Coatings for drug delivery devices having gradient of hydration and methods for fabricating thereof

• US 7,329,413 B1
• Filed: 11/06/2003
• Issued: 02/12/2008
• Est. Priority Date: 11/06/2003
• Status: Expired due to Fees

• Current Assignee: Advanced Cardiovascular Systems Incorporated (Abbott Laboratories)
• Original Assignee: Advanced Cardiovascular Systems Incorporated (Abbott Laboratories)
• Inventors: Tang, Yiwen, Glauser, Thierry, Pacetti, Stephen D., Hossainy, Syed F. A., Tung, Andrew C.
• Primary Examiner(s): Truong; Kevin T.
• Application Number:
  US10/703,334
• Time in Patent Office: 1,559 Days
• Field of Search: 424/422, 424/423, 424/469, 424/470, 424/489, 424/698, 428/702, 428/336, 623/1.44, 623/1.42, 623/1.47, 623/1.46
• US Class Current: 424/423
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61L 2420/08 Coatings comprising two or more layers
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: Y10T 428/24942 including components having same physical characteristic in differing degree
• CPC Class Codes: Y10T 428/3154 Of fluorinated addition polymer from unsaturated monomers
• CPC Class Codes: Y10T 428/31544 Addition polymer is perhalogenated
• CPC Class Codes: Y10T 428/31551 Of polyamidoester [polyurethane, polyisocyanate, polycarbamate, etc.]
• CPC Class Codes: Y10T 428/31565 Next to polyester [polyethylene terephthalate, etc.]
• CPC Class Codes: Y10T 428/31573 Next to addition polymer of ethylenically unsaturated monomer
• CPC Class Codes: Y10T 428/31576 Ester monomer type [polyvinylacetate, etc.]
• CPC Class Codes: Y10T 428/31786 Of polyester [e.g., alkyd, etc.]
• CPC Class Codes: Y10T 428/31797 Next to addition polymer from unsaturated monomers
• CPC Class Codes: Y10T 428/31855 Of addition polymer from unsaturated monomers
• CPC Class Codes: Y10T 428/31909 Next to second addition polymer from unsaturated monomers
• CPC Class Codes: Y10T 428/31928 Ester, halide or nitrile of addition polymer
• CPC Class Codes: Y10T 428/31935 Ester, halide or nitrile of addition polymer

Abstract

Coatings for implantable medical devices, and methods for fabricating thereof, are provided. The coatings include a first polymer layer and a second polymer layer, where the second polymer has a higher degree of hydration than the first polymer.

Claims

1. A coating for an implantable medical device, including a first layer comprising a first polymer, and a second layer comprising a second polymer, the second layer being disposed over at least a portion of the first layer, wherein the second polymer has a higher degree of hydration than the first polymer, and wherein the first polymer or the second polymer comprises a polyorthoester.

2. The coating of claim 1, wherein the implantable medical device is a stent.

3. The coating of claim 1, wherein the degree of hydration of the first polymer is between greater than 0% and about 20% by mass.

4. The coating of claim 1, wherein the degree of hydration of the second polymer is between greater than about 0% and about 50% by mass.

5. The coating of claim 1, wherein the first polymer is selected from a group consisting of polyorthoesters, poly(butyleneterephthalate-co-ethylene glycol), poly(ethylene glycol)-block-poly(butyleneterephthalate)-block poly(ethylene glycol), poly(n-butyl methacrylate), poly(D,L-lactide), poly(caprolactone), poly(4-hydroxybutyrate), poly(3-hydroxybutyrate), poly(hydroxyvalerate), poly(ethylene-co-vinyl alcohol), poly(vinyl alcohol), polybutyral, poly(ethylene-co-vinyl acetate), poly(vinyl acetate), polyurethanes, and blends thereof.

6. The coating of claim 5, wherein the polyorthoesters are products of co-polycondensation of a diketene acetal, a hydroxylated functional compound and a diol.

7. The coating of claim 6, wherein the diketene acetal has a formula

8. The coating of claim 6, wherein the diketene acetal is selected from a group consisting of 3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane, 3,9-dipentylidene-2,4,8,10-tetraoxaspiro-[5,5]-heptadecane, 3,9-dibutylidene-2,4,8,10-tetraoxaspiro-[5,5]-pentadecane, 3,9-dipropylidene-2,4,8,10-tetraoxaspiro-[5,5]-tridecane, and mixtures thereof.

9. The coating of claim 6, wherein the hydroxylated functional compound comprises poly(alkylene glycols), hydroxylated poly(vinyl pyrrolidone), dextran, dextrin, hyaluronic acid, derivatives of hyaluronic acid, poly(2-hydroxyethyl methacrylate), or mixtures thereof.

10. The coating of claim 9, wherein poly(alkylene glycols) are selected from a group consisting of poly(ethylene glycol), poly(propane-1,2-diol), poly(propane-1,3-diol), poly(tetramethylene glycol), and poly(ethylene oxide-co-propylene oxide).

