders into particles less than 5 ~,m in size, each particle including carbon and iron with the carbon distributed throughout the volume of each of the particles.
It is still another object of this invention to provide a method for producing a magnetically responsive composition for localized in vivo treatment of disease including the steps of providing a mixture of iron and carbon, mechanically processing the mixture sufficiently to bind the carbon and the iron into particles, a substantial portion of the particles including carbon and iron with the carbon distributed throughout the volume of each particle, separating the particles to select particles of a size of between about l~,m and 4~cm from the substantial portion of the particles, and absorbing a biologically active substance onto the selected particles.
It is yet another object of this invention to provide a method for localized in vivo treatment of disease in a body comprising providing a magnetically responsive ferrocarbon carrier having a biologically active substance selected for its efficacy in treating the disease absorbed thereon, inserting delivery means in a blood vessel to within a short distance from a site to be treated and at a branch or branches to a network of vessels carrying blood at the site, injecting the carrier through the delivery means, and establishing a magnetic field exterior to the body and adjacent to the site of sufficient field strength to guide a substantial quantity of the injected carrier to, and retain the substantial quantity of the carrier at, the site and to draw the carrier at the site adjacent to soft tissue of the network of vessels thus avoiding substantial embolization of any of the network of vessels.
It is still another object of this invention to provide a method for localized in vivo treatment of disease in a body comprising absorbing a biologically active substance onto a magnetically responsive carrier l0 composition including particles less than 5 ~.m in size, each particle including carbon and iron with the carbon distributed throughout the volume of each particle, injecting the carrier with the biologically active substance absorbed thereon into the body, and establishing a magnetic field exterior to the body and adjacent to a treatment site of sufficient field strength to guide a substantial quantity of the injected carrier to, and retain the substantial quantity of the carrier at, the site.
With these and other objects in view, which will become apparent to one skilled in the art as the description proceeds, this invention resides in the novel construction, combination, arrangement of parts and methods substantially as hereinafter described, and more particularly defined by the appended claims, it being understood that changes in the precise embodiment of the herein disclosed invention are meant to be included as come within the scope of the claims.
Brief Description of the Drawings The accompanying drawings illustrate a complete embodiment of the invention according to the best mode so far devised for the practical application of the principles thereof, and in which:
FIGURE 1 is a magnified photograph (12000x) of particles of the carrier composition of this invention;
FIGURE 2a is a magnified photograph (30,OOOx) of a particle of the carrier composition of this invention;
WO 94/16683 "~ PCT/US94/00892 FIGURE 2b is a sectional illustration of the particle of FIGURE 2a;
FIGURES 3a through 3h are illustrations of a tumor during periods of treatment utilizing drugs absorbed on the carrier composition and delivered to, and maintained at, the tumor site utilizing one method of this invention;
FIGURE 4 is a diagram illustrating one example of application and magnetic targeting of the carrier composition; and FIGURE 5 is a diagram illustrating the carrier composition (having a drug absorbed thereon) at a pathological structure.
Description of the Invention The magnetically controllable, or guided, carrier composition of this invention comprises composite, volume-compounded ferrocarbon particles of 0.2 to 5.0 ~,m in size, and preferably between 1.0 and 4.0 ~.m, containing 1.0 to 95.0% by volume of carbon, and preferably between about 20 and 50% (about 40% carbon having been found to exhibit characteristics useful in many applications). The particles are produced by a joint deformation of a mechanical mixture of iron and carbon powders, after which the obtained particles are placed in a solution of a biologically active substance, the finished product then being separated (it being understood that separation could occur before exposure to the biologically active substance).
As shown in FIGURES 1 and 2a, ferrocarbon particles 8 manufactured by the method of this invention are of a generally spheroidal shape, with the inclusions of carbon deposits 10 being located throughout the whole volume of each particle (both at the surface and the interior of each particle). Uniform distribution of carbon 10 throughout the whole volume of each composite particle provides for a strong connection between the components (iron 12 and carbon 10) cahich is not broken during -- WO 94/16683 ~~~/ PCT/US94/00892 prolonged storage of the magnetically controlled composition, its transportation, strewing, packing and direct use.
The choice of the particles' size is determined in part by the constraints imposed by technological capabilities on producing particles under 0.2 ~,m. With regard to the preferred particle size range, for particles less than 1.O~,m carrying capacity is needlessly reduced. With particle sizes exceeding 4.0 ~,m an undesired degree of embolization of vessels becomes possible, coagulation of dispersion may take place (which makes injections more difficult) and the speed of discharging biologically active substances from the particles in the targeted pathological zones slows.
Regarding the justification for the chosen range of volume content of carbon in composite particles 8, while with carbon content less than 1.00% by volume specific absorption capacity of the magnetically controlled particles 8 (in dispersion) is enough for the transport of the required amount of biologically active substance towards the pathologic zone, it takes a greater quanity of the carrier, either by increased dosage or by increased number of injections, to reach the required concentration of biologically active substance in the damaged tissues. With carbon content exceeding 95.00% by volume, the susceptibility, cr responsiveness, of composite particles 8 to a magnetic field decreases, and thus conditions for their control in the body worsen (although absorption capacity increases). In addition, the particles become rather friable at carbon content levels exceeding 95%, lacking in such case strong connection between the iron and carbon components, thus achieving less desirable technical characteristics and making their destruction (separation into constituent components) possible during storage and/or direct use.
