Methods of forming coating layers for medical devices utilizing flash vaporization

• US 8,568,764 B2
• Filed: 05/31/2006
• Issued: 10/29/2013
• 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
• Primary Examiner(s): BARHAM, BETHANY P
• Application Number:
  US11/445,041
• Publication Number:
  US 20070280988A1
• Time in Patent Office: 2,708 Days
• Field of Search: None
• US Class Current: 424/424
• 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; and

applying the coating composition onto a medical device with a surface, wherein the medical device surface is at a temperature of 150°

C. or greater, whereby the solvent or solvents are flash vaporized to form a coating layer.

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

3. The method of claim 2 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.

4. The method of claim 1 wherein the volume fraction of the one or more active agents to the one or more polymers in the coating layer is about 35% or greater.

5. The method of claim 1 wherein the volume fraction of the one or more active agents to the one or more polymers in the coating layer is about 25% or greater.

6. The method of claim 1 wherein the volume fraction of the one or more active agents to the one or more polymers in the coating layer is about 10% or greater.

7. The method of claim 1 wherein the one or more active agents comprise from about 0.02% to about 40% by weight of the total weight of the coating composition.

8. The method of claim 1 wherein the one or more active agents comprise from about 0.1% to about 9% by weight of the total weight of the coating composition.

9. The method of claim 1 wherein the one or more polymers comprise from about 0.1% to about 35% by weight of the total weight of the coating composition.

10. The method of claim 1 wherein the one or more solvents comprise from about 19.8% to about 99.8% by weight of the total weight of the coating composition.

11. The method of claim 1 wherein flash vaporization of the solvent or solvents results in the active agent morphology being fixed in a phase distribution comprising one or more members of the group of dissolved phase, dispersed phase and percolated phase;

and wherein the active agent morphology being fixed means that the active agent does not significantly change to other phases when the coating layer is subjected to further process steps.

12. The method of claim 11 wherein the phase distribution comprises primarily dissolved phase.

13. The method of claim 11 wherein the phase distribution comprises primarily dispersed phase.

14. The method of claim 11 wherein the phase distribution comprises primarily dissolved phase and dispersed phase.

15. The method of claim 11 wherein the phase distribution of the one or more active agents 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.

16. The method of claim 11 wherein the release-profile of the one or more active agents from the coating layer is determined by the phase distribution of the one or more active agent phases in the coating layer.

17. The method of claim 11 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.

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

19. 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.

20. 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.

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

22. 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, and cytostatic agents, and combinations thereof.

23. The method of claim 1 wherein the one or more polymers are selected from the group consisting of poly(acrylates), acrylic polymers and copolymers, 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 methacrylate, 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, polyvinyl acetate, copolymers of vinyl monomers with each other and olefins, ethylene vinyl alcohol copolymers, polyamides, alkyd resins, polyoxymethylenes, polyimides, polyester amides, polyethers, poly(alkylene glycols), poly(tyrosine derived carbonates), poly(tyrosine derived arylates), epoxy resins, rayon, rayon-triacetate, poly(N-acetylglucosamine), chitosan, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, CELLOPHANE, cellulose nitrate, cellulose propionate, cellulose ethers, carboxymethyl-cellulose, and copolymers and combinations thereof.

24. 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.

25. The method of claim 1, wherein applying the coating composition comprises spraying the coating composition.

26. The method of claim 1, wherein the medical device surface is at a temperature of 200°

C. or greater.

27. The method of claim 1, wherein the medical device surface is at a temperature of 300°

C. or greater.

28. The method of claim 1, wherein the medical device surface is at a temperature of 400°

C. or greater.

29. The method of claim 1, wherein flash vaporization of the solvent or solvents results in the active agent morphology being fixed;

and wherein the active agent morphology being fixed means that the active agent does not significantly change to other phases when the coating layer is subjected to further process steps.

30. The method of claim 19, wherein at least one of the one or more additives is a plasticizer.

31. The method of claim 19, wherein at least one of the one or more additives is a ceramic.