Drug delivery compositions and medical devices containing block copolymer

• US 6,855,770 B2
• Filed: 12/13/2002
• Issued: 02/15/2005
• Est. Priority Date: 12/12/2000
• Status: Expired due to Term

• Current Assignee: Scimed Life Systems Incorporated (Boston Scientific Corporation)
• Original Assignee: Scimed Life Systems Incorporated (Boston Scientific Corporation)
• Inventors: Nott, Sepideh, Kamath, Kalpana, Schwarz, Marlene, Pinchuk, Leonard
• Primary Examiner(s): Seidleck, James J.
• Assistant Examiner(s): Asinovsky, Olga
• Application Number:
  US10/319,802
• Publication Number:
  US 20030171496A1
• Time in Patent Office: 795 Days
• Field of Search: 525/240, 525/242, 525/221, 424/501, 424/423, 424/424
• US Class Current: 525/240
• 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 medical device comprising:

a block copolymer comprising one or more polyolefin elastomeric blocks and one or more thermoplastic blocks selected from vinyl aromatic blocks and methacrylate blocks; and

a therapeutic agent, said block copalymer being loaded with said therapeutic agent, wherein said medical device is adapted for implantation or insertion in the coronary vasculature, peripheral vasculature, esophagus, colon, biliary tract or brain of a patient.

2. The medical device of claim 1, wherein said one or more polyolefin elastomeric blocks comprise isobutylene monomers and wherein said one or more thermoplastic blocks comprise one or more monomers selected from styrene and α

-methylstyrene.

3. The medical device of claim 1, wherein said block copolymer is of the formula X—

(AB)_n, where A is a polyolefin block, B is a vinyl aromatic block or a methacrylate block, n is a positive whole number and X is a seed molecule.

4. The medical device of claim 3, 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 B is a methacrylate polymer block.

5. The medical device of claim 3, 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.

6. The medical device of claim 5, 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.

7. The medical device of claim 1, wherein only a portion of said medical device comprises said block copolymer.

8. The medical device of claim 7, wherein said portion of said medical device is a coating on said medical device.

9. The medical device of claim 1, wherein therapeutic agent is released over an extended period after implantation in a patient.

10. The medical device of claim 1, 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.

11. The medical device of claim 8, wherein said coating ranges from about 0.1 to 50 microns in thickness.

12. The medical device of claim 1, 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 vasoactive mechanisms.

13. The medical device of claim 1, 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.

14. The medical device of claim 1, wherein said therapeutic agent is selected from autologous cells, allogeneic cells and xenogeneic cells.

15. A method of treatment comprising implanting or inserting the device of claim 1 into a patient such that said therapeutic agent is released in said patient.

16. The medical device of claim 1, 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.

17. The medical device of claim 16, wherein said polymer or copolymer is selected from a polyacrylic acid, an ethylene-vinyl acetate copolymer, and a copolymer of polylactic acid and polycaprolactone.

18. The medical device of claim 16, wherein said polymer or copolymer is blended with said biocompatible block copolymer.

19. The medical device of claim 16, wherein said polymer or copolymer is provided in a layer that does not contain said biocompatible block copolymer.

20. The medical device of claim 1, wherein the amount of polyolefin blocks ranges from between 45 and 95 mol % of the block copolymer.

21. The medical device of claim 1, wherein the molecular weight of the block copolymer ranges from 80,000 to 300,000 Daltons.

22. The medical device of claim 1, 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.

23. The medical device of claim 1, wherein said medical device is a stent or stent graft adapted for implantation or insertion in the coronary vasculature or peripheral vasculature.

24. The medical device of claim 23, wherein said one or more polyolefin elastomeric blocks comprise an isobutylene monomer and wherein said one or more thermoplastic blocks comprise one or more monomers selected from styrene and α

-methylstyrene.

25. The medical device of claim 1, wherein said medical device is a stent or stent graft adapted for implantation or insertion in the esophagus.

26. The medical device of claim 1, wherein said one or more polyolefin elastomeric blocks comprise an isobutylene monomer and wherein said one or more thermoplastic blocks comprise one or more monomers selected from styrene and α

-methylstyrene.

27. The medical device of claim 1, wherein said medical device is a stent or stent graft adapted for implantation or insertion in the colon.

28. The medical device of claim 27, wherein said one or more polyolefin elastomeric blocks comprise an isobutylene monomer and wherein said one or more thermoplastic blocks comprise one or more monomers selected from styrene and α

-methylstyrene.

29. The medical device of claim 1, wherein said medical device is a stent or stent graft adapted for implantation or insertion in the biliary tract.

30. The medical device of claim 29, wherein said one or more polyolefin elastomeric blocks comprise an isobutylene monomer and wherein said one or more thermoplastic blocks comprise one or more monomers selected from styrene and α

-methylstyrene.

31. The medical device of claim 1, wherein said medical device is a stent or stent graft adapted for implantation or insertion in the brain.

32. The medical device of claim 31, wherein said one or more polyolefin elastomeric blocks comprise an isobutylene monomer and wherein said one or more thermoplastic blocks comprise one or more monomers selected from styrene and α

-methylstyrene.

33. The medical device of claim 1, wherein said therapeutic agent is a deposition inhibitor.

34. The medical device of claim 33, wherein said deposition inhibitor is halofuginone.

35. The medical device of claim 33, wherein said one or more polyolefin elastomeric blocks comprise an isobutylene monomer and wherein said one or more thermoplastic blocks comprise one or more monomers selected from styrene and α

-methylstyrene.

36. The medical device of claim 34, wherein said one or more polyolefin elastomeric blocks comprise an isobutylene monomer and wherein said one or more thermoplastic blocks comprise one or more monomers selected from styrene and α

-methylstyrene.

37. The medical device of claim 1, wherein said therapeutic agent is a free-radical scavenger.

38. The medical device of claim 37, wherein said free-radical scavenger is trans-retinoic acid.

39. The medical device of claim 37, wherein said one or more polyolefin elastomeric blocks comprise an isobutylene monomer and wherein said one or more thermoplastic blocks comprise one or more monomers selected from styrene and α

-methylstyrene.

40. The medical device of claim 38, wherein said one or more polyolefin elastomeric blocks comprise an isobutylene monomer and wherein said one or more thermoplastic blocks comprise one or more monomers selected from styrene and α

-methylstyrene.

41. The medical device of claim 1, wherein said therapeutic agent is an antiproliferative agent.

42. The medical device of claim 41, wherein said antiproliferative agent is paclitaxel.

43. The medical device of claim 41, wherein said one or more polyolefin elastomeric blocks comprise an isobutylene monomer and wherein said one or more thermoplastic blocks comprise one or more monomers selected from styrene and α

-methylstyrene.

44. The medical device of claim 42, wherein said one or more polyolefin elastomeric blocks comprise an isobutylene monomer and wherein said one or more thermoplastic blocks comprise one or more monomers selected from styrene and α

-methylstyrene.

45. The medical device of claim 1, wherein the medical device is a stent.

46. The medical device of claim 2, wherein the medical device is a stent.

47. The medical device of claim 1, wherein said medical device is a stent graft.

48. The medical device of claim 2, wherein said medical device is a stent graft.