Polymer coating for medical devices

• US 20030219562A1
• Filed: 02/14/2003
• Published: 11/27/2003
• Est. Priority Date: 02/15/2002
• Status: Active Grant

• Current Assignee: Gilead Palo Alto Incorporated (Gilead Sciences Inc.)
• Original Assignee: Gilead Palo Alto Incorporated (Gilead Sciences Inc.)
• Inventors: Rypacek, Frantisek, Machova, Ludka, Lapcikova, Monika
• Granted Patent: US 7,160,592 B2
• Time in Patent Office: Days
• US Class Current: 428/36.91
• 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, other body fluids and the like, the coating comprising:

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

a lactone polymer covalently bonded to the functional groups of the polymerized silane derivative via in-situ ring opening polymerization.

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

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

a lactone polymer covalently bonded to the functional groups of the polymerized silane derivative via in-situ ring opening polymerization; and

at least one polymer deposited on the bonded lactone polymer layer.

3. The coating of claim 2 wherein the coating comprises from about 0.5% to about 60% by weight of one or more biologically active agents.

4. The coating of claim 3 wherein the coating comprises from about 0.5% to about 34% by weight of one or more biologically active agents.

5. The coating of claim 3 wherein the biologically active agent is an anti-proliferative.

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

7. The coating of claim 3 wherein the biologically active agent is an anti-inflammatory steroid.

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

9. The coating of claim 2 wherein the bonded 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).

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

11. The coating of claim 2 wherein the deposited polymer layer comprises at least one polymer that as a whole or through at least one of its parts is compatible or miscible with the covalently bonded lactone polymer layer.

12. The coating of claim 11 wherein the deposited polymer layer is a polyester or a block copolymer comprising polyester blocks.

13. The coating of claim 2 wherein the polymer deposited on the bonded lactone polymer layer comprises two or more polymer sublayers.

14. The coating of claim 12 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).

15. The coating of claim 14 wherein the deposited polymer comprises poly(L-lactide) or poly(D,L-lactide).

16. 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.

17. The coating of claim 16 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.

18. The coating of claim 2 wherein the deposited polyester polymer has a molecular weight of 10³ to 10⁶.

19. The coating of claim 3 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.

20. The coating of claim 2 that further comprises a polymer skin or barrier layer.

21. The coating of claim 20 wherein the polymer skin or barrier layer comprises a polyester polymer.

22. The coating of claim 21 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).

23. The coating of claim 2 wherein the medical device is a stent.

24. A method for coating a medical device comprising:

(a) reacting the surface of a medical device with a silane-based activating reagent to form a polymerized silane derivative covalently bonded to the surface of the medical device, said polymerized silane derivative containing hydroxyl or other functional groups that can be transformed into hydroxyl groups;

(b) reacting the device of step (a) with at least one lactone monomer in the presence of a metal catalyst to form a lactone polymer covalently bonded to the polymerized silane derivative by in-situ grafting ring opening polymerization initiated by the functional groups of the polymerized silane derivative; and

(c) treating the device of step (b) with a polymer solution and subsequently removing the solvent to deposit a layer of the polymer adherent to the covalently bonded lactone polymer layer.

25. The method of claim 24 wherein the silane-based activating reagent comprises a compound of the formula R¹—

Si(R²)₃, wherein R¹ is independently selected from substituted alkyl, substituted alkenyl, substituted alkynyl, substituted araalkyl, substituted heteroaryl, and substituted alkoxy, with the proviso that R¹ contains a hydroxy or amino group, or a functional group that can be transformed to a radical that contains a hydroxy or amino group, wherein R² is independently selected from halo, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted silyloxy, or optionally substituted alkyl, with the proviso that all three R² substituents are not simultaneously substituted alkyl.

26. The method of claim 24 wherein step (c) is repeated two or more times to provide multiple layers of polymer deposited on the covalently bonded lactone polymer.

27. The method of claim 24 that further comprises depositing a barrier or skin layer on top of the deposited polymer.

28. The method of claim 26 that further comprises depositing a barrier or skin layer on top of the deposited polyester polymer.

29. The method of claim 27 wherein the barrier or skin layer comprises a lactone polymer.

30. The method of claim 29 wherein the lactone polymer 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).

31. The method of claim 28 wherein the barrier or skin layer comprises a lactone polymer.

32. The method of claim 31 wherein the lactone polymer 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).

33. The method of claim 24 wherein the polymer deposited on the bonded lactone polymer layer comprises two or more polymer sublayers.

34. The method of claim 33 wherein the deposited polymer sublayers each independently comprise a lactone polymer, wherein the lactone polymer 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).

35. The method of claim 34 wherein the deposited polymer comprises poly(L-lactide) or poly(D,L-lactide).

36. The method of claim 24 wherein the polymer of step (c) is deposited by spray coating.

37. The method of claim 24 wherein the polymer deposited includes a biologically active agent.

38. The method of claim 24 wherein the coated device is sterilized prior to use.

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

a polymerized surface-activating layer covalently secured to the body fluid-contacting surface of the medical device, said activating layer containing hydroxyl or amino functional groups;

a lactone polymer covalently bonded to the functional groups of the polymerized silane derivative via in-situ ring opening polymerization; and

at least one polymer deposited on the bonded lactone polymer layer.

40. The device of claim 39 wherein the coating comprises from about 0.5% to about 60% by weight of one or more biologically active agents.

41. The device of claim 40 wherein the coating comprises from about 0.5% to about 34% by weight of one or more biologically active agents.

42. The device of claim 40 wherein the biologically active agent is an anti-proliferative.

43. The device of claim 42 wherein the biologically active agent is a CDK2 inhibitor.

44. The device of claim 40 wherein the biologically active agent is an anti-inflammatory steroid.

45. The device of claim 44 wherein the biologically active agent is dexamethasone.

46. The device of claim 39 wherein the medical device is a stent.

47. A method of reducing cell proliferation in a mammal comprising providing to the mammal a medical device having a coating over a body fluid-contacting surface of the medical device for contacting blood, other body fluids and the like, wherein the coating comprises:

a polymerized surface-activating layer covalently secured to the body fluid-contacting surface of the medical device, said activating layer containing hydroxyl or amino functional groups;

a lactone polymer covalently bonded to the silane derivative via in-situ ring opening polymerization; and

at least one polyester polymer deposited on the bonded lactone polymer layer.

48. The method of claim 47 wherein the device further comprises from about 0.5% to about 60% by weight of one or more biologically active agents.

49. The method of claim 47 wherein the medical device is a stent.

50. The method of claim 48 wherein the biologically active agent is an anti-proliferative.

51. The method of claim 50 wherein the biologically active agent is a CDK2 inhibitor.