11. The coating of claim 6, wherein the diol comprises alkylene glycols, oligoalkylene glycols, or cycloaliphatic diols.

12. The coating of claim 11, wherein alkylene glycols are selected from a group consisting of ethylene glycol, propane-1,2-diol, propane-1,3-diol, butane-1,4-diol, pentane-1,5-diol, hexane-1,6-diol, heptane-1,7-diol, octane-1,8-diol, nonane-1,9-diol, decane-11,10-diol, undecane-1,11-diol, dodecane-1,12-diol, tridecane-1,13-diol, tetradecane-11,14-diol, pentadecane-1,15-diol, hexadecane-1,16-diol, butane-1,3-diol, pentane-2,4-diol, hexane-2,5-diol, or mixtures thereof.

13. The coating of claim 11, wherein oligoalkylene glycols are selected from a group consisting of diethylene glycol, trimethylene glycol, tetramethylene glycol, tetraethylene glycol, poly(tetraethylene glycol), poly(propylene glycol), and mixtures thereof.

14. The coating of claim 11, wherein cycloaliphatic diols are selected from a group consisting of trans-cyclohexanedimethanol, 1,4-cyclohexanediol, and mixtures thereof.

15. The coating of claim 1, wherein the second polymer is selected from a group consisting of polyorthoesters, poly(butyleneterephthalate-co-ethylene glycol), poly(ethylene glycol)-block-poly(butyleneterephthalate)-block poly(ethylene glycol), poly(n-butyl methacrylate), poly(ethyl methacrylate), poly(methyl methacrylate), poly(n-propyl methacrylate), other polymethacrylates, poly(D,L-lactide), poly(caprolactone), poly(4-hydroxybutyrate), poly(3-hydroxybutyrate), poly(hydroxyvalerate), poly(ethylene-co-vinyl alcohol), poly(vinyl alcohol), poly(ethylene-co-vinyl acetate), poly(vinyl acetate), poly(vinylidene fluoride), poly(vinylidene fluoride-co-hexafluoropropene), poly(vinylidene fluoride-co-chlorotrifluoroethylene), polyurethanes, and blends thereof.

16. The coating of claim 15, wherein the polyorthoesters are products of co-polycondensation of a diketene acetal, a hydroxylated functional compound and a diol.

17. The coating of claim 16, wherein the diketene acetal has a formula

18. The coating of claim 16, wherein the diketene acetal is selected from a group consisting of 3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane, 3,9-dipentylidene-2,4,8,10-tetraoxaspiro-[5,5]-heptadecane, 3,9-dibutylidene-2,4,8,10-tetraoxaspiro-[5,5]-pentadecane, 3,9-dipropylidene-2,4,8,10-tetraoxaspiro-[5,5]-tridecane, and mixtures thereof.

19. The coating of claim 16, wherein the hydroxylated functional compound comprises poly(alkylene glycols), hydroxylated poly(vinyl pyrrolidone), dextran, dextrin, hyaluronic acid, derivatives of hyaluronic acid, poly(2-hydroxyethyl methacrylate), or mixtures thereof.

20. The coating of claim 19, wherein poly(alkylene glycols) are selected from a group consisting of poly(ethylene glycol), poly(propylene glycol), poly(tetramethylene glycol), and poly(ethylene oxide-co-propylene oxide).

21. The coating of claim 16, wherein the diol comprises alkylene glycols, oligoalkylene glycols, or cycloaliphatic diols.

22. The coating of claim 21, wherein alkylene glycols are selected from a group consisting of ethylene glycol, propane-1,2-diol, propane-1,3-diol, butane-1,4-diol, pentane-1,5-diol, hexane-1,6-diol, heptane-1,7-diol, octane-1,8-diol, nonane-1,9-diol, decane-1,10-diol, undecane-1,11-diol, dodecane-1,12-diol, tridecane-1,13-diol, tetradecane-1,14-diol, pentadecane-1,15-diol, hexadecane-1,16-diol, butane-1,3-diol, pentane-2,4-diol, hexane-2,5-diol, or mixtures thereof.

23. The coating of claim 21, wherein oligoalkylene glycols are selected from a group consisting of diethylene glycol, trimethylene glycol, tetramethylene glycol, tetraethylene glycol, poly(tetraethylene glycol), poly(propylene glycol), and mixtures thereof.

24. The coating of claim 21, wherein cycloaliphatic diols are selected from a group consisting of trans-cyclohexanedimethanol, 1,4-cyclohexanediol, and mixtures thereof.

25. The coating of claim 1, wherein the first polymer is a polymer having a formula

26. The coating of claim 25, wherein R₂ is a poly(methylene oxide structure).

27. The coating of claim 25, wherein the hydroxylated functional compound comprises poly(alkylene glycols), hydroxylated poly(vinyl pyrrolidone), dextran, dextrin, hyaluronic acid, derivatives of hyaluronic acid, poly(2-hydroxymethyl methacrylate), or mixtures thereof.

