Polymer coating for medical devices

• US 7,160,592 B2
• Filed: 02/14/2003
• Issued: 01/09/2007
• Est. Priority Date: 02/15/2002
• Status: Expired due to Fees

• Current Assignee: CV Therapeutics Inc (Gilead Sciences Inc.)
• Original Assignee: CV Therapeutics Inc (Gilead Sciences Inc.)
• Inventors: Rypacek, Frantisek, Machova, Ludka, Lapcikova, Monika
• Primary Examiner(s): McNeil; Jennifer C.
• Assistant Examiner(s): BRUENJES, CHRISTOPHER P
• Application Number:
  US10/366,767
• Publication Number:
  US 20030219562A1
• Time in Patent Office: 1,425 Days
• Field of Search: 428/36.91, 428/447, 428/448, 428/450, 428/480, 428/36.9, 424422-426, 623/1.38, 623/1.42, 623/1.43, 623/1.44, 623/1.46, 604/890.1, 604/891.1
• US Class Current: 428/36.9
• CPC Class Codes: A61L 2300/606 Coatings
• 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: A61L 33/0076 Chemical modification of the substrate
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence
• CPC Class Codes: C08L 83/04 Polysiloxanes
• CPC Class Codes: Y10T 428/1352 Polymer or resin containing [i.e., natural or synthetic]
• CPC Class Codes: Y10T 428/139 Open-ended, self-supporting conduit, cylinder, or tube-type article
• CPC Class Codes: Y10T 428/1393 Multilayer [continuous layer]
• CPC Class Codes: Y10T 428/31663 As siloxane, silicone or silane
• CPC Class Codes: Y10T 428/31786 Of polyester [e.g., alkyd, etc.]

Abstract

Coatings are provided in which surfaces may be activated by covalently bonding a silane derivative to the metal surface, covalently bonding a lactone polymer to the silane derivative by in situ ring opening polymerization, and depositing at least one layer of a polyester on the bonded lactone. Biologically active agents may be deposited with the polyester layers. Such coated surfaces may be useful in medical devices, in particular stents.

Claims

1. A coating for a medical device having a body fluid-contacting surface for contacting blood or other body fluids, the coating comprising:

a silane derivative covalently bonded to the surface of a medical device, said silane derivative containing hydroxyl or amino functional groups;

a layer of lactone polymer chains grown on the hydroxyl or amino functional groups of the silane derivative through in-situ ring opening graft polymerization of lactone monomers, said polymerization initiated by the said hydroxyl or amino functional groups of the silane derivative covalently bonded to the surface of a medical device, said lactone polymer chains and said silane derivative together forming a grafted lactone polymer layer; and

at least one polyester polymer/biologically active agent layer deposited on the grafted lactone polymer layer, wherein at least the first of the deposited polymer/biologically active agent layers is chemically compatible with the grafted lactone polymer layer to allow for entanglement of said deposited polyester polymer chains with the chains of said grafted lactone polymer chains for strong adhesion.

2. The coating of claim 1 wherein the at least one deposited polyester polymer layer comprises from about 0.5% to about 60% by weight of one or more biologically active agents.

3. The coating of claim 2 wherein the at least one deposited polyester polymer layer comprises from about 0.5% to about 34% by weight of one or more biologically active agents.

4. The coating of claim 2 wherein the biologically active agent is an anti-proliferative.

5. The coating of claim 4 wherein the biologically active agent is a CDK2 inhibitor.

6. The coating of claim 2 wherein the biologically active agent is an anti-inflammatory steroid.

7. The coating of claim 6 wherein the biologically active agent is dexamethasone.

8. The coating of claim 2 wherein the concentration of biologically active agent in the layers of the coating may be the same for each layer or the concentration may vary from layer to layer of the coating.

9. The coating of claim 1 wherein the grafted lactone polymer comprises poly(L-lactide) or poly(D,L-lactide).

10. The coating of claim 1 wherein the deposited polyester polymer layer is a polylactone homopolymer or a block copolymer comprising polylactone blocks.