The utilization of a method (such as is described below) which jointly deforms a mechanical mixture of iron and activated carbon powders enables achievement of a I
WO 94/16683 ~ PCT/US94/00892 substantially uniform distribution of carbon throughout the volume of each composite particle, ensures their spheroidal form and achieves a share of 0.2 to 4.0 ~m size composite particles of 50.00 to 95.00% or more of 5 production volume.
Due to the fact that it is metallic (i.e., substantially elemental) iron and not its oxides (as is the~case in previously known magnetically controlled dispersions) which is the ferromagnetic component in the 10 produced composite particles of this invention, the magnetic susceptibility, or responsiveness, of ferrocarbon particles 8 is considerably higher.
In addition, intensive mechanical deformation and/or reintegration of iron particles 12 and the resulting formation within the particles of a well-developed substructure (see FIGURE 2b), a connected network of iron forming a network of voids having carbon deposits 10 captured therein, which takes place during the process of joint deformation of the mechanical mixture of iron and carbon particles, also leads to an increase in the magnetic susceptibility of iron inclusions in ferrocarbon particles 8 as compared with non-deformed iron particles.
Thus, the composite ferrocarbon particles produced by the herein suggested method have, for example, from 2.5 to 4.0 times greater magnetic susceptibility than the particles of the previously known magnetically controlled dispersion shown in European Patent Office Publication No. 0 451 299 A1, though ferromagnetic content in both is about the same. This improved responsiveness of ferrocarbon particles 8 makes it possible, in some cases, to decrease if desired the intensity of the magnetic field or fields utilized to guide the particles, and thereby lessen its effect on the human organism subjected to the therapy.
Because of a larger surface of carbon deposits 10 in particles 8 in comparison with other previously known ferrocarbon carriers described above, specific absorption capacity is increased (from about 2.5% of the absorbed -- WO 94/16683 2 1 5 ~ g ~ 3 : ~ PCT/LJS94/00892 biologically active substance out of the mass of a previously known magnetically controlled particle to up to about 7.5% in the case of particles 8; or, in different terms, from 25 mg of biologically active substance per gram of the previously known magnetically controlled dispersion up to about 75 mg of absorbed biologically active substance per gram of particles 8).
This allows, in use, for injection of much less of the carrier to achieve a given dose of the biologically active substance or, alternatively, for higher dosage of the biologically active substance per injection over some previously known carriers.
The following describes a method of production of the carrier composition of this invention utilized to produce small quantities of the carrier, it being understood that other means and mechanisms could be conceived of for the joint deformation of iron and carbon powders which comprise the essential starting elements for production of the carrier. The procedure utilized exerts mechanical pressure on iron particles (normally spherical) to deform the iron particles and develop a substantial substructure which captures the carbon. It is felt that no molecular bonding is involved. The formation of the carrier particles is accomplished without the addition of heat in the process, and is conducted in the presence of a liquid, for example 96% ethanol, to inhibit oxidation of the iron and to assure that the carrier particles produced are clean (sterile). The liquid may also serve as a lubricant during the joint deformation of the iron and carbon particles, and it is felt that use of ethanol reduces compacting of carbon during processing resulting in less dense carbon deposits in the carrier composition, thereby providing greater absorption capacity.
For example, to produce carrier composition having a 60%/40% iron/carbon makeup, one part of substantially pure iron particles form l~,m to 300~cm (preferable 2/cm to 10~m) in size are mixed with 0.3 to 0.6 parts of s substantially pure activated carbon granules (typically about 50~,m to 600~Cm in size). The iron particles and carbon granules are mixed vigorously to achieve good distribution throughout the volume.
The mixture is put into a standard laboratory planetary ball, or attrition, mill of the type used in powdered metallurgy, for example having 6mm diameter balls (any other device capable of mechanically processing the mixture to its desired state could be utilized), with a ball spacing adequate for deformation of the iron and carbon (and depending on the size of the particles of iron and granules of carbon initially, ball spacing being adjusted during milling until the space between balls is ultimately about 2 to 3 ~,m at the end of the process). A liquid (for example, by volume, 1 part ethanol to one part of the iron/carbon mixture initially) is added and the mixture is milled for between 4 and 12 hours (or for the time necessary to produce the particles as heretofore described) with liquid being added periodically to maintain wetness of the mixture.
Depending on the mill used, the mill may be run at anywhere from 120 RPM to 1000 RPM, the process not being overly sensitive to the speed of the mill (it being felt that speeds over 1000 RPM could create an undesirable quantity of overly small particles).
After milling, the resulting particles are moved to a sterile environment (for example, an ultra-violet chamber) and are ambiently air dried (i.e., to evaporate the liquid).
By a combined process of magnetic selection and sievi.ng (for example, blowing the particles through a 4~cm filter), the particles are separated to obtain particles of 1-4 microns in size which exhibit desired magnetic responsiveness. It has been found that, utilizing a carefully monitored milling process, typically less than 5% of production is not within the appropriate size range and/or is otherwise unusable. The particles are then sorted into dosages (typically one gram doses) and packaged, care being taken at each stage to maintain a sterile environment.
When ready for use (or, in the alternative, before packaging where a carrier is to be delivered with a preselected biologically active substance already absorbed thereon), up to 75mg (50mg is preferred to be absolutely assured of 100% absorption) of the biologically active substance in solution is added to 1 gram of the carrier. When ready for application to a patient, the combination is placed into suspension (for example, 5 to 10 ml) utilizing normal procedures.
