Stent coatings comprising hydrophilic additives

• US 20040224001A1
• Filed: 05/08/2003
• Published: 11/11/2004
• Est. Priority Date: 05/08/2003
• Status: Active Grant

• Current Assignee: Advanced Cardiovascular Systems Incorporated
• Original Assignee: Advanced Cardiovascular Systems Incorporated
• Inventors: Tang, Yiwen, Pacetti, Stephen D.
• Granted Patent: US 7,279,174 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C08L 2666/04 Macromolecular compounds according to groups C08L7/00 - C08L49/00, or C08L55/00 - C08L57/00; Derivatives thereof
• CPC Class Codes: C08L 2666/22 Macromolecular compounds not provided for in C08L2666/16 - C08L2666/20
• CPC Class Codes: C08L 33/08 Homopolymers or copolymers of acrylic acid esters
• CPC Class Codes: C08L 33/10 Homopolymers or copolymers of methacrylic acid esters
• CPC Class Codes: C08L 71/02 Polyalkylene oxides
• CPC Class Codes: C08L 75/04 Polyurethanes
• CPC Class Codes: C09D 133/08 Homopolymers or copolymers of acrylic acid esters
• CPC Class Codes: C09D 133/10 Homopolymers or copolymers of methacrylic acid esters
• CPC Class Codes: C09D 133/12 Homopolymers or copolymers of methyl methacrylate

Abstract

A coating for implantable medical devices and a method for fabricating thereof are disclosed. The coating includes a mixture of a hydrophobic polymer and a polymeric hydrophilic additive, wherein the hydrophobic polymer and the hydrophilic additive form a physically entangled or interpenetrating system.

Claims

1. An implantable medical device comprising a coating, the coating including a mixture of at least one poly(meth)acrylate and at least one polyalkylene glycol, wherein the macromolecular chains of the poly(meth)acrylate and the polyalkylene glycol form a physically entangled or interpenetrating system.

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

3. The device of claim 1, wherein a ratio between the poly(meth)acrylate and the polyalkylene glycol is between about 99:

1 and about 9;

1.

4. The device of claim 1, wherein the poly(meth)acrylate is selected from a group consisting of poly(methyl methacrylate), poly(ethyl methacrylate), poly(n-propyl methacrylate), poly(iso-propyl methacrylate), poly(n-butyl methacrylate), poly(iso-butyl methacrylate), poly(tert-butyl methacrylate), poly(methyl acrylate), poly(ethyl acrylate), poly(n-propyl acrylate), poly(iso-propyl acrylate), poly(n-butyl acrylate), poly(iso-butyl acrylate), and mixtures thereof.

5. The device of claim 1, wherein the polyalkylene glycol is selected from a group consisting of poly(ethylene glycol), poly(ethylene oxide), poly(propylene glycol), poly(ethylene oxide-co-propylene oxide), poly(trimethylene glycol), poly(tetramethylene glycol), and mixtures thereof.

6. The device of claim 1, wherein the coating additionally comprises a drug.

7. The device of claim 6, wherein the drug is selected from a group consisting of rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, and combinations thereof.

8. An implantable medical device comprising a coating, the coating including a mixture of at least one hydrophobic polymer and at least one polymeric hydrophilic compound, wherein the macromolecular chains of the hydrophobic polymer and the hydrophilic compound form a physically entangled or interpenetrating system.

9. The device of claim 8, wherein the device is a stent.

10. The device of claim 8, wherein the hydrophobic polymer has a Hildebrand solubility parameter lower than about 10.7 (cal/cm³)^1/2.

11. The device of claim 8, wherein the hydrophobic polymer has an equilibrium water adsorption less than about 10 mass % at room temperature.

12. The device of claim 8, wherein the hydrophobic polymer comprises poly(meth)acrylates, vinyl polymers, polyolefins, halogenanated polymers, polymers having urethane groups, polybutyrals, nylon, silicones, polycarbonate, or polysulfone.

13. The device of claim 12, wherein the poly(meth)acrylates are selected from a group consisting of poly(methyl methacrylate), poly(ethyl methacrylate), poly(n-propyl methacrylate), poly(iso-propyl methacrylate), poly(n-butyl methacrylate), poly(iso-butyl methacrylate), poly(tert-butyl methacrylate), poly(methyl acrylate), poly(ethyl acrylate), poly(n-propyl acrylate), poly(iso-propyl acrylate), poly(n-butyl acrylate), poly(iso-butyl acrylate), and mixtures thereof.

