Drug delivery compositions and medical devices containing block copolymer

• US 20030171496A1
• Filed: 12/13/2002
• Published: 09/11/2003
• Est. Priority Date: 12/12/2000
• Status: Active Grant

• Current Assignee: Kalpana Kamath, Leonard Pinchuk, Marlene Schwarz, Sepideh Nott
• Original Assignee: Kalpana Kamath, Leonard Pinchuk, Marlene Schwarz, Sepideh Nott
• Inventors: Kamath, Kalpana, Schwarz, Marlene, Pinchuk, Leonard, Nott, Sepideh
• Granted Patent: US 6,855,770 B2
• Time in Patent Office: Days
• US Class Current: 525/242
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 27/16 obtained by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 31/048 obtained by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C08F 293/005 using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent
• CPC Class Codes: C08F 297/00 Macromolecular compounds obtained by successively polymerising different monomer systems using a catalyst of the ionic or coordination type without deactivating the intermediate polymer
• CPC Class Codes: C08F 297/04 polymerising vinyl aromatic monomers and conjugated dienes
• CPC Class Codes: C08L 2666/02 Organic macromolecular compounds, natural resins, waxes or and bituminous materials
• CPC Class Codes: C08L 53/00 Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 53/02 of vinyl-aromatic monomers and conjugated dienes
• CPC Class Codes: C09D 153/00 Coating compositions based on block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Coating compositions based on derivatives of such polymers
• CPC Class Codes: C09D 153/02 Vinyl aromatic monomers and conjugated dienes

Abstract

A composition for delivery of a therapeutic agent is provided. The composition comprises: (a) a biocompatible block copolymer comprising one or more elastomeric blocks and one or more thermoplastic blocks and (b) a therapeutic agent, wherein the block copolymer is loaded with the therapeutic agent. The block copolymer is preferably of the formula X-(AB)_n, where A is an elastomeric block, B is a thermoplastic block, n is a positive whole number and X is a seed molecule. The elastomeric blocks are preferably polyolefin blocks, and the thermoplastic blocks are preferably selected from vinyl aromatic blocks and methacrylate blocks. According to another aspect of the invention, a medical device is provided, at least a portion of which is insertable or implantable into the body of a patient. The medical device comprises (a) the above biocompatible block copolymer and (b) a therapeutic agent, wherein the block copolymer is loaded with the therapeutic agent. According to another aspect of the present invention, a method of treatment is provided in which the above device is implanted or inserted into a patient, resulting in the release of therapeutic agent in the patient over an extended period. According to yet another aspect of the invention, a coated medical device is provided which comprises: (a) an intravascular or intervascular medical device and (b) a coating over at least a portion of the intravascular or intervascular a medical device, wherein the coating comprises the above biocompatible block copolymer.

Claims

1. A composition for delivery of a therapeutic agent comprising:

a biocompatible block copolymer comprising one or more elastomeric blocks and one or more thermoplastic blocks; and

a therapeutic agent, said block copolymer being loaded with said therapeutic agent.

2. The composition of claim 1, wherein said one or more elastomeric blocks are polyolefin blocks and wherein said one or more thermoplastic blocks are selected from vinyl aromatic blocks and methacrylate blocks.

3. The composition of claim 1, wherein said block copolymer is of the formula X-(AB)_n, where A is an elastomeric block, B is a thermoplastic block, n is a positive whole number and X is a seed molecule

4. The composition of claim 3, wherein A is a polyolefin block and B is a vinyl aromatic block or a methacrylate polymer block.

5. The composition of claim 4, wherein B comprises one or more monomers selected from methylmethacrylate, ethylmethacrylate and hydroxyethyl methacrylate.

6. The composition of claim 4, wherein A is a polyolefin block of the general formula —

(CRR′

—

CH₂)_n—

, where R and R′

are linear or branched aliphatic groups or cyclic aliphatic groups and wherein B is a vinyl aromatic polymer block.

7. The composition of claim 6, wherein said polyolefin block comprises an isobutylene monomer and wherein said vinyl aromatic polymer block comprises one or more monomers selected from styrene and α

-methylstyrene.

8. The composition of claim 6, wherein the amount of polyolefin blocks ranges from between 95 and 45 mol % of the block copolymer.

9. The composition of claim 6, wherein the molecular weight of the block copolymer ranges from 80,000 to 300,000 Daltons.

10. The composition of claim 6, wherein the molecular weight of the polyolefin blocks ranges from 60,000 to 200,000 and the molecular weight of the vinyl aromatic polymer blocks ranges from 20,000 to 100,000.

