Claims for Patent: 6,316,522

Summary for Patent: 6,316,522

Title:	Bioresorbable hydrogel compositions for implantable prostheses
Abstract:	Crosslinked compositions formed from water-insoluble copolymers are disclosed. These compositions are copolymers having a bioresorbable region, a hydrophilic region and at least two cross-linkable functional groups per polymer chain. Crosslinking of these polymers can be effected in solution in organic solvents or in solvent-free systems. If crosslinking occurs in a humid environment, a hydrogel will form. If crosslinking occurs in a non-humid environment, a xerogel will form which will form a hydrogel when exposed to a humid environment and the resulting crosslinked materials form hydrogels when exposed to humid environments. These hydrogels are useful as components in medical devices such as implantable prostheses. In addition, such hydrogels are useful as delivery vehicles for therapeutic agents and as scaffolding for tissue engineering applications.
Inventor(s):	Loomis; Gary L. (Morristown, NJ), Lentz; D. Christian (Pompton Plains, NJ)
Assignee:	Scimed Life Systems, Inc. (Maple Grove, MN)
Application Number:	09/395,725
Patent Claims:	1. A composition comprising an organic solution of a water-insoluble copolymer having (1) a bioresorbable region; (2) a hydrophilic region; and (3) a plurality of cross-linkable functional groups per polymer chain. 2. The composition of claim 1, wherein said water-insoluble copolymer has the following general formula: ##STR3## wherein x is from about 10 to about 100 and y is from about 50 to about 500. 3. The composition of claim 1, wherein said water-insoluble copolymer has the following general formula: ##STR4## wherein the ratio of A to B is about 3:1, x is from about 10 to about 100, and y is from about 50 to about 300, so long as the composition remains substantially water-insoluble as a whole. 4. The composition of claim 1, wherein said water-insoluble copolymer is selected from the group consisting of di-block copolymers, tri-block copolymers, and star copolymers. 5. The composition of claim 4, wherein said tri-block copolymer has the general formula: wherein A is the bioresorbable region, B is the hydrophilic region, and x is the cross-linkable functional group. 6. The composition of claim 1, wherein the solvent solution comprises a mixture of an organic solvent and up to 50% water. 7. The composition of claim 6, wherein said mixture is selected from the group consisting of a mixture of 1-propanol and water and a mixture of ethanol and water. 8. The composition of claim 1, wherein the solvent of said solution comprises a substantially non-aqueous organic solvent. 9. The composition of claim 8, wherein said solvent is selected from the group consisting of aliphatic and aromatic alcohols. 10. The composition of claim 9, wherein said solvent is selected from the group consisting of 1-propanol and ethanol. 11. The composition of claim 1, wherein said bioresorbable region is selected from the group consisting of poly(esters), poly(hydroxy acids), poly(lactones), poly(amides), poly(ester-amides), poly(amino acids), poly(anhydrides), poly(ortho-esters), poly(carbonates), poly(phosphazines), poly(thioesters), polysaccharides and mixtures thereof. 12. The composition of claim 1, wherein said bioresorbable region is a poly(hydroxy) acid, said poly(hydroxy) acid is selected from the group consisting of polylactic acid, polyglycolic acid, polycaproic acid, polybutyric acid, polyvaleric acid, and copolymers and mixtures thereof. 13. The composition of claim 1, wherein said hydrophilic region is selected form the group consisting of polyethers, polyalkylene oxides, polyols, poly(vinylpyrrolidine), poly(vinyl alcohol), poly(alkyl oxazolines), polysaccharides, carbohydrates, peptides, proteins, and copolymers and mixtures thereof. 14. The composition of claim 1, wherein said hydrophilic region is a poly(alkylene) oxide, said poly(alkylene) oxide is selected from the group consisting of poly(ethylene) oxide, poly(propylene) oxide, and mixtures and copolymers thereof. 15. The composition of claim 1, wherein said bioresorbable region is hydrophilic. 16. The composition of claim 1, wherein said bioresorbable region has hydrophilic character without rendering the polymer water-soluble. 17. The composition of claim 1, wherein said bioresorbable region is hydrolytically and/or enzymatically cleavable. 18. The composition of claim 1, wherein said hydrophilic region forms an excretable and/or metabolizable fragment. 19. The composition of claim 1, wherein the relative properties and proportions of said bioresorbable region and said hydrophilic region are selected to render said composition substantially insoluble in water. 20. The composition of claim 1, wherein said plurality of cross-linkable functional groups are olefinically unsaturated groups. 21. The composition of claim 20, wherein said olefinically unsaturated functional groups are selected from acrylates, methacrylates, butenoates, maleates, allyl ethers, allyl thioesters, and N-ally carbamates. 22. The composition of claim 1, wherein said copolymer is crosslinked in a non-humid environment. 23. The composition of claim 1, wherein said copolymer is crosslinked in a humid environment. 24. The composition of claim 23, wherein said humid environment contains from about 20% to about 100% water. 25. The composition of claim 23, wherein said humid environment contains from about 60% to about 100% water. 