14. The device of claim 12, wherein the vinyl polymers are selected from a group consisting of poly(ethylene-co-vinyl alcohol), poly(ethylene-co-vinyl acetate), poly(vinyl acetate), polystyrene, poly(styrene-co-iso-butylene), poly(styrene-co-ethylene-co-butylene-co-styrene) terpolymers, and poly(styrene-co-butadiene-co-styrene) terpolymers, and mixtures thereof.

15. The device of claim 12, wherein the polyolefin is atactic polypropylene.

16. The device of claim 12, wherein the halogenanated polymers are selected from a group consisting of poly(vinyl fluoride), poly(vinylidene fluoride), polyhexafluoropropene, poly(hexafluoropropene-co-vinylidene fluoride), poly(ethylene-co-hexafluoropropene), polytetrafluoroethylene, poly(vinyl chloride), poly(vinylidene chloride), and mixtures thereof.

17. The device of claim 12, wherein the polymers having urethane groups are selected from a group consisting of polyether urethanes, polyester urethanes, polyurethaneureas, polycarbonate urethanes, silicone urethanes, and mixtures thereof.

18. The coating of claim 8, wherein the polymeric hydrophilic compound is selected from a group consisting of polyalkylene glycols, hyaluronic acid, chondroitan sulfate, chitosan, glucosaminoglucans, dextran, dextrin, dextran sulfate, cellulose acetate, carboxymethyl cellulose, hydroxyethyl cellulose, cellulosics, polypeptides, poly(2-hydroxyethyl methacrylate), polyacrylamide, polyacrylimide, poly(ethylene amine), poly(allyl amine), poly(vinyl pyrrolidone), poly(vinyl alcohol), poly(acrylic acid), poly(methacrylic acid), acrylic acid copolymers, methacrylic acid copolymers, polyvinyl alkyl ethers, non-ionic tetrafunctional block-copolymer surfactants, gelatin, collagen, albumin, chitin, heparin, elastin, fibrin, and mixtures thereof.

19. The device of claim 18, wherein the polyalkylene glycols are selected from a group consisting of poly(ethylene glycol), poly(ethylene oxide), poly(propylene glycol), poly(ethylene oxide-co-propylene oxide), poly(trimethylene glycol), poly(tetramethylene glycol), and mixtures thereof.

20. The device of claim 8, wherein the ratio between the hydrophobic polymer and the polymeric hydrophilic additive is between about 99:

1 and about 9;

1.

21. The device of claim 8, wherein the coating additionally comprises a drug.

22. The device of claim 21, wherein the drug is selected from a group consisting of rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, and combinations thereof.

23. A medical article comprising an implantable substrate and a coating, the coating including:

(a) a bulk polymer;

(b) an additive polymer in less quantity in the coating that the bulk polymer, the additive polymer being entangled or interpenetrated with the bulk polymer; and

(c) a drug,

wherein the additive polymer changes the rate of release of the drug from the coating.

24. The medical article of claim 23, wherein by increasing the ratio of the additive polymer to the bulk polymer, the rate of release of the drug is increased.

25. The medical article of claim 23, wherein the bulk polymer is more hydrophobic that the additive polymer.

26. The medical article of claim 23, wherein the bulk polymer includes a poly(meth)acrylate.

27. The medical article of claim 23, wherein the poly(meth)acrylate is selected from a group consisting of poly(methyl methacrylate), poly(ethyl methacrylate), poly(n-propyl methacrylate), poly(iso-propyl methacrylate), poly(n-butyl methacrylate), poly(iso-butyl methacrylate), poly(tert-butyl methacrylate), poly(methyl acrylate), poly(ethyl acrylate), poly(n-propyl acrylate), poly(iso-propyl acrylate), poly(n-butyl acrylate), poly(iso-butyl acrylate), and mixtures thereof.

28. The medical article of claim 23, wherein the additive polymer includes a polyalkylene glycol.

29. The medical article of claim 28, wherein the polyalkylene glycol is selected from a group consisting of poly(ethylene glycol), poly(ethylene oxide), poly(propylene glycol), poly(ethylene oxide-co-propylene oxide), poly(trimethylene glycol), poly(tetramethylene glycol), and mixtures thereof.

