Coating compositions for bioactive agents

• US 7,544,673 B2
• Filed: 04/06/2005
• Issued: 06/09/2009
• Est. Priority Date: 04/06/2004
• Status: Expired due to Fees

• Current Assignee: Surmodics Incorporated
• Original Assignee: Surmodics Incorporated
• Inventors: Lawin, Laurie R., Finley, Michael J., DeWitt, David M.
• Primary Examiner(s): Henley, III; Raymond J
• Application Number:
  US11/099,796
• Publication Number:
  US 20050220839A1
• Time in Patent Office: 1,525 Days
• Field of Search: 514/171, 514/182, 424/486, 424/487, 424/497
• US Class Current: 514/171
• CPC Class Codes: A61F 2/86 Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61L 2300/222 Steroids, e.g. corticosteroids
• CPC Class Codes: A61L 2300/404 Biocides, antimicrobial agents, antiseptic agents
• CPC Class Codes: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2300/43 Hormones, e.g. dexamethasone
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• 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: C08L 33/06 of esters containing only carbon, hydrogen and oxygen, which oxygen atoms are present only as part of the carboxyl radical
• CPC Class Codes: C08L 33/10 Homopolymers or copolymers of methacrylic acid esters
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

Abstract

A coating composition and related method for use in applying a bioactive agent to a surface in a manner that will permit the bioactive agent to be released from the coating in vivo. The composition is particularly well suited for coating the surface of implantable medical device, such as a stent or catheter, in order to permit the device to release bioactive agent to the surrounding tissue over time. The composition includes a plurality of compatible polymers having different properties that can permit them to be combined together to provide an optimal combination of such properties as durability, biocompatibility, and release kinetics.

Claims

1. A composition for coating the surface of a medical device with at least one bioactive agent in a manner that permits the coated surface to release the bioactive agent over time when implanted in vivo, the composition comprising at least one bioactive agent in combination with a plurality of polymers, including a first polymer component comprising at least one epichlorohydrin-containing polymer and a second polymer component comprising a polymer selected from the group consisting of poly(alkyl(meth)acrylates) and poly(aromatic(meth)acrylates).

2. A composition according to claim 1 wherein the first polymer component is a poly(epichlorohydrin-co-alkylene oxide).

3. A composition according to claim 2 wherein the poly(epichlorohydrin-co-alkylene oxide) is poly(epichlorohydrin-co-ethylene oxide).

4. A composition according to claim 1 wherein the first polymer component includes a homopolymer derived from epichlorohydrin.

5. A composition according to claim 1 wherein the epichlorohydrin-containing polymer includes an epichlorohydrin content of from about 30% to 100%.

6. A composition according to claim 5 wherein the epichlorophydrin-containing polymer includes an epichlorohydrin content of from about 50% to 100%.

7. A composition according to claim 1 wherein the epichlorohydrin-containing polymers have a weight average molecular weight from about 100 kilodaltons to about 300 kilodaltons.

8. A composition according to claim 1, the first polymer component having a molecular weight from about 100 kilodaltons to about 300 kilodaltons.

9. A composition according to claim 1 wherein the composition includes at least one additional polymer selected from the group consisting of poly(alkylene-co-alkyl(meth)acrylates), ethylene copolymers with other alkylenes, polybutenes, diolefin derived non-aromatic polymers and copolymers, aromatic group-containing copolymers, and poly (ethylene-co-vinyl acetate).

10. A composition according to claim 9 wherein the poly(alkylene-co-alkyl(meth)acrylates) are selected from the group consisting of poly(ethylene-co-methyl acrylate), poly(ethylene-co-ethyl acrylate), poly(ethylene-co-2-ethylhexyl acrylate) and poly(ethylene-co-butyl acrylate), ethylene copolymers with other alkylenes are selected from the group consisting of poly(ethylene-co-propylene), poly(ethylene-co-1-butene), poly(ethylene-co-1-butene-co-1-hexene) and poly(ethylene-co-1-octene), the polybutenes are selected from the group consisting of polyisobutylene, poly-1-butene and poly-2-butene, the diolefin derived non-aromatic polymers and copolymers are selected from the group consisting of polybutadiene, poly(butadiene-co-acrylonitrile), polybutadiene-block-polyisoprene, polybutadiene-graft-poly(methyl acrylate-co-acrylonitrile), polyisoprene and partially hydrogenated polyisoprene, the aromatic group-containing copolymers include a copolymer derived from copolymerization of styrene monomer and one or more monomers selected from the group consisting of butadiene, isoprene, acrylonitrile, a C₁-C₄ alkyl (meth)acrylate and butene, and the poly (ethylene-co-vinyl acetate) polymers have a vinyl acetate concentration from about 8% to about 90%.

