Microspheres for active embolization

• US 20030211165A1
• Filed: 12/12/2002
• Published: 11/13/2003
• Est. Priority Date: 03/24/2000
• Status: Active Grant

• Current Assignee: Biosphere Medical Inc. (Merit Medical Systems, Inc.)
• Original Assignee: Biosphere Medical Inc. (Merit Medical Systems, Inc.)
• Inventors: Vogel, Jean-Marie, Boschetti, Egisto
• Granted Patent: US 8,697,137 B2
• Time in Patent Office: Days
• US Class Current: 424/493
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61L 2430/36 for embolization or occlusion, e.g. vaso-occlusive compositions or devices
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]

Abstract

The present invention relates to injectable compositions comprising biocompatible, swellable, substantially hydrophilic, non-toxic and substantially spherical polymeric material carriers which are capable of efficiently delivering bioactive therapeutic factor(s) for use in embolization drug therapy. The present invention further relates to methods of embolization gene therapy, particularly for the treatment of angiogenic and non-angiogenic-dependent diseases, using the injectable compositions.

Claims

1. A microsphere suitable for active embolization comprising a biocompatible, cross-linked and substantially hydrophilic polymer and one or more active components comprising a drug, a vaccine, or any combination thereof.

2. The microsphere of claim 1, wherein the microsphere comprises one or more elastomers.

3. The microsphere of claim 2, wherein the elastomers are selected from the group consisting of acrylic polymers, acrylamide polymers, vinyl alcohol polymers, acrylate polymers, polysaccharides, silicones, and mixtures thereof.

4. The microsphere of claim 2, wherein the diameter of the microsphere ranges from about 10 μ

m to about 2000 μ

m.

5. The microsphere of claim 4, wherein the diameter of the microsphere ranges from about 50 μ

m to about 300 μ

m.

6. The microsphere of claim 1, wherein the microsphere is swellable.

7. The microsphere of claim 6, wherein the microsphere comprises polymers selected from the group consisting of sodium acrylate polymer, acrylamide polymer, acrylamide derivative polymer or copolymer, sodium acrylate and vinyl alcohol copolymer, vinyl acetate and acrylic acid ester copolymer, vinyl acetate and methyl maleate copolymer, isobutylene-maleic anhydride crosslinked copolymer, starch-acrylonitrile graft copolymer, crosslinked sodium polyacrylate polymer, and crosslinked polyethylene oxide.

8. The microsphere of claim 6, wherein the diameter of the microsphere ranges from about 10 μ

m to about 400 μ

m before swelling.

9. The microsphere of claim 8, wherein the diameter of the microsphere ranges from about 10 μ

m to about 200 μ

m before swelling.

10. The microsphere of claim 6, where the diameter of the microsphere ranges from about 10 μ

m to about 2000 μ

m after swelling.

11. The microsphere of claim 1, wherein the drug is selected from the group consisting of anti-tumor, anti-angiogenesis, anti-fungal, antiviral, anti-inflammatory drug, anti-bacterial drug, and anti-histamine drug.

12. The microsphere of claim 1, wherein the vaccine is selected from the group consisting of pneumococcus vaccine, poliomyelitis vaccine, anthrax vaccine, tuberculosis (BCG) vaccine, hepatitis A vaccine, cholera vaccine, meningococcus A, C, Y vaccines, W135 vaccine, plague vaccine, rabies (human diploid) vaccine, yellow fever vaccine, Japanese encephalitis vaccine, typhoid (phenol and heat-killed) vaccine, hepatitis B vaccine, diptheria vaccine, tetanus vaccine, pertussis vaccine, H. influenzae type b vaccine, polio vaccine, measles vaccine, mumps vaccine, rubella vaccine, varicella vaccine, streptococcus pneumoniae Ty (live mutant bacteria) vaccine, Vi (Vi capsular polysaccharide) vaccine, DT (toxoid) vaccine, Td (toxoid) vaccine, aP (inactive bacterial antigen/accelular (DtaP)) vaccine, Hib (bacterial polysaccharide-protein conjugate) vaccine, hepatitis B virus (inactive serum derived viral antigen/recombinant antigen) vaccine, influenza vaccine, rotavirus vaccine, respiratory syncytial virus (RSV) vaccine, human astrovirus vaccine, rotavirus vaccine, human influenza A and B virus vaccine, hepatitis A virus vaccine, live attenuated parainfluenza virus type 3 vaccine, enterovirus vaccines, retrovirus vaccines, and picornavirus vaccines.

13. The microsphere of claim 1, further comprising an imaging agent or contrast media selected from the group consisting of fluorescent markers derivatives, chemical dyes, and magnetic resonance imaging agents.

14. The microsphere of claim 1, wherein the polymer comprises from about 0.5% to about 20%, by molecular weight, of crosslinkers.

15. An injectable composition comprising the microsphere of claim 1 and a biocompatible carrier.

16. The composition of claim 15, wherein the composition comprises the microsphere in an amount from about 10% to about 90% by weight and the biocompatible carrier in an amount from about 10% to about 30% by weight.

17. The composition of claim 16, wherein the composition comprises the microspheres in an amount from about 10% to about 50% by weight and the biocompatible carrier in an amount from about 50% to about 90% by weight.

18. The composition of claim 15, wherein the composition is a suspension of said microspheres in said biocompatible carrier.

19. The composition of claim 18, wherein the biocompatible polymer is in an emulsion.

20. The composition of claim 18, wherein the biocompatible polymer is in an organic or non-aqueous solution.

21. The composition of claim 18, wherein the biocompatible polymer is in an aqueous based solution, a hydro-organic solution, or mixtures thereof.