11. The coating of claim 10 wherein the polyester component of the deposited polymer comprises a lactone homopolymer or a lactone copolymer, wherein the lactone homopolymer comprises polyglycolide, poly(L-lactide), poly(D-lactide), poly(ε

-caprolactone), poly(p-dioxanone), poly(dioxepanone), or poly(D,L-lactide), or wherein the lactone copolymer comprises statistical or block copolymers, wherein the statistical or block copolymers comprise poly(L-lactide-co-D-lactide), poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(lactide-co-caprolactone), poly(lactide-co-dioxanone), or poly(lactide-co-dioxepanone).

12. The coating of claim 11 wherein the deposited polymer comprises poly(L-lactide) or poly(D,L-lactide).

13. The coating of claim 1 wherein the polyester polymer deposited on the grafted lactone polymer layer comprises two or more polyester polymer sublayers.

14. The coating of claim 13 wherein each of the deposited polymer sublayers is independently a lactone polymer, wherein the lactone polymer comprises lactone homopolymers or copolymers.

15. The coating of claim 14 wherein the lactone copolymer comprises a block copolymer wherein at least one polylactone block comprises polyglycolide, poly(L-lactide), poly(D-lactide), poly(ε

-caprolactone), poly(p-dioxanone), poly(dioxepanone), poly(D,L-lactide), poly(L-lactide-co-D-lactide), poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(lactide-co-caprolactone), poly(lactide-co-dioxanone), or poly(lactide-co-dioxepanone) and, wherein the other block copolymer comprises polyalkyleneoxide, poly(amino acid), poly(acrylate), poly(methacrylate), or a polybutadiene.

16. The coating of claim 1 wherein the deposited polyester polymer has a molecular weight of 10³ to 10⁶.

17. The coating of claim 1 that further comprises a polymer skin or a topcoat layer deposited on the deposited polyester polymer layer.

18. The coating of claim 17 wherein the polymer skin or topcoat layer comprises a polyester polymer.

19. The coating of claim 18 wherein the polyester polymer is a lactone homopolymer or a lactone block copolymer, wherein the lactone homopolymer comprises polyglycolide, poly(L-lactide), poly(D-lactide), poly(ε

-caprolactone), poly(p-dioxanone), poly(dioxepanone), or poly(D,L-lactide), or wherein the lactone copolymer comprises a statistical or block copolymer, wherein the statistical or block copolymer comprise poly(L-lactide-co-D-lactide), poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(lactide-co-caprolactone), poly(lactide-co-dioxanone), or poly(lactide-co-dioxepanone).

20. The coating of claim 1 wherein the medical device is a stent.

21. A coating for a medical device having a body fluid-contacting surface for contacting blood or other body fluids, the coating comprising:

a silane derivative layer covalently bonded to the body fluid-contacting surface of the medical device, said silane derivative layer containing hydroxyl or amino functional groups;

lactone polymer chains grown on the hydroxyl or amino functional groups of the silane derivative through in-situ ring opening graft polymerization of lactone monomers, said polymerization initiated by said hydroxyl or amino functional groups of the silane derivative covalently bonded to the surface of the medical device, said lactone polymer chains and said silane derivative together forming a grafted lactone polymer layer;

at least one polyester polymer/biologically active agent layer deposited on the grafted lactone polymer layer, wherein at least the first of the deposited polymer/biologically active agent layers is chemically compatible with the grafted lactone polymer layer to allow for entanglement of said deposited polyester polymer chains with the chains of said grafted lactone polymer chains for strong adhesion; and

optionally at least one polymer layer deposited on said deposited polyester polymer/biologically active agent layer forming a skin or topcoat layer.

22. A coating for a medical device having a body fluid-contacting surface for contacting blood or other body fluids, the coating comprising:

a silane derivative covalently bonded to the surface of a medical device, said silane derivative containing hydroxyl or amino functional groups;

a layer of lactone polymer grown on the hydroxyl or amino functional groups of the silane derivative through in-situ ring-opening graft polymerization of lactone monomers, said polymerization initiated by the said hydroxyl or amino functional groups of the silane derivative covalently bonded to the surface of a medical device, said lactone polymer chains and said silane derivative together forming a grafted lactone polymer layer, said grafted lactone polymer comprises a lactone homopolymer or a lactone copolymer, wherein the lactone homopolymer comprises polyglycolide, poly(L-lactide), poly(D-lactide), poly(ε