Experimental evidence shows increased therapeutic efficiency of the use of the magnetically controlled carrier composition of this invention with an anti-tumorous preparation on a tumorous growth in comparison with previously known magnetically controlled dispersions.
Tests were carried out on male rats of the Vistor Line (bred at Stolbovaya Station of the USSR Academy of Medical Sciences). The rats were infused with carcinosarcoma Worker 256 under the tail's skin. When the tumorous volume averaged 986 + 98 mm3 the animals were divided into 4 groups, 10 rats in each. The first group (group I) was a control group, and groups II
through IV where experimental ones.
The animals in group II were given intravenous injections of a water solution of rubomicine in the amount of 2 mg/kg during 5 days (the model of traditional use of such anti-cancerous preparat.ions in clinics). The rats in group III were injected with a suspension of ferrocarbon dispersion produced by the previously known method described in European Patent Office Publication No. 0 451 299 A1. The dosage of ferrocarbon particles was 160 mg/kg, and the dosage of absorbed rubomicine thereon was 3.2 mg/kg. This suspension was injected into the tail vein after placing a permanent magnet with an intensity of the magnetic field of 6000 oersteds on the surface of the tumor. Magnetic localization of the magnetically controlled suspension in the tumorous growth zone was monitored by x-ray pictures.
The animals from group IV were given (using the same injection and magnetic control techniques, including placement of a permanent magnet with an intensity of the magnetic field of 600 oersteds on the surface of the tumor and x-ray monitoring) a one-time intravenous injection of the magnetically controlled dispersion produced in accord with the methods of this invention, the dosage being 160 mg/kg. The combination of components (iron/carbon) in each individual particle of the dispersion was 60/40, which was similar to the ratio in the dispersion produced by the previously known method used in experimental group III.
Due to the improved absorptive capability of particles 8, the dose of rubomicine absorbed on the magnetically controlled carrier particles of this invention was 9.96 mg/kg, which was 2.8 times more than the rubomicine absorbed by the previously known carrier particles in the experiment with the rats of group III.
This result was achieved solely due to the relative specific absorption capacities of the given carriers.
Observation of the animals gave the following results. The life span of animals in control group I
averaged 21 + 1.5 days. In group II, as a results of prescribed intravenous injections of the water solution of rubomicine (model of traditional use of antitumorous drugs), the rats' life span increased by an average of 4.5 days (P < 0.05). The animals from experimental group III lived during 46 ~ 4.3 days, which was 2.2 times more (P > 0.001) than the life span of control animals.
In group IV, 6 rats out of 10 (i.e., 60% of the cases) demonstrated complete dissolution of the tumor, which took place during 5 to 7 days after the one-time injection of the suspension of the magnetically controlled composition. Moreover, the remaining 4 rats from this group lived during 57.4 + 5.9 days, which exceeded the life span of the animals from group III by 25.0%, and is 2.7 times more as compared with the rats from control group I. The animals from group IV which showed complete regression of the tumors did not see any recurrence of tumorous growth during 157 days of 5 observation which testifies to a complete elimination of the tumors in these rats.
Further cl~inical observation has documented the effectiveness of this invention. FIGURES 4 and 5 illustrate use of this invention for treatment and 10 observation of a 61 year-old woman admitted on February 13, 1992 to the Zil Hospital in Moscow, Russia (CIS) and diagnosed with cancer of the left mammary gland T3NXMx.
The diagnosis was first made in 1989 when a biopsy was done. In December of 1991, focal radiation therapy 15 (10 grey) resulted in the tumor being partially reduced.
The decision was made to use the intra-arterial selective chemotherapy method of localized in vivo treatment of this invention utilizing the carrier of this invention wi th doxorubycin (Adriamycin) absorbed on the carrier.
Before the treatment, the dimensions of the tumor (illustrated in FIGURES 3a and 3b) were 44mm x 33mm x 37mm (65mm x 45mm, manual). On February 24, 1992 a puncture of the femoral artery (FIGURE 4) and injection of a vascular catheter into the aorta according to the Seldinger method were performed under local anaesthesia (0.5% novocaine, 30 ml). Under roentgenologic and contrast control, the catheter was placed at 25mm distance from the branch to the left intra-pectoral artery (a. mammaria interna sinisra). A newly prepared suspension of gelatinol with ferrocarbon particles 8 having 15 mg doxorubycin (Adriamycin) absorbed thereon was injected through the catheter. At this time, a magnet having a magnetic field intensity of 15,000 oersteds was placed over the tumor. As a result, the injected suspension was localized and was kept by the magnetic field in the zone of the tumor for 20 minutes (a time sufficient for full microembolization of the tumor feeding capillaries). The patient's condition was satisfactory at the time of therapy.
As shown in FIGURES 3c and 3d, by February 28, 1992 the patient's condition had improved, with an ultrasonic examination of the left mammary gland showing the dimensions of the tumor at 42mm x 33mm x 40mm. The tumor had a legible contour. By March 12, 1992, the dimensions of the tumor were found to have been reduced by 66.3% to 32mm x 27mm x 2lmm (FIGURES 3e and 3f), and by April 14 l0 to have been reduced by 99.22% to lOmm x 6mm x 7mm (FIGURES 3g and 3h).
It is felt that by releasing the carrier immediately upstream of the tumor (or other pathological) site, rather than penetrating the tumor, equally effective application of the biologically active substance occurs while potentially benefitting the patient by limiting spread of disease occasioned by puncture of the tumorous tissue. While a larger magnetic field was utilized in the above example of treatment, it has been found that the carrier composition of this invention begins to react in a field as small as 250 oersteds/cm (prior art carriers needing a field as large a 500 oersteds/cm before being influenced).
