Methods of forming coatings with a crystalline or partially crystalline drug for implantable medical devices using supercritical fluid assisted sorption

Abstract

Methods for making coatings on an implantable device such as a drug-eluting stent comprising a polymer and nano or microparticles of a drug in slow-dissolving polymorph, implantable devices produced by the methods and methods of using the coatings are provided.

1 . A method of forming a coating comprising nano-particles or microparticles of a drug in slow-dissolving polymorph on an implantable device, comprising:
 a) applying to an implantable device a composition comprising a drug and a polymeric material to form a coating on the device, and   b) inducing formation of a slow-dissolving polymorph of the drug by supercritical fluid assisted sorption and subsequent pressure swing to form nano-particles or microparticles of the drug in a slow-dissolving polymorph.   
     
     
         2 . The method of  claim 1 , wherein the supercritical fluid used in the process is supercritical CO 2 . 
     
     
         3 . The method of  claim 1 , wherein the coated device is exposed to the supercritical fluid for a period of about 1 minute to about 2 hours such that the drug becomes crystalline having a crystallinity of about 1% to about 100%. 
     
     
         4 . The method of  claim 1 , wherein the polymeric material is selected from the group consisting of poly(ethylene glycol terephthalate)-co-poly(butylene terephthalate), hyaluronic acid, poly(ethylene glycol), phosphoryl choline, poly(amide ester), poly(D,L-lactide), polyhydroxyalkanoate, polycaprolactone, poly(vinylidene fluoride), poly(hexafluoro propylene), poly(ethylene vinyl alcohol), and combinations thereof. 
     
     
         5 . The method of  claim 4 , wherein the drug is selected from the group consisting of ABT-578™, paclitaxel, docetaxel, tacrolimus, pimecrolimus, batimastat, mycophenolic acid, estradiol, clobetasol, dexamethasone, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), and combinations thereof. 
     
     
         6 . The method of  claim 1 , wherein the crystallinity of the drug is selected from the group consisting of about 30%, about 40%, about 50%, about 60%, about 70%, about 75%, about 80%, about 90%, about 95%, about 99%, and about 100%. 
     
     
         7 . The method of  claim 1 , wherein the drug is everolimus and the polymer is poly(ethylene glycol terephthalate)-co-poly(butylene terephthalate). 
     
     
         8 . The method of  claim 1 , wherein the implantable device is a stent. 
     
     
         9 . The method of  claim 5 , wherein the implantable device is a stent. 
     
     
         10 . The method of  claim 7 , wherein the implantable device is a stent.