11. A composition according to claim 1 wherein the poly(alkyl(meth)acrylate) includes an alkyl chain length from two to eight carbons.

12. A composition according to claim 1, wherein the poly(alkyl(meth)acrylate) has a molecular weight from about 50 kilodaltons to about 900 kilodaltons.

13. A composition according to claim 1 wherein the poly(alkyl(meth)acrylate) is selected from the group consisting of poly(n-butyl methacrylate), poly(n-butyl methacrylate-co-isobutyl methacrylate), and poly(t-butyl methacrylate).

14. A composition according to claim 1 wherein the poly(aromatic(meth)acrylate) includes aryl groups having from six to sixteen carbon atoms.

15. A composition according to claim 1, wherein the poly(aromatic(meth)acrylate) has a molecular weight from about 50 kilodaltons to about 900 kilodaltons.

16. A composition according to claim 1 wherein the poly(aromatic(meth)acrylate) is selected from the group consisting of poly(aryl (meth)acrylates), poly(aralkyl (meth)acrylates), poly(alkaryl (meth)acrylates), poly(aryloxyalkyl (meth)acrylates), and poly (alkoxyaryl (meth)acrylates).

17. A composition according to claim 16, wherein the poly(aryl (meth)acrylates) are selected from the group consisting of poly(9-anthracenyl methacrylate), poly(chlorophenyl acrylate), poly(methacryloxy-2-hydroxybenzophenone), poly(methacryloxybenzotriazole), poly(naphthyl acrylate), poly(naphthylmethacrylate), poly-4-nitrophenylacrylate, poly(pentachloro(bromo, fluoro) acrylate) and methacrylate, poly(phenyl acrylate) and poly(phenyl methacrylate);

the poly(aralkyl (meth)acrylates) are selected from the group consisting of poly(benzyl acrylate), poly(benzyl methacrylate), poly(2-phenethyl acrylate), poly(2-phenethyl methacrylate) and poly(1-pyrenylmethyl methacrylate);

the poly(alkaryl(meth)acrylates) are selected from the group consisting of poly(4-sec-butylphenyl methacrylate), poly(3-ethylphenyl acrylate), and poly(2-methyl-1-naphthyl methacrylate);

the poly(aryloxyalkyl (meth)acrylates) are selected from the group consisting of poly(phenoxyethyl acrylate), poly(phenoxyethyl methacrylate), and poly(polyethylene glycol phenyl ether acrylate) and poly(polyethylene glycol phenyl ether methacrylate) with varying polyethylene glycol molecular weights; and

the poly(alkoxyaryl(meth)acrylates) are selected from the group consisting of poly(4-methoxyphenyl methacrylate), poly(2-ethoxyphenyl acrylate) and poly(2-methoxynaphthyl acrylate).

18. A composition according to claim 1 wherein the composition further comprises a solvent in which the first and second polymer components form a true solution.

19. A composition according to claim 1 wherein the composition includes a bioactive agent at a concentration of 0.01% to 90% by weight.

20. A composition according to claim 1 wherein the device is one that undergoes flexion and expansion in the course of implantation or use in vivo.

21. A composition according to claim 1 wherein the composition permits the amount and rate of release of bioactive agent(s) from the medical device to be controlled by adjusting the relative types and concentrations of the first and second polymer components in the mixture.

40. A composition according to claim 1, further comprising a pretreatment layer including a multi-interface system to facilitate adhesion and cohesion interaction relative to the medical device and composition.

41. A composition according to claim 40, wherein the pretreatment layer includes organosilane and Parylene™

.

22. A combination comprising a medical device and a composition for coating the surface of the medical device with at least one bioactive agent in a manner that permits the coated surface to release the bioactive agent over time when implanted in vivo, the composition comprising at least one bioactive agent in combination with a plurality of polymers, including a first polymer component comprising at least one epichlorohydrin-containing polymer and a second polymer component comprising a polymer selected from the group consisting of poly(alkyl(meth)acrylates) and poly(aromatic(meth)acrylates).

23. The combination of claim 22 wherein a pretreatment coating, adapted to alter the surface properties of the medical device, is applied to the surface of the medical device.

24. The combination according to claim 22 wherein the first polymer component is a poly(epichlorohydrin-co-alkylene oxide).

25. The combination according to claim 22 wherein the first polymer component includes a homopolymer derived from epichlorohydrin.

26. The combination according to claim 22 wherein the epichlorohydrin-containing polymer includes an epichlorohydrin content of from about 30% to 100%.