-caprolactone), poly(p-dioxanone), poly(dioxepanone), or poly(D,L-lactide), or wherein the lactone copolymer comprises statistical or block copolymers, wherein the statistical or block copolymers comprise poly(L-lactide-co-D-lactide), poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(lactide-co-caprolactone), poly(lactide-co-dioxanone), or poly(lactide-co-dioxepanone); and

at least one polyester polymer/biologically active agent layer deposited on the bonded lactone polymer layer, wherein at least the first of the deposited polymer/biologically active agent layers is chemically compatible with the grafted lactone polymer layer to allow for entanglement of said deposited polyester polymer chain with the chains of said grafted lactone polymer chains for strong adhesion.

23. A coating for a medical device having a body fluid-contacting surface for contacting blood or other body fluids, the coating comprising:

a silane derivative covalently bonded to the surface of a medical device, said silane derivative containing hydroxyl or amino functional groups;

a layer of lactone polymer chains grown on the hydroxyl or amino functional groups of the silane derivative through in-situ ring-opening graft polymerization of lactone monomers, said polymerization initiated by the said hydroxyl or amino functional groups of the silane derivative covalently bonded to the surface of a medical device, said lactone polymer chains and said silane derivative together forming a grafted lactone polymer layer; and

two or more polyester polymer/biologically active agent layers deposited on the grafted lactone polymer layer, wherein at least the first of the deposited polymer/biologically active agent layers is chemically compatible with the grafted lactone polymer layer to allow for entanglement of said deposited polyester polymer chains with the chains of said grafted lactone polymer chains for strong adhesion.

24. A coating for a medical device having a body fluid-contacting surface for contacting blood or other body fluids, the coating comprising:

a silane derivative covalently bonded to the surface of a medical device, said silane derivative containing hydroxyl or amino functional groups;

a layer of lactone polymer chains grown on the hydroxyl or amino functional groups of the silane derivative through in-situ ring-opening graft polymerization of lactone monomers, said polymerization initiated by the said hydroxyl or amino functional groups of the silane derivative covalently bonded to the surface of a medical device, said lactone polymer chains and said silane derivative together forming a grafted lactone polymer layer;

two or more polyester polymer/biologically active agent layers deposited on the grafted lactone polymer layer, wherein at least the first of the deposited polymer/biologically active agent layers is chemically compatible with the grafted lactone polymer layer to allow for entanglement of said deposited polyester polymer chains with the chains of said grafted lactone polymer chains for strong adhesion; and

at least one polymer layer deposited on the topmost said deposited polyester polymer/biologically active agent layer forming a skin or topcoat layer.

25. The coating of claim 24 wherein at least one deposited polyester polymer layer comprises from about 0.5% to about 60% by weight of one or more biologically active agents.

26. The coating of claim 25 wherein the concentration of biologically active agent in the layers of the coating may be the same for each layer or the concentration may vary from layer to layer of the coating.

27. The coating of claim 25 wherein at least one deposited polyester polymer layer comprises from about 0.5% to about 34% by weight of one or more biologically active agents.

28. The coating of claim 25 wherein the biologically active agent is an anti-proliferative.

29. The coating of claim 28 wherein the biologically active agent is a CDK2 inhibitor.

30. The coating of claim 25 wherein the biologically active agent is an anti-inflammatory steroid.

31. The coating of claim 30 wherein the biologically active agent is dexamethasone.

32. The coating of claim 24 wherein the grafted lactone polymer comprises a lactone homopolymer or a lactone copolymer, wherein the lactone homopolymer comprises polyglycolide, poly(L-lactide), poly(D-lactide), poly(ε

-caprolactone), poly(p-dioxanone), poly(dioxepanone), or poly(D,L-lactide), or wherein the lactone copolymer comprises statistical or block copolymers, wherein the statistical or block copolymers comprise poly(L-lactide-co-D-lactide), poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(lactide-co-caprolactone), poly(lactide-co-dioxanone), or poly(lactide-co-dioxepanone).

33. The coating of claim 32 wherein the grafted lactone polymer comprises poly(L-lactide) or poly(D,L-lactide).

34. The coating of claim 24 wherein at least the first deposited polyester polymer layer comprises at least one polyester polymer that is compatible or miscible with the grafted lactone polymer.