Figure 5 illustrates what is believed to occur under magnetic control at the treatment site. Under the influence of the applied magnetic field, the carrier particles are induced into the capillary network feeding the tumor. The particles are drawn closely adjacent to the soft tissue of the lumen of the capillaries (or perhaps even into the soft tissue) thereby reducing or eliminating the potential for embolization of the vessels. The biologically active substance is released from the carrier particles by a dynamic process of replacement of the substance in the carrier by materials produced by the body (for example the necrotic products of the tumor itself), such as proteins, glucose, lipids, peptides, or the like, thus literally pushing the ~r WO 94/16683 2 1 5 4 9 1 3 ' ~ PCTIUS94/00892 biologically active substance out of the carrier particles.
To replace the biologically active substance in the carrier particles, it is felt that the replacing substance must have a higher specific gravity than the biologically active substance, thus accounting for the low degree of washout of the biologically active substance in the blood stream (typically under 10%). Even fractions of the carrier not attracted to the treatment site by the magnetic field or escaping from the treatment site (typically around l00) are effective, as these fractions remain active against tumor cells in the blood and elsewhere (metastasis reduction has been observed in some cases). Since the carrier composition is formed of material which is readily processed or metabolized by the body, all carrier particles are excreted or metabolized within 30 days of application.
As may be appreciated, an improved magnetically responsive carrier for biologically active substances and methods for producing and using the same are provided by this invention, particles forming the carrier exhibiting improved responsiveness to magnetic fields, having improved absorptive capacity, and being durable during storage and use.
Claims (38)
OR PROPERTY IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A magnetically responsive composition comprising particles including carbon and iron with the carbon substantially uniformly distributed throughout the particle volume, wherein the cross-sectional size of each particle is less than 5 µm.
2. The composition of claim 1, wherein the carbon is between 1% and 95% by volume of the composition.
3. The composition of claim 1, wherein the carbon is between 20% and 50% by volume of the composition.
4. The composition of any one of claims 1 to 3, wherein said particles have an absorption capacity for a biologically active substance, on average of up to about 7.5%
of the mass of said particles.
of the mass of said particles.
5. The composition of any one of claims 1 to 4, wherein said iron is substantially unoxidized.
6. The composition of any one of claims 1 to 5, wherein said particles are generally spheriodal in shape.
7. The composition of any one of claims 1 to 6, wherein said iron forms a substructure throughout the volume of each particle, with the carbon residing in the substructure.
8. The composition of any one of claims 1 to 7, wherein the carbon and iron are mechanically connected, with the carbon being bound by contact with the iron at both the surface and the interior of the particles.
9. A magnetically responsive composition for localized in vivo treatment of disease comprising:
a carrier including particles between 0.2 µm and 5 µm in cross-sectional size, each particle comprising between 1% to 95% carbon and iron, with said carbon being distributed throughout the volume of each said particle; and a biologically or therapeutically active substance, selected for its efficacy in treating the disease, absorbed on the particles.
a carrier including particles between 0.2 µm and 5 µm in cross-sectional size, each particle comprising between 1% to 95% carbon and iron, with said carbon being distributed throughout the volume of each said particle; and a biologically or therapeutically active substance, selected for its efficacy in treating the disease, absorbed on the particles.
10. The composition of claim 9, wherein said active substance comprises an amount equal to between 2.5% and 7.5% of the mass of the particle on average.
11. The composition of any one of claims 9 or 10, wherein the iron in each said particle forms a substructure throughout the volume of each said particle, said carbon being held in said substructure.
12. The composition of any one of claims 9 to 11, wherein the particles are substantially spheroidal in shape, and wherein the iron and the carbon in the particles are mechanically connected with the carbon being bound at both the surface and the interior of the particles by contact with the iron.
13. The composition of any one of claims 9 to 12, wherein said active substance is an anti-tumorous substance.
14. A method for producing a magnetically responsive composition for carrying a biologically active substance comprising mixing iron and carbon powders and milling the mixed powders for a time sufficient to bind said powders into particles having a diameter of less than 5 µm and containing 1% to 95% by volume of the carbon, each particle including carbon and iron with said carbon distributed throughout the volume of each said particle and at both particle surface and particle interior.
15. The method of claim 14, wherein the step of milling said powders occurs at ambient temperature and wherein said particles are from 1.0 µm to 4.0 µm in size and contain from 20% to 50% by volume of the carbon.
16. The method of claim 14, wherein said carbon powder is activated carbon powder.
17. The method of any one of claims 14 to 16, wherein the step of mixing and milling said powders includes distributing iron particles having a size of less than about 300 µm throughout carbon granules having a size of less than about 600 µm to achieve a relatively even mixture and milling said mixture for up to about 12 hours.
18. The method of any one of claims 14 to 17, wherein the step of milling said powders includes performing said step in the presence of a liquid selected to inhibit substantial oxidation of said iron.
19. The method of claim 18, wherein said liquid is selected also to maintain substantial sterility of said particles.
20. The method of claim 14, further comprising the step of sorting said particles by size and by responsiveness to a magnetic field.