22. The composition of claim 18, wherein the biocompatible carrier comprises salts composed of cations selected from the group consisting of sodium, potassium, calcium, magnesium, iron, zinc, and ammonium in an amount of from about 0.01 M to about 5 M.

23. The composition of claim 22, wherein the salt is supplied in form of a contrast agent.

24. The composition of claim 18, wherein the contrast agent is monomeric (acrylamido-3-propionamido)-3-triiodo-2,4,6-benzoic acid.

25. The composition of claim 15, where the composition is injectable through a needle of about 18 gauge or smaller.

43. The microsphere of claim 1, wherein the anti-tumor drug is taxol, doxorubicin, tamoxifen, or a combination thereof.

26. A method for active embolization in a mammal comprising administering to a mammal in need of treatment a microsphere comprising a biocompatible, cross-linked and substantially hydrophilic polymer and one or more drugs, vaccines, or combinations thereof.

27. The method of claim 26, wherein the microsphere comprises one or more elastomers.

28. The method of claim 27, wherein the elastomers are selected from the group consisting of acrylic polymers, acrylamide polymers, vinyl alcohol polymers, acrylate polymers, polysaccharides, silicones, and mixtures thereof.

29. The method of claim 27, wherein diameter of the microsphere ranges from about 10 μ

m to about 2000 μ

m.

30. The method of claim 29, wherein the diameter of the microsphere ranges from about 50 μ

m to about 300 μ

m.

31. The method of claim 26, wherein the microsphere is swellable.

32. The method of claim 31, wherein the microsphere comprises ionic polysaccharides and ionic synthetic polymers.

33. The method of claim 32, wherein the ionic polysaccharides are selected from the group consisting of carboxymethyldextran, dextran sulphate, and algenic acid.

34. The method of claim 32, wherein the ionic synthetic polymers are selected from the group consisting of sodium acrylate polymer, acrylamide polymer, acrylamide derivative polymer or copolymer, sodium acrylate and vinyl alcohol copolymer, vinyl acetate and acrylic acid ester copolymer, vinyl acetate and methyl maleate copolymer, isobutylene-maleic anhydride crosslinked copolymer, starch-acrylonitrile graft copolymer, crosslinked sodium polyacrylate polymer, and crosslinked polyethylene oxide.

35. The method of claim 31, wherein diameter of the microsphere ranges from about 10 μ

m to about 400 μ

m before swelling.

36. The method of claim 35, wherein the diameter of the microsphere ranges from about 10 μ

m to about 200 μ

m before swelling.

37. The method of claim 31, where diameter of the microsphere ranges from about 10 μ

m to about 2000 μ

m after swelling.

38. The method of claim 26, wherein the therapeutically active drug is selected from the group consisting of anti-tumor, anti-angiogenesis, anti-fungal, antiviral, anti-inflammatory drug, anti-bacterial drug, and anti-histamine drug, anti-angiogenic factor, antineoplastic agents, hormones and steroids, vitamins, peptides and peptide analogs, enzymes, anti-allergenic agents, circulatory drugs, anti-tubercular agents, anti-viral agents, anti-anginal agents, anti-protozoan agents, anti-rheumatic agents, narcotics, cardiac glycoside agents, sedatives, local anesthetic agents, general anesthetic agents.

39. The method of claim 26, wherein the vaccine is selected from the group consisting of pneumococcus vaccine, poliomyelitis vaccine, anthrax vaccine, tuberculosis (BCG) vaccine, hepatitis A vaccine, cholera vaccine, meningococcus A, C, Y vaccines, W135 vaccine, plague vaccine, rabies (human diploid) vaccine, yellow fever vaccine, Japanese encephalitis vaccine, typhoid (phenol and heat-killed) vaccine, hepatitis B vaccine, diptheria vaccine, tetanus vaccine, pertussis vaccine, H. influenzae type b vaccine, polio vaccine, measles vaccine, mumps vaccine, rubella vaccine, varicella vaccine, streptococcus pneumoniae Ty (live mutant bacteria) vaccine, Vi (Vi capsular polysaccharide) vaccine, DT (toxoid) vaccine, Td (toxoid) vaccine, aP (inactive bacterial antigen/accelular (DtaP)) vaccine, Hib (bacterial polysaccharide-protein conjugate) vaccine, hepatitis B virus (inactive serum derived viral antigen/recombinant antigen) vaccine, influenza vaccine, rotavirus vaccine, respiratory syncytial virus (RSV) vaccine, human astrovirus vaccine, rotavirus vaccine, human influenza A and B virus vaccine, hepatitis A virus vaccine, live attenuated parainfluenza virus type 3 vaccine, enterovirus vaccines, retrovirus vaccines, and picornavirus vaccines.

40. The method of claim 26, wherein the microsphere further comprises a contrast media or a diagnostic agent selected from the group consisting of fluorescent markers derivatives, chemical dyes, and magnetic resonance imaging agents.

41. The method of claim 26, wherein the polymer comprises from about 0.5% to about 20%, by molecular weight, of crosslinkers.

42. The method of claim 26, wherein the administration comprises injecting into an area of said mammal in need of embolization.

44. A method for active embolization in a mammal comprising administering to a mammal in need of treatment a microsphere comprising a biocompatible, cross-linked and substantially hydrophilic polymer and one or more drugs, vaccines, or combinations thereof, wherein said microsphere is delivered to the site of action by the use of targeting antibodies.