28. The coating of claim 1, wherein the second polymer is a polymer having a formula

29. The coating of claim 28, wherein R₂ is a poly(methylene oxide structure).

30. The coating of claim 28, wherein the hydroxylated functional compound comprises poly(alkylene glycols), hydroxylated poly(vinyl pyrrolidone), dextran, dextrin, hyaluronic acid, derivatives of hyaluronic acid, poly(2-hydroxymethyl methacrylate), or mixtures thereof.

31. The coating of claim 1, additionally including a third layer comprising a third polymer, the third layer being disposed over at least a portion of the second layer, wherein the third polymer has a higher degree of hydration than the second polymer.

32. The coating of claim 31, wherein the degree of hydration of the third polymer is between greater than 0% and 50% by mass.

33. The coating of claim 31, wherein the third polymer is selected from a group consisting of polyorthoesters, poly(butyleneterephthalate-co-ethylene glycol), poly(ethylene glycol)-block-poly(butyleneterephthalate)-block poly(ethylene glycol), polyorthoesters having poly(ethylene glycol) incorporated into the polymer backbone, copolymers of alkyl methacrylates and 2-hydroxyethyl methacrylate, copolymers of poly(ethylene glycol)-acrylates and alkyl methacrylates, copolymers of poly(ethylene glycol)-methacrylates and alkyl methacrylates, poly(ester-amides) with poly(ethylene glycol) functionality, derivatives of hyaluronic acid, heparin conjugates, sulfonated polystyrenes, and poly(ethylene-co-vinyl alcohol) with pendant poly(ethylene glycol) functionality.

34. The coating of claim 33, wherein the polyorthoesters are products of co-polycondensation of a diketene acetal, a hydroxylated functional compound and a diol.

35. The coating of claim 34, wherein the diketene acetal has a formula

36. The coating of claim 34, wherein the diketene acetal is selected from a group consisting of 3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane, 3,9-dipentylidene-2,4,8,10-tetraoxaspiro-[5,5]-heptadecane, 3,9-dibutylidene-2,4,8,10-tetraoxaspiro-[5,5]-pentadecane, 3,9-dipropylidene-2,4,8,10-tetraoxaspiro-[5,5]-tridecane, and mixtures thereof.

37. The coating of claim 34, wherein the hydroxylated functional compound comprises poly(alkylene glycols), hydroxylated poly(vinyl pyrrolidone), dextran, dextrin, hyaluronic acid, derivatives of hyaluronic acid, poly(2-hydroxyethyl methacrylate), or mixtures thereof.

38. The coating of claim 37, wherein poly(alkylene glycols) are selected from a group consisting of poly(ethylene glycol), poly(propylene glycol), poly(tetramethylene glycol), and poly(ethylene oxide-co-propylene oxide).

39. The coating of claim 34, wherein the diol comprises alkylene glycols, oligoalkylene glycols, or cycloaliphatic diols.

40. The coating of claim 39, wherein alkylene glycols are selected from a group consisting of ethylene glycol, propane-1,2-diol, propane-1,3-diol, butane-1,4-diol, pentane-1,5-diol, hexane-1,6-diol, heptane-1,7-diol, octane-1,8-diol, nonane-1,9-diol, decane-1,10-diol, undecane-1,1′

-diol, dodecane-1,12-diol, tridecane-1,13-diol, tetradecane-1,14-diol, pentadecane-1,15-diol, hexadecane-1,16-diol, butane-1,3-diol, pentane-2,4-diol, hexane-2,5-diol, or mixtures thereof.

41. The coating of claim 39, wherein oligoalkylene glycols are selected from a group consisting of diethylene glycol, trimethylene glycol, tetramethylene glycol, tetraethylene glycol, poly(tetraethylene glycol), poly(propylene glycol), and mixtures thereof.

42. The coating of claim 39, wherein cycloaliphatic diols are selected from a group consisting of trans-cyclohexanedimethanol, 1,4-cyclohexanediol, and mixtures thereof.

43. The coating of claim 31, wherein the third polymer is a polymer having a formula

44. The coating of claim 43, wherein R₂ is a poly(methylene oxide structure).

45. The coating of claim 43, wherein the hydroxylated functional compound comprises poly(alkylene glycols), hydroxylated poly(vinyl pyrrolidone), dextran, dextrin, hyaluronic acid, derivatives of hyaluronic acid, poly(2-hydroxymethyl methacrylate), or mixtures thereof.

46. A medical article, comprising an implantable substrate and a coating disposed over at least a portion of the substrate, the coating comprising a first layer and a second layer disposed over at least a portion of the first layer, wherein the second layer has a higher degree of hydration than the first layer, and wherein the first polymer or the second polymer comprises a polyorthoester.