21. A method for producing a magnetically responsive composition for localized in vivo treatment of disease comprising:
providing a mixture of iron and carbon;
mechanically processing said mixture sufficiently to bind said carbon and said iron into particles having a diameter of from 0.2 to 5.0 µm, a substantial portion of said particles including carbon and iron with 1.0 to 95% by volume of carbon distributed throughout the volume of each particle;
separating said particles to select particles of a size between 1 µm and 4 µm from said substantial portion of said particles; and absorbing a biologically or therapeutically active substance, selected for its efficacy in treating the disease, onto said selected particles.
providing a mixture of iron and carbon;
mechanically processing said mixture sufficiently to bind said carbon and said iron into particles having a diameter of from 0.2 to 5.0 µm, a substantial portion of said particles including carbon and iron with 1.0 to 95% by volume of carbon distributed throughout the volume of each particle;
separating said particles to select particles of a size between 1 µm and 4 µm from said substantial portion of said particles; and absorbing a biologically or therapeutically active substance, selected for its efficacy in treating the disease, onto said selected particles.
22. The method of claim 21, wherein the step of absorbing said substance includes sufficient absorption so that said substance, in an amount between 2.5% and 7.5% of the mass on average of each said particle, is absorbed.
23. The method of any one of claims 21 or 22, further comprising wetting said mixture with a liquid.
24. The method of claim 23, wherein said liquid is ethanol, the method further comprising the step of drying said particles after they have been mechanically processed.
25. The method of any one of claims 21 to 24, wherein the step of separating said particles includes magnetically selecting particles to eliminate uncombined said carbon and particles under about 1 µm.
26. The method of any one of claims 21 to 25, wherein the step of separating said particles includes the step of filtering said particles to eliminate particles larger than about 5 µm.
27. The use of a magnetically responsive composition, for localized in vivo treatment of disease comprising:
a carrier including particles between 0.2 µm and 5 µm in cross-sectional size, each particle comprising between 1% to 95% carbon and iron, with said carbon being distributed throughout the volume of each said particle; and a biologically or therapeutically active substance, selected for its efficacy in treating the disease, absorbed on the particles;
a delivery means for insertion in a blood vessel of a body being treated to within a short distance from a site to be treated and at a branch to a network of vessels carrying blood at said site, said carrier being for injection through said delivery means;
a magnetic field being established exterior to the body and adjacent to said site of sufficient field strength to guide a substantial quantity of said injected carrier to, and retain said substantial quantity of said carrier at, said site and to draw said carrier at said site adjacent to soft tissue of said network of vessels thus avoiding substantial embolization of any said network of vessels.
a carrier including particles between 0.2 µm and 5 µm in cross-sectional size, each particle comprising between 1% to 95% carbon and iron, with said carbon being distributed throughout the volume of each said particle; and a biologically or therapeutically active substance, selected for its efficacy in treating the disease, absorbed on the particles;
a delivery means for insertion in a blood vessel of a body being treated to within a short distance from a site to be treated and at a branch to a network of vessels carrying blood at said site, said carrier being for injection through said delivery means;
a magnetic field being established exterior to the body and adjacent to said site of sufficient field strength to guide a substantial quantity of said injected carrier to, and retain said substantial quantity of said carrier at, said site and to draw said carrier at said site adjacent to soft tissue of said network of vessels thus avoiding substantial embolization of any said network of vessels.
28. The use of the magnetically responsive composition of claim 27, wherein said active substance is released from said carrier at said site by a process of replacement of said substance in said carrier by materials produced by the body having a higher specific gravity.
29. The use of the magnetically responsive composition of claim 28, wherein washout of said active substance from said carrier by blood is less than 30%.
30. The use of the magnetically responsive composition of any one of claims 27 to 29, wherein said carrier for injection is entirely excreted from or metabolized by the body within 30 days of injection.
31. The use of the magnetically responsive composition of any one of claims 27 to 30, wherein said carrier includes particles with each particle having iron and carbon therein, said carbon being distributed throughout the volume of each said particle.
32. The use of the magnetically responsive composition of any one of claims 27 to 31, wherein the step of establishing a magnetic field includes utilizing a magnetic field as small as 250 oersteds/cm to induce a response of said carrier.
33. The use of a magnetically responsive composition for localized in vivo treatment of disease comprising:
a carrier including particles between 0.2 µm and 5 µm in cross-sectional size, each particle comprising between 1% to 95% carbon and iron, with said carbon being distributed throughout the volume of each said particle; and a biologically or therapeutically active substance, selected for its efficacy in the treatment of the disease, absorbed on the particles;
said carrier with said biologically active substance absorbed thereon for injection into a body; and a magnetic field being established exterior to the body and adjacent to a treatment site of sufficient field strength to guide a substantial quantity of said injected carrier to, and retain said substantial quantity of said carrier at, said site.
a carrier including particles between 0.2 µm and 5 µm in cross-sectional size, each particle comprising between 1% to 95% carbon and iron, with said carbon being distributed throughout the volume of each said particle; and a biologically or therapeutically active substance, selected for its efficacy in the treatment of the disease, absorbed on the particles;
said carrier with said biologically active substance absorbed thereon for injection into a body; and a magnetic field being established exterior to the body and adjacent to a treatment site of sufficient field strength to guide a substantial quantity of said injected carrier to, and retain said substantial quantity of said carrier at, said site.
34. The use of the magnetically responsive composition of claim 33, wherein said magnetic field induces a response by said carrier composition at a field strength as low as 250 oersteds/cm.
35. The use of the magnetically responsive composition of any one of claims 33 to 34 wherein said carrier composition will absorb an amount of said active substance in excess of 2.5% of its mass.
36. The use of the magnetically responsive composition of any one of claims 33 to 35, wherein said carrier composition will absorb up to about 7.5% of its mass of said active substance.