30. The medical article of claim 23, wherein the contour length of the additive polymer is between about 10% and about 100% of the contour length of the bulk polymer.

31. A method of fabricating a coating for an implantable medical device, comprising forming a coating on the device, the coating including a mixture of at least one hydrophobic polymer and at least one polymeric hydrophilic compound, wherein the macromolecular chains of the hydrophobic polymer and the hydrophilic compound form a physically entangled or intertwined system.

32. The method of claim 31, wherein the device is a stent.

33. The method of claim 31, wherein the hydrophobic polymer has a Hildebrand solubility parameter lower than about 10.7 (cal/cm³)^1/2.

34. The method of claim 31, wherein the hydrophobic polymer has an equilibrium water adsorption less than about 10 mass % at room temperature.

35. The method of claim 31, wherein the hydrophobic polymer comprises poly(meth)acrylates, vinyl polymers, polyolefins, halogenanated polymers, polymers having urethane groups, polybutyrals, nylon, silicones, polycarbonate, or polysulfone.

36. The method of claim 35, wherein the poly(meth)acrylates are selected from a group consisting of poly(methyl methacrylate), poly(ethyl methacrylate), poly(n-propyl methacrylate), poly(iso-propyl methacrylate), poly(n-butyl methacrylate), poly(iso-butyl methacrylate), poly(tert-butyl methacrylate), poly(methyl acrylate), poly(ethyl acrylate), poly(n-propyl acrylate), poly(iso-propyl acrylate), poly(n-butyl acrylate), poly(iso-butyl acrylate), and mixtures thereof.

37. The method of claim 35, wherein the vinyl polymers are selected from a group consisting of poly(ethylene-co-vinyl alcohol), poly(vinyl acetate), polystyrene, poly(styrene-co-iso-butylene), poly(styrene-co-ethylene-co-butylene-co-styrene) terpolymers, poly(styrene-co-butadiene-co-styrene) terpolymers, and mixtures thereof.

38. The method of claim 35, wherein the polyolefin is atactic polypropylene.

39. The method of claim 35, wherein the halogenanated polymers are selected from a group consisting of poly(vinyl fluoride), poly(vinylidene fluoride), polyhexafluoropropene, poly(hexafluoropropene-co-vinylidene fluoride), poly(ethylene-co-hexafluoropropene), polytetrafluoroethylene, poly(vinyl chloride), poly(vinylidene chloride), and mixtures thereof.

40. The method of claim 35, wherein the polymers having urethane groups are selected from a group consisting of polyether urethanes, polyester urethanes, polyurethaneureas, polycarbonate urethanes, silicone urethanes, and mixtures thereof.

41. The method of claim 31, wherein the polymeric hydrophilic compound is selected from a group consisting of polyalkylene glycols, hyaluronic acid, chondroitan sulfate, chitosan, glucosaminoglucans, dextran, dextrin, dextran sulfate, cellulose acetate, carboxymethyl cellulose, hydroxyethyl cellulose, cellulosics, polypeptides, poly(2-hydroxyethyl methacrylate), polyacrylamide, polyacrylimide, poly(ethylene amine), poly(allyl amine), poly(vinyl pyrrolidone), poly(vinyl alcohol), poly(acrylic acid), poly(methacrylic acid), acrylic acid copolymers, methacrylic acid copolymers, polyvinyl alkyl ethers, non-ionic tetrafunctional block-copolymer surfactants, gelatin, collagen, albumin, chitin, heparin, elastin, fibrin, and mixtures thereof.

42. The method of claim 41, wherein the polyalkylene glycols are selected from a group consisting of poly(ethylene glycol), poly(ethylene oxide), poly(propylene glycol), poly(ethylene oxide-co-propylene oxide), poly(trimethylene glycol), poly(tetramethylene glycol), and mixtures thereof.

43. The method of claim 31, wherein a ratio between the hydrophobic polymer and the polymeric hydrophilic additive is between about 99:

1 and about 9;

1.

44. The method of claim 31, wherein the coating additionally comprises a drug.

45. The device of claim 44, wherein the drug is selected from a group consisting of rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, and combinations thereof.