27. The combination according to claim 22 wherein the epichlorohydrin-containing polymers have a weight average molecular weight from about 100 kilodaltons to about 300 kilodaltons.

28. The combination according to claim 22 wherein the composition includes at least one additional polymer selected from the group consisting of poly(alkylene-co-alkyl(meth)acrylates), ethylene copolymers with other alkylenes, polybutenes, diolefin derived non-aromatic polymers and copolymers, aromatic group-containing copolymers, and poly (ethylene-co-vinyl acetate).

29. The combination according to claim 23 wherein the pretreatment coating includes one or more materials selected from the group consisting of Parylene™

, silane, photografted polymers, epoxy primers, polycarboxylate resins and combinations thereof.

30. The combination according to claim 22 wherein the composition permits the amount and rate of release of agent(s) from the medical device to be controlled by adjusting the relative types and concentrations of the first and second polymer components in the mixture.

31. A composition for coating the surface of a medical device with at least one bioactive agent in a manner that permits the coated surface to release the bioactive agent over time when implanted in vivo, the composition comprising at least one bioactive agent in combination with a plurality of polymers, including a first polymer component comprising at least one epichlorohydrin-containing polymer and a second polymer component comprising a polymer selected from the group consisting of poly(alkyl(meth)acrylates) and poly(aromatic(meth)acrylates), wherein the composition includes at least one additional polymer selected from the group consisting of poly(alkylene-co-alkyl(meth)acrylates), ethylene copolymers with other alkylenes, polybutenes, diolefin derived non-aromatic polymers and copolymers, aromatic group-containing copolymers, and poly (ethylene-co-vinyl acetate).

32. A method of delivering at least one bioactive agent from a surface of a medical device to an animal comprising providing a composition including at least one bioactive agent in combination with a plurality of polymers, including a first polymer component comprising at least one epichlorohydrin-containing polymer and a second polymer component comprising a polymer selected from the group consisting of poly(alkyl(meth)acrylates) and poly(aromatic(meth)acrylates), applying the composition to the surface of the device and administering the medical device to the animal.

33. A combination comprising a stent and a composition for coating the surface of a stent with at least one bioactive agent in a manner that permits the coated surface to release the bioactive agent over time when implanted in vivo, the composition comprising at least one bioactive agent in combination with a plurality of polymers, including a first polymer component comprising a poly(epichlorohydrin), a second polymer component comprising poly(n-butyl methacrylate), a solvent in which the first and second polymer components form a true solution, and at least one biocompatible additive, and further comprising a pretreatment layer including a multi-interface system to facilitate adhesion and cohesion interaction relative to the stent and coating composition.

34. A combination according to claim 33, wherein the bioactive agent is selected from the group consisting of rapamycin, paclitaxel, dexamethasone, and estradiol.

35. A combination according to claim 33, wherein the stent includes a material selected from the group consisting of polymers, tissue, metals, ceramics, and combinations thereof.

36. A combination according to claim 35, wherein the polymers include polycarbonates and the metals are selected from the group consisting of titanium, stainless steel, gold, silver, and nitinol.

37. A combination according to claim 33, wherein the solvent is selected from the group consisting of tetrahydrofuran, chloroform, methylene chloride, toluene, cyclohexane and combinations thereof.

38. A combination according to claim 33, wherein the biocompatible additive includes one or more antioxidants selected from the group consisting of butylated hydroxytoluene, vitamin E, BNX, and dilauryl thiodipropionate.

39. A combination according to claim 33, wherein the pretreatment layer includes organosilane and Parylene™

.

42. A combination comprising a medical device and a composition for coating the surface of a medical device with at least one bioactive agent in a manner that permits the coated surface to release the bioactive agent over time when implanted in vivo, the composition comprising at least one bioactive agent in combination with a plurality of polymers, including a first polymer component comprising poly(epichlorohydrin), a second polymer component comprising poly(n-butyl methacrylate), a solvent in which the first and second polymer components form a true solution selected from the group consisting of tetrahydrofuran, chloroform, methylene chloride, and cyclohexane, and at least one biocompatible additive including one or more antioxidants selected from the group consisting of butylated hydroxytoluene, vitamin E, BNX, and dilauryl thiodipropionate, and further comprising a pretreatment layer including a multi-interface system to facilitate adhesion and cohesion interaction relative to the medical device and coating composition.

43. A combination according to claim 42, wherein the bioactive agent is selected from the group consisting of rapamycin, paclitaxel, dexamethasone, and estradiol.

44. The combination of claim 42 further comprising a topcoat including poly(butyl methacrylate).

45. The combination of claim 42, wherein the medical device comprises a stent.