37. The use of the magnetically responsive composition of any one of claims 33 to 36, wherein the step of establishing a magnetic field includes establishing said magnetic field of sufficient field strength to draw said carrier composition at said site adjacent to soft tissue of a network of vessels at the treatment site thus avoiding substantial embolization of any of said network of vessels.
38. The use of the magnetically responsive composition of any one of claims 33 to 37, wherein said active substance is released from said carrier composition at said site by a process of replacement of said substance in said carrier composition by materials produced by the body having a higher specific gravity.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1136393A | 1993-01-29 | 1993-01-29 | |
| US08/011,363 | 1993-01-29 | ||
| PCT/US1994/000892 WO1994016683A1 (en) | 1993-01-29 | 1994-01-26 | Magnetically responsive composition for carrying biologically active substances and methods of production and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2154913A1 CA2154913A1 (en) | 1994-08-04 |
| CA2154913C true CA2154913C (en) | 1999-10-19 |
Family
ID=21750068
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002154913A Expired - Fee Related CA2154913C (en) | 1993-01-29 | 1994-01-26 | Magnetically responsive composition for carrying biologically active substances and methods of production and use |
Country Status (12)
| Country | Link |
|---|---|
| US (3) | US5549915A (en) |
| EP (1) | EP0683665B1 (en) |
| JP (2) | JP3145120B2 (en) |
| AT (1) | ATE210967T1 (en) |
| AU (1) | AU6165394A (en) |
| CA (1) | CA2154913C (en) |
| DE (1) | DE69429507T2 (en) |
| DK (1) | DK0683665T3 (en) |
| ES (1) | ES2165385T3 (en) |
| HK (1) | HK1013256A1 (en) |
| PT (1) | PT683665E (en) |
| WO (1) | WO1994016683A1 (en) |
Families Citing this family (45)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6482436B1 (en) | 1993-01-29 | 2002-11-19 | Ferx Incorporated | Magnetically responsive composition |
| CA2154913C (en) * | 1993-01-29 | 1999-10-19 | Viktor Alexeevich Volkonsky | Magnetically responsive composition for carrying biologically active substances and methods of production and use |
| US6200547B1 (en) * | 1994-01-26 | 2001-03-13 | Ferx Incorporated | Magnetically responsive compositions for carrying biologically active substances and methods of production and use |
| US5958458A (en) * | 1994-06-15 | 1999-09-28 | Dumex-Alpharma A/S | Pharmaceutical multiple unit particulate formulation in the form of coated cores |
| US5985312A (en) * | 1996-01-26 | 1999-11-16 | Brown University Research Foundation | Methods and compositions for enhancing the bioadhesive properties of polymers |
| US6368586B1 (en) | 1996-01-26 | 2002-04-09 | Brown University Research Foundation | Methods and compositions for enhancing the bioadhesive properties of polymers |
| US7090636B2 (en) * | 2000-03-31 | 2006-08-15 | Fe Rx Incorporated | Permanent magnet keeper-shield assembly |
| US6488615B1 (en) * | 2000-03-31 | 2002-12-03 | Ferx Incorporated | Permanent magnet keeper-shield assembly |
| EP1428228A4 (en) * | 2001-02-26 | 2008-04-30 | Univ Utah Res Found | Magnetic activated particles for adsorption of solutes from solution |
| US6921283B2 (en) * | 2001-08-27 | 2005-07-26 | Trompeter Electronics, Inc. | BNC connector having visual indication |
| FR2832598B1 (en) * | 2001-11-26 | 2006-01-27 | Oreal | ARTICLE OF PACKAGING AND / OR APPLICATION OF A PRODUCT |
| AU2003214812A1 (en) * | 2002-01-09 | 2003-07-30 | Ferx Incorporated | Magnetic delivery compositions |
| US20030219785A1 (en) * | 2002-02-01 | 2003-11-27 | Vanderbilt University | Targeted drug delivery methods |
| US8097185B2 (en) * | 2002-02-26 | 2012-01-17 | University Of Utah Research Foundation | Magnetic activated carbon particles for adsorption of solutes from solution |
| CA2549994A1 (en) * | 2002-12-18 | 2004-08-12 | Hough Ear Institute | Otologic nanotechnology |
| US7723311B2 (en) * | 2003-06-18 | 2010-05-25 | Nanobiomagnetics, Inc. | Delivery of bioactive substances to target cells |
| US7344491B1 (en) | 2003-11-26 | 2008-03-18 | Nanobiomagnetics, Inc. | Method and apparatus for improving hearing |
| US8651113B2 (en) * | 2003-06-18 | 2014-02-18 | Swr&D Inc. | Magnetically responsive nanoparticle therapeutic constructs and methods of making and using |
| ES2264839B1 (en) * | 2003-11-24 | 2007-10-01 | Universidad De Zaragoza (Inst Denanociencia De Ar Agom. | PARENTERAL PHARMACOTHERAPY FOCUSED THROUGH THE IMPLANT OF PERMANENT MAGNETS IN THE DIANA ORGANS. |
| DE10359252A1 (en) * | 2003-12-17 | 2005-07-28 | Siemens Ag | Navigated heat treatment of tumors with enzyme-coated iron particles |
