Methods for fabricating coatings for drug delivery devices having gradient of hydration

• US 8,277,926 B2
• Filed: 01/18/2008
• Issued: 10/02/2012
• 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: Pacetti, Stephen D., Hossainy, Syed F. A., Tang, Yiwen, Tung, Andrew C., Glauser, Thierry
• Primary Examiner(s): Chen, Vivian
• Application Number:
  US12/016,820
• Publication Number:
  US 20080138498A1
• Time in Patent Office: 1,719 Days
• Field of Search: None
• US Class Current: 428/212
• 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

A method for fabricating a coating for an implantable medical device is provided comprising applying a first polymer on at least a portion of the device to form a first layer of the coating and applying a second polymer on at least a portion of the first layer to form a second layer of the coating. The second polymer has a lower degree of hydration than the first polymer.

Claims

1. A method for fabricating a coating for an implantable medical device, the method comprising applying a first polymer on at least a portion of the device to form a first layer of the coating, and applying a second polymer on at least a portion of the first layer to form a second layer of the coating, wherein the second polymer has a lower degree of hydration than the first polymer;

and

wherein the first or the second polymer comprises a polyorthoester.

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

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

4. The method of claim 1, wherein the degree of hydration of the second polymer is between greater than 0% and about 20% by mass.

5. The method 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(butyl methacrylate) (PBMA), poly(n-butyl methacrylate), poly(ethyl methacrylate), poly(methyl methacrylate), poly(n-propyl methacrylate), polymethacrylates, 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), poly(vinylidene fluoride), poly(vinylidene fluoride-co-hexafluoropropene), poly(vinylidene fluoride-co-chlorotrifluoroethylene), polyurethanes, and blends thereof.

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

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

8. The method 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 method of claim 6, wherein the hydroxylated functional compound comprises poly(alkylene glycols), poly(ethylene oxide-co-propylene oxide, hydroxylated poly(vinyl pyrrolidone), dextran, dextrin, hyaluronic acid, derivatives of hyaluronic acid, poly(2-hydroxyethyl methacrylate), or mixtures thereof.

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

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

12. The method of claim 11, wherein the alkylene glycols are selected from a group consisting of C₂ to C₁₆ α

,ω

-glycols.

13. The method of claim 11, wherein the 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, and mixtures thereof.

14. The method of claim 11, wherein the 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.

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

16. The method 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), polyorthoesters having poly(ethylene glycol) (PEG) incorporated into the polymer backbone, copolymers of alkyl methacrylates and 2-hydroxyethyl methacrylate, copolymers of PEG-acrylates and alkyl methacrylates, copolymers of PEG-methacrylates and alkyl methacrylates, poly(ester-amides) with PEG functionality, derivatives of hyaluronic acid, heparin conjugates, sulfonated polystyrenes, and poly(ethylene-co-vinyl alcohol) with pendant PEG functionality, poly(n-butyl methacrylate), poly(ethyl methacrylate), poly(methyl methacrylate), poly(n-propyl methacrylate), 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.

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

18. The method of claim 17, wherein the diketene acetal has a formula

19. The method of claim 17, 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.

20. The method of claim 17, wherein the hydroxylated functional compound comprises poly(alkylene glycols), poly(ethylene oxide-co-propylene oxide, hydroxylated poly(vinyl pyrrolidone), dextran, dextrin, hyaluronic acid, derivatives of hyaluronic acid, poly(2-hydroxyethyl methacrylate), or mixtures thereof.

21. The method of claim 20, wherein the poly(alkylene glycols) are selected from a group consisting of poly(ethylene glycol), poly(propylene glycol), poly(propane-1,2-diol), poly(propane-1,3-diol) and poly(tetramethylene glycol).

22. The method of claim 17, wherein the diol comprises alkylene glycols, oligoalkylene glycols, or cycloaliphatic diols.

23. The method of claim 22, wherein the alkylene glycols are selected from a group consisting of C₂ to C₁₆ α

,ω

-glycols.

24. The method of claim 22, wherein the 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, and mixtures thereof.

25. The method of claim 22, wherein the 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.

26. The method of claim 22, wherein the cycloaliphatic diols are selected from a group consisting of trans-cyclohexanedimethanol, 1,4-cyclohexanediol, and mixtures thereof.

27. The method of claim 1, wherein the first polymer is a polymer having a formula

28. The method of claim 27, wherein R₂ is a polymethylene structure.

29. The method of claim 27, 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.

30. The method of claim 1, wherein the second polymer is a polymer having a formula

31. The method of claim 30, wherein R₂ is a polymethylene structure.

32. The method of claim 30, 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.

33. The method of claim 1, additionally including applying a third polymer on at least a portion of the second layer, wherein the third polymer has a lower degree of hydration than the second polymer or a higher degree of hydration than the second polymer.

34. The method of claim 33, wherein the degree of hydration of the third polymer is between greater than 0 and about 50% by mass.

35. The method of claim 33, 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.

36. The method of claim 35, wherein the polyorthoesters are products of co-polycondensation of a diketene acetal, a hydroxylated functional compound and a diol.

37. The method of claim 36, wherein the diketene acetal has a formula

38. The method of claim 36, 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.

39. The method of claim 36, wherein the hydroxylated functional compound comprises poly(alkylene glycols), poly(ethylene oxide-co-propylene oxide, hydroxylated poly(vinyl pyrrolidone), dextran, dextrin, hyaluronic acid, derivatives of hyaluronic acid, poly(2-hydroxyethyl methacrylate), or mixtures thereof.

40. The method of claim 39, wherein the poly(alkylene glycols) are selected from a group consisting of poly(ethylene glycol), poly(propylene glycol), poly(propane-1,2-diol), poly(propane-1,3-diol) and poly(tetramethylene glycol).

41. The method of claim 36, wherein the diol comprises alkylene glycols, oligoalkylene glycols, or cycloaliphatic diols.

42. The method of claim 41, wherein the alkylene glycols are selected from a group consisting of C₂ to C₁₆ α

,ω

-glycols.

43. The method of claim 41, wherein the 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, and mixtures thereof.

44. The method of claim 41, wherein the 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.

45. The method of claim 41, wherein the cycloaliphatic diols are selected from a group consisting of trans-cyclohexanedimethanol, 1,4-cyclohexanediol, and mixtures thereof.

46. The method of claim 33, wherein the third polymer is a polymer having a formula

47. The method of claim 46, wherein R₂ is a polymethylene structure.

48. The method of claim 46, 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.

49. The method of claim 33, wherein the first polymer, the second polymer or the third polymer is selected from a group consisting of poly(hydroxyvalerate), poly(L-lactic acid), polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester urethane, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), co-poly(ether-esters), polyethylene oxide-co-polylactic acid, polyalkylene oxalates, polyphosphazenes, biomolecules, fibrin, fibrinogen, cellulose, starch, collagen, hyaluronic acid, polyurethanes, silicones, polyesters, polyolefins, polyisobutylene, ethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinyl halide polymers and copolymers, polyvinyl chloride, polyvinyl ethers, polyvinyl methyl ether, polyvinylidene halides, polyvinylidene fluoride, poly(vinylidene fluoride-co-hexafluoropropene), poly(vinylidene fluoride-co-chlorotrifluoroethylene), polyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics, polystyrene, polyvinyl esters, polyvinyl acetate, copolymers of vinyl monomers with each other and olefins, ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, ethylene-vinyl acetate copolymers, polyamides, Nylon 66, polycaprolactam, alkyd resins, polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxy resins, polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, soluble fluorinated polymers and carboxymethyl cellulose.