Coating layers for medical devices and methods of making the same

• US 20070280988A1
• Filed: 05/31/2006
• Published: 12/06/2007
• Est. Priority Date: 05/31/2006
• Status: Active Grant

• Current Assignee: Advanced Cardiovascular Systems Incorporated
• Original Assignee: Advanced Cardiovascular Systems Incorporated
• Inventors: Ludwig, Florian N., Hossainy, Syed F.A., Sridharan, Srinivasan, Lee, Carol
• Granted Patent: US 8,568,764 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61L 2300/406 Antibiotics
• 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 2300/606 Coatings
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61M 31/002 Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time artificial gland structures or devices A61F2/022; intra-uterine contraceptive devices A61F6/14; tampons for introducing into the vagina A61F13/20, A61L15/00; suppositories or bougies for intra-vaginal or intra-uterine application A61K9/02; physical forms of medicinal preparations for sustained or differential drug release A61K9/20, A61K9/50

Abstract

Methods are disclosed for controlling the morphology and the release-rate of active agent from coating layers for medical devices comprising a polymer matrix and one or more active agents. The methods comprise fixing the morphology or phase distribution of the active agent prior to removing solvent from the coating composition. The coating layers can be used for controlled the delivery of an active agent or a combination of active agents.

Claims

1. A method comprising:

preparing a coating composition comprising one or more polymers, one or more active agents, and one or more solvents;

applying the coating composition onto a medical device to form a wet coating layer;

fixing a morphology of the one or more active agents; and

removing solvent from the wet coating layer to form a coating layer.

2. The method of claim 1 wherein the morphology is fixed by a method selected from the group consisting of exposing to cold gas, dipping in cold liquid, exposing to shock freezing, exposing to flash vaporization, exposing to a non-solvent exchange, and combinations thereof.

3. The method of claim 1 wherein the morphology is fixed by cross-linking the polymer matrix.

4. The method of claim 1 further comprising removing a fraction of the solvent from the wet coating layer before fixing the morphology.

5. The method of claim 4 wherein the fraction is between about 1 and 90% by weight of solvent.

6. The method of claim 4 wherein the fraction is between about 1 and 50% by weight of solvent.

7. The method of claim 1 wherein the solvent is removed by a method selected from the group consisting of evaporation, freeze-drying, non-solvent exchange, critical point drying, and combinations thereof.

8. The method of claim 4 wherein the fraction of the solvent is removed by a method selected from the group consisting of evaporation, freeze-drying, non-solvent exchange, critical point drying, and combinations thereof.

9. The method of claim 7 wherein the non-solvent is selected from the group consisting of supercritical CO₂, isopropyl alcohol, acetone, heptane, hexane, ethanol, fluorocarbons, chlorofluorocarbons, and blends thereof.

10. The method of claim 7 wherein the non-solvent is supercritical CO₂.

11. The method of claim 10 wherein solvent is removed by critical point drying.

12. The method of claim 1 wherein after forming the coating layer the method comprises one or more post-formation process steps.

13. The method of claim 12 wherein the post-formation process steps are selected from the group consisting of annealing, applying a topcoat coating or barrier layer to the surface of the coating layer, applying a finishing coat layer, and sterilizing.

14. The method of claim 1 wherein the volume fraction of active agent to polymer in the coating layer is about 35% or greater.

15. The method of claim 1 wherein the volume fraction of active agent to polymer in the coating layer is about 25% or greater.

16. The method of claim 1 wherein the volume fraction of active agent to polymer in the coating layer is about 10% or greater.

17. The method of claim 1 wherein the active agent comprises from about 0.02 to about 40% by weight of the total weight of the coating composition.

18. The method of claim 1 wherein the active agent comprises from about 0.1 to about 9% by weight of the total weight of the coating composition.

19. The method of claim 1 wherein the polymer comprises from about 0.1 to about 35% by weight of the total weight of the coating composition.

20. The method of claim 1 wherein the solvent comprises from about 19.8 to about 99.8% by weight of the total weight of the coating composition.

21. The method of claim 1 wherein the active agent morphology is fixed in a phase distribution comprising one or more of dissolved phase, dispersed phase and percolated phase.

22. The method of claim 21 wherein the phase distribution comprises primarily dissolved phase.

23. The method of claim 21 wherein the phase distribution comprises primarily dispersed phase.

24. The method of claim 21 wherein the phase distribution comprises primarily dissolved phase and dispersed phase.

25. The method of claim 21 wherein the phase distribution of active agent comprises dissolved phase, dispersed phase and percolated phase, and wherein the amount of dissolved phase in the coating layer is greater than the amount of either dispersed or percolated phase.

26. The method of claim 21 wherein the release-profile of active agent from the coating layer is determined by the phase distribution of the one or more active agent phases in the coating layer.