| US20070100457A1 (en) * | 2004-03-04 | 2007-05-03 | Hyde Edward R Jr | Paramagnetic liquid interface |
| CN1976681A (en) * | 2004-03-26 | 2007-06-06 | 弗尔克斯破产财产公司 | Magnetically targetable mitomycin C compositions and methods of their use |
| US20060024378A1 (en) * | 2004-08-02 | 2006-02-02 | Mehta Rakesh H | Magnetically responsive carbon nano-structures for transporting biologically active substances, and methods relating thereto |
| US20070281007A1 (en) * | 2004-08-27 | 2007-12-06 | Jacob Jules S | Mucoadhesive Oral Formulations of High Permeability, High Solubility Drugs |
| US8568286B2 (en) * | 2006-06-14 | 2013-10-29 | Cardiac Pacemakers, Inc. | Methods to position therapeutic agents using a magnetic field |
| CN103705947A (en) | 2006-06-28 | 2014-04-09 | 株式会社Ihi | Drug, drug induction device, magnetic detector and method of designing drug |
| US20080097606A1 (en) * | 2006-10-19 | 2008-04-24 | Cragg Andrew H | Knee joint prosthesis and hyaluronate compositions for treatment of osteoarthritis |
| US20090169484A1 (en) | 2007-12-28 | 2009-07-02 | Ihi Corporation | Iron-salen complex |
| JP5433155B2 (en) * | 2008-02-20 | 2014-03-05 | 株式会社Ｉｈｉ | Magnetic drug, drug guidance system, and magnetic detection device |
| JP2009274962A (en) * | 2008-05-12 | 2009-11-26 | Yoshihiro Ishikawa | Iron salen complex, medicine having magnetism, guiding system of medicine and device for detecting magnetism |
| WO2010058280A1 (en) | 2008-11-20 | 2010-05-27 | 株式会社Ihi | Auto magnetic metal salen complex compound |
| WO2011077750A1 (en) | 2009-12-25 | 2011-06-30 | 株式会社Ihi | Magnet body and drug delivery control device using magnet body |
| WO2011151978A1 (en) | 2010-06-01 | 2011-12-08 | 株式会社Ihi | Fluorescent dye material and use thereof |
| US9744235B2 (en) | 2010-10-19 | 2017-08-29 | The Board Of Regents Of The University Of Oklahoma | Treatment of cardiovascular disorders with targeted nanoparticles |
| US8740872B2 (en) | 2010-10-19 | 2014-06-03 | The Board Of Regents Of The University Of Oklahoma | Magnetically-targeted treatment for cardiac disorders |
| US10398668B2 (en) | 2010-10-19 | 2019-09-03 | The Board Of Regents Of The University Of Oklahoma | Glutamate treatment of cardiovascular disorders |
| EP2944627B1 (en) | 2010-12-21 | 2021-01-27 | IHI Corporation | Nanometersized metal salen complex compounds, their preparation and their use as systemic antitumor agents |
| JP2012131737A (en) * | 2010-12-21 | 2012-07-12 | Ihi Corp | Metal-salen complex compound and production method therefor |
| JP2012176905A (en) * | 2011-02-25 | 2012-09-13 | Ihi Corp | Metal-salen complex compound |
| JP2012167067A (en) | 2011-02-15 | 2012-09-06 | Ihi Corp | Auto-magnetic metal salen complex compound |
| JP5873656B2 (en) | 2011-06-13 | 2016-03-01 | 株式会社Ihi | Metal salen complex compounds, local anesthetics and antineoplastic agents |
| JP6017766B2 (en) | 2011-07-26 | 2016-11-02 | 株式会社Ihi | Novel anticancer agent of metal salen complex compound |
| JP6155190B2 (en) | 2011-10-04 | 2017-06-28 | 株式会社Ihi | In-vivo behavior control system of metal-salen complex compound responsive drug and metal-salen complex compound |
| JP5694549B2 (en) * | 2011-10-06 | 2015-04-01 | 株式会社Ihi | Liquid |
| WO2016046989A1 (en) | 2014-09-26 | 2016-03-31 | 株式会社Ihi | Anti-cancer agent and method for killing cancer cells |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3718594A (en) * | 1970-11-30 | 1973-02-27 | Eastman Kodak Co | Method of preparing magnetically responsive carrier particles |
| US4106488A (en) * | 1974-08-20 | 1978-08-15 | Robert Thomas Gordon | Cancer treatment method |
| US4247406A (en) * | 1979-04-23 | 1981-01-27 | Widder Kenneth J | Intravascularly-administrable, magnetically-localizable biodegradable carrier |
| US4345588A (en) * | 1979-04-23 | 1982-08-24 | Northwestern University | Method of delivering a therapeutic agent to a target capillary bed |
| US4331654A (en) * | 1980-06-13 | 1982-05-25 | Eli Lilly And Company | Magnetically-localizable, biodegradable lipid microspheres |
| EP0093757A1 (en) * | 1981-11-12 | 1983-11-16 | Ulf SCHRÖDER | Intravascularly administrable, magnetically responsive nanosphere or nanoparticle, a process for the production thereof, and the use thereof |
| JPS59122429A (en) * | 1982-12-28 | 1984-07-14 | Japan Synthetic Rubber Co Ltd | Magnetic particle for carrier of biological substance |
| US4652257A (en) * | 1985-03-21 | 1987-03-24 | The United States Of America As Represented By The Secretary Of The Navy | Magnetically-localizable, polymerized lipid vesicles and method of disrupting same |
| US4849209A (en) * | 1985-06-07 | 1989-07-18 | Cadema Medical Products, Inc. | Treatment of arthritis, including rheumatoid arthritis with 166 Holmium radionuclide |
| US4818614A (en) * | 1985-07-29 | 1989-04-04 | Shiseido Company Ltd. | Modified powder |
