Coatings for drug delivery devices having gradient of hydration

• US 8,231,962 B2
• Filed: 01/18/2008
• Issued: 07/31/2012
• Est. Priority Date: 11/06/2003
• Status: Active Grant

• Current Assignee: Advanced Cardiovascular Systems Incorporated
• Original Assignee: Advanced Cardiovascular Systems Incorporated
• Inventors: Pacetti, Stephen D., Hossainy, Syed F. A., Tang, Yiwen, Tung, Andrew C., Glauser, Thierry
• Primary Examiner(s): Chen, Vivian
• Application Number:
  US12/016,811
• Publication Number:
  US 20080113207A1
• Time in Patent Office: 1,656 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 coating for an implantable medical device is provided comprising a first layer including a first polymer and a second layer including a second polymer. The second layer is disposed over at least a portion of the first layer. The second polymer has a lower degree of hydration than the first polymer.

Claims

1. A coating for an implantable medical device, comprising 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 lower degree of hydration than the first polymer;

and

wherein the first or second polymer comprises a poly(ortho ester) which is the product of co-polycondensation of a diketene acetal, a hydroxylated functional compound and a diol;

wherein the hydroxylated functional compound is selected from the group consisting of poly(alkylene glycols), poly(ethylene oxide-co-propylene oxide) surfactants, hydroxylated poly(vinyl pyrrolidone), dextran, dextrin, hyaluronic acid, derivatives of hyaluronic acid, poly(2-hydroxyethyl methacrylate), and mixtures thereof; and

wherein the diol is selected from the group consisting of alkylene glycols, oligoalkylene glycols, cycloaliphatic diols and blends and combinations thereof.

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 from greater than 0% to about 20% by mass.

4. The coating of claim 1, wherein the degree of hydration of the second polymer is from greater than 0% to about 20% by mass.

5. The coating of claim 1, wherein the first polymer is selected from the 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 coating of claim 1, wherein the first polymer is the poly(ortho ester).

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

8. The coating of claim 7, wherein the diketene acetal is selected from the 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 is selected from the group consisting of hydroxylated poly(vinyl pyrrolidone), dextran, dextrin, hyaluronic acid, derivatives of hyaluronic acid, poly(2-hydroxyethyl methacrylate), and mixtures thereof.

10. The coating of claim 6, wherein the poly(alkylene glycols) are selected from the group consisting of poly(ethylene glycol), poly(propylene glycol), poly(propane-1,2-diol), poly(propane-1,3-diol), poly(tetramethylene glycol), and mixtures thereof.

11. The coating of claim 6, wherein the alkylene glycols are selected from the group consisting of C₂ to C₁₆ α

,ω

-glycols, and mixtures thereof.

12. The coating of claim 11, wherein the alkylene glycols are selected from the 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, and mixtures thereof.

13. The coating of claim 6, wherein oligoalkylene glycols are selected from the 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 6, wherein cycloaliphatic diols are selected from the group consisting of trans-cyclohexanedimethanol, 1,4-cyclohexanediol, and mixtures thereof.

15. The coating of claim 1, wherein the second polymer is selected from the 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.

16. The coating of claim 1, wherein the second polymer is the poly(ortho ester).

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

18. The coating of claim 17, wherein the diketene acetal is selected from the 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 poly(alkylene glycols) are selected from the group consisting of poly(ethylene glycol), poly(propylene glycol), poly(propane-1,2-diol), poly(propane-1,3-diol), poly(tetramethylene glycol), and mixtures thereof.

20. The coating of claim 16, wherein the alkylene glycols are selected from the group consisting of C₂ to C₁₆ α

,ω

-glycols, and mixtures thereof.

21. The coating of claim 20, wherein the alkylene glycols are selected from the group consisting of ethylene glycol, 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, and mixtures thereof.

22. The coating of claim 16, wherein the oligoalkylene glycols are selected from the group consisting of diethylene glycol, trimethylene glycol, tetramethylene glycol, tetraethylene glycol, poly(tetraethylene glycol), poly(propylene glycol), and mixtures thereof.

23. The coating of claim 16, wherein cycloaliphatic diols are selected from the group consisting of trans-cyclohexanedimethanol, 1,4-cyclohexanediol, and mixtures thereof

24. A coating for an implantable medical device, comprising

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 lower degree of hydration than the first polymer;

wherein at least one of the group of the first and second polymers is a polymer of the formula;

25. The coating of claim 24, wherein the first polymer is of the formula:

26. The coating of claim 25, wherein R₂ is a polymethylene structure.

27. The coating of claim 24, wherein the second polymer is of the formula:

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

29. A coating for an implantable medical device, comprising 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 lower degree of hydration than the first polymer;

and wherein the first or second polymer comprises a poly(ortho ester); and

the coating additionally comprising 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 lower degree of hydration than the second polymer or a higher degree of hydration than the second polymer.

30. The coating of claim 29, wherein the degree of hydration of the third polymer is from greater than 0% to about 50% by mass.

31. The coating of claim 29, wherein the third polymer is selected from the 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.

32. The coating of claim 31, wherein the polyorthoesters are products of co-polycondensation of a diketene acetal, a hydroxylated functional compound and a diol.

33. The coating of claim 32, wherein the diketene acetal is of the formula

34. The coating of claim 33, wherein the diketene acetal is selected from the 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

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

36. The coating of claim 35, wherein poly(alkylene glycols) are selected from the group consisting of poly(ethylene glycol), poly(propylene glycol), poly(propane-1,2-diol), poly(propane-1,3-diol), poly(tetramethylene glycol), and mixtures thereof.

37. The coating of claim 36, wherein the diol comprises alkylene glycols, oligoalkylene glycols, cycloaliphatic diols, and blends and combinations thereof.

38. The coating of claim 37, wherein alkylene glycols are selected from the group consisting of C₂ to C₁₆ α

,ω

-glycols, and mixtures thereof.

39. The coating of claim 37, wherein the alkylene glycols are selected from the 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, pentane2,4-diol, hexane-2,5-diol, and mixtures thereof.

40. The coating of claim 37, wherein the oligoalkylene glycols are selected from the group consisting of diethylene glycol, trimethylene glycol, tetramethylene glycol, tetraethylene glycol, poly(tetraethylene glycol), polypropylene glycol), and mixtures thereof.

41. The coating of claim 37, wherein the cycloaliphatic diols are selected from the group consisting of trans-cyclohexanedimethanol, 1,4-cyclohexanediol, and mixtures thereof.

42. The coating of claim 29, wherein the third polymer is a polymer of a formula

43. The coating of claim 42, wherein R₂ is a polymethylene structure.

44. The coating of claim 42, 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.

45. The coating of claim 29, wherein at least one of the group of the first polymer, the second polymer and the third polymer is selected from the 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.