35. The coating of claim 34 wherein at least the first deposited polyester polymer layer is a polylactone homopolymer or a block copolymer comprising polylactone blocks.

36. The costing of claim 24 wherein the polyester component of at least one of the deposited polyester polymer/biologically active agent layers comprises a lactone homopolymer or a lactone copolymer, wherein the lactone homopolymer comprises polyglycolide, poly(L-lactide), poly(D-lactide), poly(ε

-caprolactone), poly(p-dioxanone), poly(dioxepanone), or poly(D,L-lactide), or wherein the lactone copolymer comprises statistical or block copolymers, wherein the statistical or block copolymers comprise poly(L-lactide-co-D-lactide), poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(lactide-co-caprolactone), poly(lactide-co-dioxanone), or poly(lactide-co-dioxepanone).

37. The coating of claim 36 wherein the deposited polyester polymer comprises poly(L-lactide) or poly(D,L-lactide).

38. The coating of claim 24 wherein each of the deposited polyester polymer/biologically active agent sublayers is independently a lactone polymer, wherein the lactone polymer comprises lactone homopolymers or copolymers.

39. The coating of claim 38 wherein the lactone copolymer comprises a block copolymer wherein at least one polylactone block comprises polyglycolide, poly(L-lactide), poly(D-lactide), poly(ε

-caprolactone), poly(p-dioxanone), poly(dioxepanone), poly(D,L-lactide), poly(L-lactide-co-D-lactide), poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(lactide-co-caprolactone), poly(lactide-co-dioxanone), or poly(lactide-co-dioxepanone) and, wherein the other block copolymer comprises polyalkyleneoxide, poly(amino acid), poly(acrylate), poly(methacrylate), or a polybutadiene.

40. The coating of claim 24 wherein the deposited polyester polymer has a molecular weight of 10³ to 10⁶.

41. The coating of claim 24 wherein the polymer layer deposited on the topmost said deposited polyester polymer/biologically active agent layer comprises a polyester polymer.

42. The coating of claim 41 wherein the polyester polymer deposited on the topmost said deposited polyester polymer/biologically active agent layer is a lactone homopolymer or a lactone block copolymer, wherein the lactone homopolymer comprises polyglycolide, poly(L-lactide), poly(D-lactide), poly(ε

-caprolactone), poly(p-dioxanone), poly(dioxepanone), or poly(D,L-lactide), or wherein the lactone copolymer comprises a statistical or block copolymer, wherein the statistical or block copolymer comprise poly(L-lactide-co-D-lactide), poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(lactide-co-caprolactone), poly(lactide-co-dioxanone), or poly(lactide-co-dioxepanone).

43. The coating of claim 24 wherein the medical device is a stent.

44. A medical device having a coating over a body fluid-contacting surface of the medical device for contacting blood or other body fluids, wherein the coating comprises:

a silane derivative layer covalently bonded to the body fluid-contacting surface of the medical device, said silane derivative layer containing hydroxyl or amino functional groups;

lactone polymer chains grown on the hydroxyl or amino functional groups of the silane derivative through in-situ ring-opening graft polymerization of lactone monomers, said polymerization initiated by said hydroxyl or amino functional groups of the silane derivative covalently bonded to the surface of the medical device, said lactone polymer chains and said silane derivative together forming a grafted lactone polymer layer; and

at least one polyester polymer/biologically active agent layer deposited on the grafted lactone polymer layer, wherein at least the first of the deposited polymer/biologically active agent layers is chemically compatible with the grafted lactone polymer layer to allow for entanglement of said deposited polyester polymer chains with the chains of said grafted lactone polymer chains for strong adhesion.

45. The device of claim 44 wherein the coating comprises from about 0.5% to about 60% by weight of one or more biologically active agents.

46. The device of claim 45 wherein the coating comprises from about 0.5% to about 34% by weight of one or more biologically active agents.

47. The device of claim 45 wherein the biologically active agent is an anti-proliferative.

48. The device of claim 47 wherein the biologically active agent is a CDK2 inhibitor.

49. The device of claim 45 wherein the biologically active agent is an anti-inflammatory steroid.

50. The device of claim 49 wherein the biologically active agent is dexamethasone.

51. The device of claim 44 wherein the medical device is a stent.