26. The composition of claim 1, wherein said composition is crosslinked by high energy radiation, thermal radiation, or visible light, or combinations thereof. 27. The composition of claim 1, wherein said composition further includes a free radical initiator. 28. The composition of claim 27, wherein said free radical initiator is an azo compound. 29. The composition of claim 28, wherein said azo compound is 2,2'-Azobis (N,N'dimethyleneisobutyramidine) dihydrochloride. 30. The composition of claim 1, wherein said crosslinked polymer forms a hydrogel in a humid environment. 31. The composition of claim 30, wherein said hydrogel is applied to a medical device. 32. The composition of claim 31, wherein said medical device is selected from the group consisting of conduits, vascular grafts, endovascular grafts, stents, graft-stents, catheters, guidewires, trocars, and introducer sheaths. 33. The composition of claim 30, wherein said hydrogel is a drug or bioactive agent delivery vehicle. 34. The composition of claim 33, wherein said drug or bio-active agent is selected from the group consisting of thrombo-resistant agents, antibiotic agents, anti-tumor agents, anti-viral agents, anti-angiogenic agents, angiogenic agents, anti-inflammatory agents, cell cycle regulating agents, and chemically modified equivalents and combinations thereof. 35. The composition of claim 34, wherein said thrombo-resistant agent is selected from the group consisting of heparin, heparin sulfate, hirudin, chondroitin sulfate, dermatan sulfate, keratin sulfate, lytic agents, and chemically modified equivalents thereof. 36. The composition of claim 34, wherein said antibiotic agent is selected from the group consisting of penicillins, cephalosporins, vancomycins, aminoglycosides, quinolones, polymyxins, erytbromycins, tetracyclines, chloramphenicols, clindamycins, lincomycins, sulfonamides, and chemically modified equivalents and combinations thereof. 37. The composition of claim 34, wherein said anti-tumor agent is selected from the group consisting of paclitaxel, docetaxel, alkylating agents, antimetabolites, plant alkaloids, antibiotics, nitrosureas, inorganic ions, biological response modifiers, enzymes, hormones, and chemically modified equivalents and combinations thereof. 38. The composition of claim 34, wherein said anti-viral agent is selected from the group consisting of amantadines, rimantadines, ribavirins, idoxuridines, vidarabines, trifluridines, acyclovirs, ganciclovirs, zidovudines, foscarnets, interferons, and chemically modified equivalents and combinations thereof. 39. A process for forming a bioresorbable hydrogel comprising: a. providing an organic solution of a water-insoluble copolymer comprising (1) a bioresorbable region; (2) a hydrophilic region; and (3) a plurality of cross-linkable functional groups per polymer chain; b. effecting a crosslinking reaction; and c. exposing the composition to a humid environment to form a hydrogel. 40. The process of claim 39, wherein said water-insoluble copolymer has the following general formula: ##STR5## wherein x is from about 10 to about 100 and y is from about 50 to about 500. 41. The process of claim 39, wherein said water-insoluble copolymer has the following general formula: ##STR6## wherein the ratio of A or B is about 3:1, x is from about 10 to about 100, and y is from about 50 to about 300, so long as the composition remains substantially water-insoluble as a whole. 42. The process of claim 39, wherein the solvent solution comprises a mixture of an organic solvent up to 50% water. 43. The process of claim 42, wherein said mixture is selected from the group consisting of a mixture of 1-propanol and water and a mixture of ethanol and water. 44. The process of claim 39, wherein the solvent of said solution comprises a substantially non-aqueous organic solvent. 45. The process of claim 44, wherein said solvent is selected from the group cosisting of 1-propanol and ethanol. 46. The process of claim 39, wherein said bioresorbable region is selected from the group consisting of poly(esters), poly(hydroxy acids), poly(lactones), poly(amides), poly(ester-amides), poly(amino acids), poly(anhydrides), poly(ortho-esters), poly(carbonates), poly(phosphazines), poly(thioesters), polysaccharides and mixtures thereof. 47. The process of claim 39, wherein said bioresorbable region is a poly(hydroxy) acid, said poly(hydroxy) acid is selected from the group consisting of polylactic acid, polyglycolic acid, polycaproic acid, polybutyric acid, polyvaleric acid, and copolymers and mixtures thereof. 48. The process of claim 39, wherein said hydrophilic region is selected form the group consisting of polyethers, polyalkylene oxides, polyols, poly(vinylpyrrolidine), poly(vinyl alcohol), poly(alkyl oxazolines), polysaccharides, carbohydrates, peptides, proteins, and copolymers and mixtures thereof. 49. The process of claim 39, wherein said hydrophilic region is a poly(alkylene) oxide, said poly(alkylene) oxide is selected from the group consisting of poly(ethylene) oxide, poly(propylene) oxide, and mixtures and copolymers thereof. 50. The process of claim 39, wherein said bioresorbable region is hydrophilic. 51. The process of claim 39, wherein said bioresorbable region has hydrophilic character without rendering the polymer water-soluble. 52. The process of claim 39, wherein said bioresorbable region is hydrolytically and/or enzymatically cleavable. 53. The process of claim 39, wherein said hydrophilic region foris an excretable and/or metabolizable fragment. 54. The process of claim 39, wherein the relative properties and proportions of said bioresorbable region and said hydrophilic region are selected to render said composition substantially insoluble in water. 55. The process of claim 39, wherein said plurality of cross-linkable functional groups are olefinically unsaturated groups. 56. The process of claim 55, wherein said olefinically unsaturated functional the group consisting of acrylates, methacrylates, butenoates, maleates, allyl ethers, allyl thioesters, and N-ally carbamates. 57. The process of claim 39, wherein said copolymer is crosslinked in a non-humid environment. 58. The process of claim 39, wherein said copolymer is crosslinked in a humid environment, said humid environment containing from about 20% to about 100% water. 59. The process of claim 39, wherein said composition is crosslinked by high energy radiation, thermal radiation, or visible light, or combinations thereof. 60. The process of claim 39, wherein said composition further includes a free radical initiator. 61. The process of claim 60, wherein said free radical initiator is an azo compound. 62. A process for forming a medical device coated with a hydrogel comprising: a. applying a cross-linkable composition to a medical device, said cross-linkable composition comprising an organic solution of a water-insoluble copolymer comprising (1) a bioresorbable region; (2) a hydrophilic region; and (3) a plurality of cross-linkable functional groups per polymer chain; b. effecting a crosslinking reaction; and c. exposing the crosslinked composition to a humid environment to form a hydrogel. 63. The process of claim 62, wherein said medical device is selected from the group consisting of conduits, vascular grafts, endovascular grafts, stents, graft-stents, catheters, guidewires, trocars, and introducer sheaths. 64. The process of claim 62, wherein said hydrogel is a drug or bioactive agent delivery vehicle. 65. The process of claim 64, wherein said drug or bio-active agent is selected from the group consisting of thrombo-resistant agents, antibiotic agents, anti-tumor agents, anti-viral agents, anti-angiogenic agents, angiogenic agents, anti-inflarnmatory agents, cell cycle regulating agents, and chemically modified equivalents and combinations thereof. 66. The process of claim 65, wherein said thrombo-resistant agent is selected from the group consisting of heparin, heparin sulfate, hirudin, chondroitin sulfate, dermatan sulfate, keratin sulfate, lytic agents, including urokinase and streptokinase, and chemically modified equivalents thereof. 67. The process of claim 65, wherein said antibiotic agent is selected from the group consisting of penicillins, cephalosporins, vancomycins, aminoglycosides, quinolones, polymyxins, erythromycins, tetracyclines, chloramphenicols, clindamycins, lincomycins, sulfonamides, and chemically modified equivalents and combinations thereof. 68. The process of claim 65, wherein said anti-tumor agent is selected from the group consisting of paclitaxel, docetaxel, alkylating agents including mechlorethamine, chlorambucil, cyclophosphamide, melphalan and ifosfamide; antimetabolites including methotrexate, 6-mercaptopurine, 5-fluorouracil and cytarabine; plant alkaloids including vinblastine, vincristine and etoposide; antibiotics including doxorubicin, daunomycin, bleomycin, and mitomycin; nitrosureas including carmustine and lomustine; inorganic ions including cisplatin; biological response modifiers including interferon; enzymes including asparaginase; and hormones including tamoxifen and flutamide; and chemically modified equivalents and combinations thereof. 69. The process of claim 65, wherein said anti-viral agent is selected from the group consisting of amantadines, rimantadines, ribavirins, idoxuridines, vidarabines, trifluridines, acyclovirs, ganciclovirs, zidovudines, foscarnets, interferons, and chemically modified equivalents and combinations thereof. 70. The composition of claim 34, wherein said thrombo-resistant agent is selected from the group consisting of urokinase, streptokinase, and chemically modified equivalents and combinations thereof. 71. The composition of claim 34, wherein said anti-tumor agent is selected from the group consisting of mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide, methotrexate, 6-mercaptopurine, 5-fluorouracil, cytarabine, vinblastine, vincristine, etoposide, doxorubicin, daunomycin, bleomycin, mitomycin, carmustine, lomustine, cisplatin, interferon, asparaginase, tamoxifen, flutamide, and chemically modified equivalents and combinations thereof. 72. The process of claim 65, wherein said thrombo-resistant agent is selected from the group consisting of urokinase, streptokinase, and chemically modified equivalents and combinations thereof. 73. The process of claim 65, wherein said anti-tumor agent is selected from the group consisting of mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide, methotrexate, 6-mercaptopurine, 5-fluorouracil, cytarabine, vinblastine, vincristine, etoposide, doxorubicin, daunomycin, bleomycin, mitomycin, carmustine, lomustine, cisplatin, interferon, asparaginase, tamoxifen, flutamide, and chemically modified equivalents and combinations thereof.

Details for Patent 6,316,522

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Microbix Biosystems Inc.	KINLYTIC	urokinase	For Injection	021846	01/16/1978		2017-08-18
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2017-08-18