27. The method of claim 1 wherein the volume fraction of active agent in the coating layer is at the percolation threshold, and where the active agent morphology is fixed primarily in a phase distribution other than the percolated phase.

28. The method of claim 1 wherein the coating composition further comprises a cross-linking agent or initiator.

29. The method of claim 1 wherein the coating layer further comprises one or more additives selected from the group consisting of plasticizers, metals, and ceramics.

30. The method of claim 1 wherein the medical device comprises a primer layer, and the coating composition is coated on all or part of the primer layer.

31. The method of claim 1 wherein the medical device is a stent.

32. The method of claim 1 wherein the one or more active agents are selected from the group consisting of antiproliferative, antineoplastic, anti-inflammatory, steroidal anti-inflammatory, non-steroidal anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic, antioxidant, cytostatic agents, and combinations thereof.

33. The method of claim 1 wherein the one or more polymers are selected from the group consisting of poly(acrylates), acrylic polymers and copolymer, poly(cyanoacrylates), fluorinated polymers or copolymers, polycaprolactones, polylactides, poly(D-lactides), poly(L-lactides), poly(D,L-lactides), Poly(lactic acids), poly(glycolic acid), poly(lactide-co-glycolide), poly(glycolic acid-co-trimethylene carbonate), poly(lactic acid-co-trimethylene carbonate, poly(amino acids), polyhydroxyalkanoates, poly(hydroxyvalerate), polyhydroxybutyrates, poly(hydroxybutyrate-co-valerate), polymers and copolymers of hydroxylethyl methacryate, polydioxanones, polyorthoesters, polyanhydrides, polyphosphoesters, polyphosphoester urethanes, polyphosphazenes, polycarbonates, polyiminocarbonates, polytrimethylene carbonates, co-poly(ether-esters), poly(alkylene oxalates), polyurethanes, silicones, polyesters, polyolefins, poly(isobutylene) and ethylene-alphaolefin copolymers, vinyl halide polymers and copolymers, polyvinyl ethers, polyvinylidene halides, polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics, polyvinyl esters (such as polyvinyl acetate), copolymers of vinyl monomers with each other and olefins, ethylene vinyl alcohol copolymers, polyamides, alkyd resins, polyoxymethylenes, polyimides, polyester amides, polyethers including poly(alkylene glycols), poly(tyrosine derived carbonates), poly(tyrosine derived arylates), epoxy resins, rayon, rayon-triacetate, biomolecules, poly(N-acetylglucosamine), chitosan, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, CELLOPHANE, cellulose nitrate, cellulose propionate, cellulose ethers, and carboxymethyl-cellulose, and derivatives, copolymers and combinations thereof.

34. The method of claim 1 wherein the one or more solvents are selected from the group consisting of dimethylacetamide, dimethylformamide, tetrahydrofuran, cyclohexanone, acetone, acetonitrile, i-propanol, n-propanol, methanol, ethanol, butanol, propylene glycol monomethyl ether, methyl butyl ketone, methyl ethyl ketone, diethyl ketone, ethyl acetate, n-butyl acetate, dioxane, chloroform, water (buffered saline), dimethylsulfoxide, dimethylformide, benzene, toluene, xylene, hexane, cyclohexane, pentane, heptane, octane, nonane, decane, decalin, i-butyl acetate, i-propyl acetate, diacetone alcohol, benzyl alcohol, 1-butanone, 2-butanone, N-methylpyrrolidinone, methylene chloride, carbon tetrachloride, tetrachloroethylene, tetachloroethane, chlorobenzene, 1,1,1-trichloroethane, formamide, hexafluoroisopropanol, 1,1,1-trifluoroethanol, hexamethyl phosphoramide, and mixtures thereof.

35. A coating layer for a medical device comprising a polymer matrix and an active agent, wherein the active agent phase distribution comprises one or more of the group consisting of dissolved phase, dispersed phase and percolated phase;

and the release-rate profile of active agent is determined by the ratio of the one or more phases of the active agent in the coating layer.

36. The coating of claim 35 wherein the volume fraction of active agent to polymer matrix in the coating layer is about 35% or greater.

37. The coating of claim 35 wherein the volume fraction of active agent to polymer in the coating layer is about 25% or greater.

38. The coating of claim 35 wherein the volume fraction of active agent to polymer in the coating layer is about 10% or greater.

39. The coating of claim 35 wherein the phase distribution comprises primarily dissolved phase.

40. The coating of claim 35 wherein the phase distribution comprises primarily dispersed phase.

41. The method of claim 35 wherein the phase distribution comprise primarily dissolved phase and dispersed phase.

42. The coating of claim 35 wherein the volume fraction of active agent in the coating layer is at the percolation threshold, and where the active agent phase distribution comprises primarily a phase other than the percolated phase.