11. The composition of claim 2, wherein said loaded block copolymer comprises 0.1 to 70 wt % therapeutic agent.

12. The composition of claim 6, wherein said loaded block copolymer comprises 0.1 to 70 wt % therapeutic agent.

13. The composition of claim 7, wherein said loaded block copolymer comprises 0.1 to 70 wt % therapeutic agent.

14. A medical device, at least a portion of which is insertable or implantable into the body of a patient, comprising:

a block copolymer comprising one or more elastomeric blocks and one or more thermoplastic blocks; and

a therapeutic agent, said block copolymer being loaded with said therapeutic agent.

15. The medical device of claim 14, wherein said one or more elastomeric blocks are polyolefin blocks and wherein said one or more thermoplastic blocks are vinyl aromatic blocks or methacrylate blocks.

16. The medical device of claim 14, wherein said block copolymer is of the formula X-(AB)_n, where A is an elastomeric block, B is a thermoplastic block, n is a positive whole number and X is a seed molecule.

17. The medical device of claim 16, wherein A is a polyolefin block and B is a vinyl aromatic block or methacrylate polymer block.

18. The medical device of claim 17, wherein A is a polyolefin block of the general formula —

(CRR′

—

CH₂)_n—

, where R and R′

are linear or branched aliphatic groups or cyclic aliphatic groups and wherein B is a vinyl aromatic polymer block.

19. The medical device of claim 18, wherein said polyolefin block comprises an isobutylene monomer and wherein said vinyl aromatic polymer block comprises one or more monomers selected from polystyrene and poly-α

-methylstyrene.

20. The medical device of claim 15, wherein only a portion of said medical device comprises said block copolymer.

21. The medical device of claim 20, wherein said portion of said medical device is a coating on said medical device.

22. The medical device of claim 15, wherein therapeutic agent is released over an extended period after implantation in a patient

23. The medical device of claim 15, wherein the medical device is adapted such that at least a portion of said block copolymer is exposed to bodily fluid upon insertion or implantation in the body

24. The medical device of claim 15, wherein the medical device is adapted such that at least a portion of said block copolymer is exposed to tissue upon insertion or implantation in the body.

25. The medical device of claim 15, wherein said medical device is a catheter, guide wire, balloon, filter, stent, stent graft, vascular graft, vascular patch, shunt or intraluminal paving system.

26. The medical device of claim 15, wherein said medical device is adapted for implantation or insertion into the coronary vasculature, peripheral vascular system, esophagus, trachea, colon, biliary tract, urinary tract, prostate or brain.

27. The medical device of claim 15, wherein said medical device is a stent or catheter which further comprises a sheath for covering the block copolymer during insertion into the body to prevent premature therapeutic agent release.

28. The medical device of claim 21, wherein said coating ranges from about 0.1 to 50 microns in thickness.

29. The medical device of claim 15, wherein said therapeutic agent is selected from one or more of the group consisting of an anti-thrombotic agent, an anti-proliferative agent, an anti-inflammatory agent, an anti-migratory agent, an agent affecting extracellular matrix production and organization, an antineoplastic agent, an anti-mitotic agent, an anesthetic agent, an anti-coagulant, a vascular cell growth promotor, a vascular cell growth inhibitor, a cholesterol-lowering agent, a vasodilating agent, and an agent that interferes with endogenous vascoactive mechanisms.

30. The medical device of claim 15, wherein said therapeutic agent is selected from anti-sense DNA, anti-sense RNA, DNA coding for anti-sense RNA, DNA coding for tRNA or rRNA, DNA coding for angiogenic factors, DNA coding for cell cycle inhibitors, DNA coding for cell proliferation inhibition agents, and DNA coding for bone morphogenic proteins.

31. The medical device of claim 15, wherein said therapeutic agent is selected from autologous cells, allogeneic cells and xenogeneic cells.

32. A method of treatment comprising implanting or inserting the device of claim 15 into a patient such that said therapeutic agent is released in said patient over an extended period.

52. The medical device of claim 14, further comprising a polymer or copolymer of one or more of the following:

a polycarboxylic acid, a cellulose acetate polymer, a cellulose nitrate polymer, a gelatin, a polyvinylpyrrolidone, a cross-linked polyvinylpyrrolidone, a polyanhydride, a polyamide, a polyvinyl alcohol, a polyvinyl ether, a polyvinyl aromatic, a polyethylene oxide, a glycosaminoglycan, a polysaccharide, a polyester, a polyacrylamide, a polyether, a polyether sulfone, a polycarbonate, a polyalkylene, a halogenated polyalkylene, a polyurethane, a polyorthoester, a polypeptide, a silicone, a siloxane polymer, a polylactic acid, a polyglycolic acid, a polycaprolactone, a polyhydroxybutyrate valerate, a fibrin, a collagen, a collagen derivative or a hyaluronic acid.