| US4690130A (en) * | 1985-12-19 | 1987-09-01 | Mirell Stuart G | Electromagnetic therapy control system |
| US4871716A (en) * | 1986-02-04 | 1989-10-03 | University Of Florida | Magnetically responsive, hydrophilic microspheres for incorporation of therapeutic substances and methods of preparation thereof |
| JPH01122037U (en) * | 1988-02-12 | 1989-08-18 | ||
| SU1722256A3 (en) * | 1989-11-02 | 1992-03-23 | Viktor A Volkonskij | Method of producing magnetically controlled dispersion |
| CA2154913C (en) * | 1993-01-29 | 1999-10-19 | Viktor Alexeevich Volkonsky | Magnetically responsive composition for carrying biologically active substances and methods of production and use |
-
1994
- 1994-01-26 CA CA002154913A patent/CA2154913C/en not_active Expired - Fee Related
- 1994-01-26 AU AU61653/94A patent/AU6165394A/en not_active Abandoned
- 1994-01-26 ES ES94908636T patent/ES2165385T3/en not_active Expired - Lifetime
- 1994-01-26 JP JP51728294A patent/JP3145120B2/en not_active Expired - Fee Related
- 1994-01-26 AT AT94908636T patent/ATE210967T1/en not_active IP Right Cessation
- 1994-01-26 US US08/188,062 patent/US5549915A/en not_active Expired - Lifetime
- 1994-01-26 EP EP94908636A patent/EP0683665B1/en not_active Expired - Lifetime
- 1994-01-26 WO PCT/US1994/000892 patent/WO1994016683A1/en active IP Right Grant
- 1994-01-26 PT PT94908636T patent/PT683665E/en unknown
- 1994-01-26 DE DE69429507T patent/DE69429507T2/en not_active Expired - Fee Related
- 1994-01-26 DK DK94908636T patent/DK0683665T3/en active
-
1995
- 1995-06-07 US US08/480,195 patent/US5705195A/en not_active Expired - Lifetime
- 1995-06-07 US US08/480,141 patent/US5651989A/en not_active Expired - Lifetime
-
1998
- 1998-12-22 HK HK98114605A patent/HK1013256A1/en not_active IP Right Cessation
-
2000
- 2000-06-12 JP JP2000175975A patent/JP3176600B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| WO1994016683A1 (en) | 1994-08-04 |
| EP0683665A1 (en) | 1995-11-29 |
| EP0683665B1 (en) | 2001-12-19 |
| JP3145120B2 (en) | 2001-03-12 |
| ES2165385T3 (en) | 2002-03-16 |
| JP3176600B2 (en) | 2001-06-18 |
| PT683665E (en) | 2002-05-31 |
| US5549915A (en) | 1996-08-27 |
| DE69429507D1 (en) | 2002-01-31 |
| DK0683665T3 (en) | 2002-04-02 |
| CA2154913A1 (en) | 1994-08-04 |
| HK1013256A1 (en) | 1999-08-20 |
| DE69429507T2 (en) | 2002-05-16 |
| ATE210967T1 (en) | 2002-01-15 |
| EP0683665A4 (en) | 1996-04-17 |
| JP2001010978A (en) | 2001-01-16 |
| US5705195A (en) | 1998-01-06 |
| US5651989A (en) | 1997-07-29 |
| AU6165394A (en) | 1994-08-15 |
| JPH08506111A (en) | 1996-07-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2154913C (en) | Magnetically responsive composition for carrying biologically active substances and methods of production and use | |
| US6200547B1 (en) | Magnetically responsive compositions for carrying biologically active substances and methods of production and use | |
| US6099864A (en) | In situ activation of microcapsules | |
| KR100904931B1 (en) | Nanoparticles and Method for the Preparation Thereof | |
| JP5117439B2 (en) | Protein-stabilized pharmacologically active agent, method for producing the same and method for using the same | |
| Anderson et al. | The role of the fibrous capsule in the function of implanted drug‐polymer sustained release systems | |
| US20060057192A1 (en) | Localized non-invasive biological modulation system | |
| US7968117B1 (en) | Externally triggered microcapsules | |
| US20030108614A1 (en) | Magnetically responsive composition | |
| JP2005200426A (en) | Magnetic targeted carrier | |
| EP1077686B1 (en) | Externally triggered microcapsules | |
| Xu et al. | Balancing the toxicity, photothermal effect, and promotion of osteogenesis: Photothermal scaffolds for malignant bone tumor therapy | |
| Kato et al. | Magnetic microcapsules for targeted delivery of anticancer drugs | |
| EP1790335A1 (en) | Composition and its use for the manufacture of a medicament for treating, prophylactically treating, preventing cancer and/or infections in the urinary tract | |
| KR101180181B1 (en) | Nanoparticles and Method for the Preparation Thereof | |
| KR102460624B1 (en) | A drug delivery system capable of controlled drug release and x-ray imaging and use thereof | |
| WO2005102280A1 (en) | Magnetically targetable mitomycin c compositions and methods of their use | |
| RU2143266C1 (en) | Magnetically controlled carrier, method of manufacturing thereof, method for preparing suspension of magnetically controlled drug, treatment method, antitumor, antimetastatic, chemotherapeutic, radiation, hemo- and immunostimulating agent | |
| MXPA00006625A (en) | Magnetically responsive composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |