Coating Designs For The Tailored Release Of Dual Drugs From Polymeric Coatings

Abstract

Provided herein are coating designs for the tailored release of two therapeutic agents from polymer coatings and methods of making and using the same.

1 . A coating for an implantable medical device, the coating comprising a first layer having a hydrophobic polymer and an olimus therapeutic agent; a second layer having a hydrophobic polymer and a crystallized non-olimus therapeutic agent; and a third optional primer layer, wherein the first layer is deposited over the second layer, wherein the second layer is deposited over the third layer if present, or if not present, over a surface of the implantable medical device, and wherein the crystallized non-olimus therapeutic agent in the coating provides control of the release of the olimus and non-olimus therapeutic agents. 
     
     
         2 . The coating of  claim 1 , wherein the implantable medical device is a stent. 
     
     
         3 . The coating of  claim 1 , further comprising an optional finishing coating layer for enhancing biocompatibility. 
     
     
         4 . The coating of  claim 1 , wherein the hydrophobic polymer in the first or second layer is selected from the group consisting of poly(vinylidene fluoride), poly(vinylidene fluoride-co-chlorotrifluoroethylene), poly(vinylidene fluoride-co-hexafluoropropylene), poly(vinylidene chloride), poly(vinyl fluoride), poly(vinyl chloride), polyvinyl acetate, polystyrene, polyisobutylene, copolymers of styrene and isobutylene, poly(styrene-b-isobutylene-b-styrene), poly(n-butyl methacrylate), poly(butyl methacrylates), polycaprolactone, poly(trimethylene carbonate), poly(L-lactide), poly(L-lactic acid), poly(lactide-co-glycolide), poly(hydroxyvalerate), poly(3-hydroxyvalerate), poly(hydroxybutyrate), poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), poly(hydroxybutyrate-co-valerate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(glycolide), poly(glycolic acid), poly(D,L-lactide-co-L-lactide), poly(D,L-lactide-co-glycolide), poly(D,L-lactide), poly(D,L-lactic acid), poly(glycolic acid-co-trimethylene carbonate), polyanhydride, polyorthoester, SOLEF™ 21508 (formulation available from Solvay Solexis), acrylic polymers and acrylic copolymers, copolymers of vinyl monomers with each other and olefins, ethylene-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers; ethylene-α-olefin copolymers, poly(silicone-urethanes), poly(tyrosine arylates), poly(tyrosine-derived carbonates); polyacrylates, polycarbonates, poly-hydroxycarboxylic acids, polyisobutylene and ethylene-α-olefin copolymers, polymethacrylates, polyolefins, polyorthoesters, polyvinyl aromatics; polyvinyl esters, silicones, vinyl copolymers, vinyl-olefin copolymers, vinyl halide polymers and copolymers. 
     
     
         5 . The coating of  claim 1 , wherein the olimus therapeutic agent in the first layer is selected from the group consisting of sirolimus (rapamycin), everolimus, zotarolimus, Biolimus A9, AP23572, tacrolimus, pimecrolimus and derivates, analogs, and combinations thereof. 
     
     
         6 . The coating of  claim 1 , wherein the non-olimus therapeutic agent in the second layer is selected from the group consisting of dexamethasone, dexamethasone acetate, dexamethasone phosphate, dexamethasone valerate, dexamethasone derivatives, momentasone, clobetasol, cortisone, cortisone acetate, hydrocortisone, corticosterone, deoxycorticosterone, hydrocortisone acetate, deoxycorticosterone acetate, hydroxyprogesterone, prednisolone, prednisolone acetate, triamicinolone, triamicinolone acetonide, triamcinolone diacetate, betamethasone, betamethasone valerate, steroids, glucocorticoids, estradiol, methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride, mitomycin, antiplatelet compounds, anticoagulants, antifibrin, antithrombins including sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin, prostacyclin analogues, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, thrombin inhibitors including Angiomax ä, calcium channel blockers including nifedipine, colchicine, fibroblast growth factor (FGF) antagonists, histamine antagonists, lovastatin, monoclonal antibodies, nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, thioprotease inhibitors, triazolopyrimidine, nitric oxide or nitric oxide donors, super oxide dismutases, super oxide dismutase mimetic, cytostatic substances including angiopeptin, angiotensin converting enzyme inhibitors including captopril, cilazapril or lisinopril, antiallergic agents as in permirolast potassium, alpha-interferon, bioactive RGD and derivates, analogs, and combinations thereof. 
     
     
         7 . A method, comprising implanting in a patient in need of treatment of a disorder an implantable medical device comprising the coating of  claim 1 , wherein the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, patent foramen ovale, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof. 
     
     
         8 . A method of forming a coating including two drugs on a medical device, the method comprising:
 optionally forming a primer layer on a surface of the medical device;   forming a first coating layer on a surface of the medical device or on the primer layer if present, the first coating layer comprising a hydrophobic polymer and a non-olimus therapeutic agent;
 wherein at least some of the non-olimus drugs forms crystals in the first coating layer; 
   and   forming a second coating layer on the first coating layer, the second coating layer comprising an olimus therapeutic agent and a hydrophobic polymer, which may be the same as or different from the hydrophobic polymer of the first coating layer;
 wherein the formation of the second coating layer uses a solvent, the solvent being acetone, 2-butanone, or a combination thereof; 
   wherein the coating provides a control of release of the olimus and the non-olimus therapeutic agents.   
     