53. The medical device of claim 52, wherein said polymer or copolymer is selected from a polyacrylic acid, an ethylene-vinyl acetate copolymer, and a copolymer of polylactic acid and polycaprolactone.

54. The medical device of claim 52, wherein said polymer or copolymer is blended with said biocompatible block copolymer.

55. The medical device of claim 52, wherein said polymer or copolymer is provided in a layer that does not contain said biocompatible block copolymer.

33. A medical device, at least a portion of which is insertable or implantable into the vasculature of a patient, comprising:

a block copolymer portion of the formula X-(AB)_n, wherein A is a polyolefin block of the general formula —

(CRR′

—

CH₂)_n—

, where R and R′

are linear or branched aliphatic groups or cyclic aliphatic groups, B is a vinyl aromatic polymer block, n is a positive whole number and X is a seed molecule; and

a therapeutic agent, said block copolymer being loaded with said therapeutic agent, and said therapeutic agent selected from of one or more of the group consisting of an anti-thrombotic agent, an anti-proliferative agent, an anti-inflammatory agent, an anti-migratory agent, an agent affecting extracellular matrix production and organization, an antineoplastic agent, an anti-mitotic agent, an anesthetic agent, an anti-coagulant, a vascular cell growth promotor, a vascular cell growth inhibitor, a cholesterol-lowering agent, a vasodilating agent, and an agent that interferes with endogenous vascoactive mechanisms.

34. The medical device of claim 33, wherein said polyolefin block is a polyisobutylene block and wherein said vinyl aromatic polymer block comprising one or more monomers selected from polystyrene and poly-α

-methylstyrene.

35. The medical device of claim 33, wherein said medical device is selected from a catheter, guide wire, balloon, filter, stent, stent graft, vascular graft, vascular patch or intraluminal paving system.

36. The medical device of claim 33, wherein said block copolymer is in the form of a coating over at least a portion of said medical device.

37. The medical device of claim 34, wherein said block copolymer is in the form of a coating over at least a portion of a medical device selected from the group consisting of a balloon, a stent and a shunt, a catheter, and a filter wherein said therapeutic agent is paclitaxel.

38. The medical device of claim 37, wherein said coating ranges from 0.1 to 40 microns in thickness.

39. The medical device of claim 37, wherein said loaded block copolymer portion comprises 0.1 to 75 wt % paclitaxel.

40. The medical device of claim 37, wherein the molecular weight of the polyisobutylene blocks ranges from 60,000 to 200,000 and the molecular weight of the polystyrene or poly-α

-methylstyrene blocks ranges from 20,000 to 100,000.

51. The device of claim 40, wherein said intravascular or intervascular medical device is selected from a balloon, a stent, a shunt, a catheter, a stent graft, a vascular graft, a vascular patch, a shunt and a filter.

41. A coated medical device comprising:

an intravascular or intervascular medical device; and

a coating over at least a portion of said intravascular or intervascular medical device, said coating comprising a biocompatible block copolymer comprising one or more elastomeric blocks and one or more thermoplastic blocks.

42. The coated medical device of claim 41, wherein said one or more elastomeric blocks are polyolefin blocks and wherein said one or more thermoplastic blocks are selected from vinyl aromatic blocks and methacrylate blocks.

43. The coated medical device of claim 41, wherein said block copolymer is of the formula X-(AB)_n, where A is an elastomeric block, B is a thermoplastic block, n is a positive whole number and X is a catalyst seed molecule.

44. The coated medical device of claim 43, wherein A is a polyolefin block and B is a vinyl aromatic block or a methacrylate polymer block.

45. The coated medical device of claim 44, wherein B comprises one or more monomers selected from methylmethacrylate, ethylmethacrylate and hydroxyethyl methacrylate.

46. The coated medical device of claim 44, wherein A is a polyolefin block of the general formula —

(CRR′

—

CH₂)_n—

, where R and R′

are linear or branched aliphatic groups or cyclic aliphatic groups and wherein B is a vinyl aromatic polymer block.

47. The coated medical device of claim 46, wherein said polyolefin block comprises an isobutylene monomer and wherein said vinyl aromatic polymer block comprises one or more monomers selected from styrene and α

-methylstyrene.

48. The coated medical device of claim 46, wherein the amount of polyolefin blocks ranges from between 95 and 45 mol % of the block copolymer.

49. The coated medical device of claim 46, wherein the molecular weight of the block copolymer ranges from 80,000 to 300,000 Daltons.

50. The coated medical device of claim 46, wherein the molecular weight of the polyolefin blocks ranges from 60,000 to 200,000 Daltons and the molecular weight of the vinyl aromatic polymer blocks ranges from 20,000 to 100,000 Daltons.