     
         9 . The method of  claim 8 , wherein the medical device is a stent. 
     
     
         10 . The method of  claim 8 , the method further comprising forming an optional finishing coating layer for enhancing biocompatibility over the second coating layer. 
     
     
         11 . The method of  claim 8 , wherein the hydrophobic polymer in the first and/or second layer is selected from the group consisting of poly(vinylidene fluoride), poly(vinylidene fluoride-co-chlorotrifluoroethylene), poly(vinylidene fluoride-co-hexafluoropropylene), poly(vinylidene chloride), poly(vinyl fluoride), poly(vinyl chloride), polyvinyl acetate, polystyrene, polyisobutylene, copolymers of styrene and isobutylene, poly(styrene-b-isobutylene-b-styrene), poly(n-butyl methacrylate), poly(butyl methacrylates), polycaprolactone, poly(trimethylene carbonate), poly(L-lactide), poly(L-lactic acid), poly(lactide-co-glycolide), poly(hydroxyvalerate), poly(3-hydroxyvalerate), poly(hydroxybutyrate), poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), poly(hydroxybutyrate-co-valerate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(glycolide), poly(glycolic acid), poly(D,L-lactide-co-L-lactide), poly(D,L-lactide-co-glycolide), poly(D,L-lactide), poly(D,L-lactic acid), poly(glycolic acid-co-trimethylene carbonate), polyanhydride, polyorthoester, SOLEF™ 21508 (formulation available from Solvay Solexis), acrylic polymers and acrylic copolymers, copolymers of vinyl monomers with each other and olefins, ethylene-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers; ethylene-α-olefin copolymers, poly(silicone-urethanes), poly(tyrosine arylates), poly(tyrosine-derived carbonates); polyacrylates, polycarbonates, poly-hydroxycarboxylic acids, polyisobutylene and ethylene-α-olefin copolymers, polymethacrylates, polyolefins, polyorthoesters, polyvinyl aromatics; polyvinyl esters, silicones, vinyl copolymers, vinyl-olefin copolymers, vinyl halide polymers and copolymers, and combinations thereof. 
     
     
         12 . The method of  claim 8 , wherein the olimus therapeutic agent in the first layer is selected from the group consisting of sirolimus (rapamycin), everolimus, zotarolimus, Biolimus A9, AP23572, tacrolimus, pimecrolimus, and derivates, analogs, and combinations thereof. 
     
     
         13 . The method of  claim 8 , wherein the non-olimus therapeutic agent in the second layer is selected from the group consisting of dexamethasone, dexamethasone acetate, dexamethasone phosphate, dexamethasone valerate, dexamethasone derivatives, momentasone, clobetasol, cortisone, cortisone acetate, hydrocortisone, corticosterone, deoxycorticosterone, hydrocortisone acetate, deoxycorticosterone acetate, hydroxyprogesterone, prednisolone, prednisolone acetate, triamicinolone, triamicinolone acetonide, triamcinolone diacetate, betamethasone, betamethasone valerate, steroids, glucocorticoids, estradiol, methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride, mitomycin, antiplatelet compounds, anticoagulants, antifibrin, antithrombins including sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin, prostacyclin analogues, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, thrombin inhibitors including Angiomax ä, calcium channel blockers including nifedipine, colchicine, fibroblast growth factor (FGF) antagonists, histamine antagonists, lovastatin, monoclonal antibodies, nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, thioprotease inhibitors, triazolopyrimidine, nitric oxide or nitric oxide donors, super oxide dismutases, super oxide dismutase mimetic, cytostatic substances including angiopeptin, angiotensin converting enzyme inhibitors including captopril, cilazapril or lisinopril, antiallergic agents, permirolast potassium, alpha-interferon, bioactive RGD, and derivates, analogs, and combinations thereof. 
     
     
         14 . The method of  claim 8 , wherein the non-olimus therapeutic agent is selected from the group consisting of dexamethasone, dexamethasone acetate, dexamethasone phosphate, dexamethasone valerate, dexamethasone derivatives, momentasone, clobetasol, cortisone, cortisone acetate, hydrocortisone, corticosterone, deoxycorticosterone, hydrocortisone acetate, deoxycorticosterone acetate, hydroxyprogesterone, prednisolone, prednisolone acetate, triamicinolone, triamicinolone acetonide, triamcinolone diacetate, betamethasone, betamethasone valerate, steroids, glucocorticoids, and combinations thereof. 
     
     
         15 . The method of  claim 8 , wherein the olimus therapeutic agent in the first layer is everolimus, zotarolimus, or a combination thereof. 
     
     
         16 . The method of  claim 8 , wherein the hydrophobic polymer in the first and the second layer is poly(vinylidene fluoride-co-hexafluoropropylene);
 wherein the non-olimus therapeutic agent in the second layer is dexamethasone; and   wherein the olimus therapeutic agent in the first layer is everolimus, zotarolimus, or a combination thereof.