Loading and release of water-insoluble drugs

Abstract

A medical device, polymer composition, and method for delivering substantially water-insoluble drugs to tissue at desired locations within the body. At least a portion of the exterior surface of the medical device is provided with a polymer coating. Incorporated in the polymer coating is a solution of at least one substantially water-insoluble drug in a volatile organic solvent. The medical device is positioned to a desired target location within the body, whereupon the drug diffuses out of the polymer coating.

We claim:  
     
         1 . A method for preparing a medical device having a substantially water-insoluble drug coated thereon comprising the steps of: 
 providing a polymer;    providing a medical device adapted for insertion in a body;    coating at least a portion of the exterior surface of the medical device with the polymer to form a polymer coating; and    applying a drug solution to the polymer, said drug solution comprising at least one substantially water-insoluble drug dissolved in an organic solvent.    
     
     
         2 . The method of  claim 1 , further comprising the step of drying said polymer coating such that substantially all of said solvent is evaporated.  
     
     
         3 . The method of  claim 1 , wherein said polymer is selected from the group consisting of polycarboxylic acids, cellulosic polymers, gelatin, polyvinylpyrrolidone, maleic anhydride polymers, polyamides, polyvinyl alcohols, polyethylene oxides, glycosaminoglycans, polysaccharides, polyesters, polyacrylamides, polyethers, polyurethane dispersions, acrylic latex dispersions, polyalkylenes, proteins, polypeptides, silicones, siloxanes, copolymers of vinyl monomers, polyvinyl ethers, polylactic acid, polycaprolactone, and mixtures and copolymers thereof.  
     
     
         4 . The method of  claim 3 , wherein said polymer is polyacrylic acid.  
     
     
         5 . The method of  claim 1 , wherein said at least one substantially insoluble drug is selected from the group consisting of dexamethasone, molsidomine, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, mesalamine, paclitaxel, cisplatin, vinblastine, vincristine, epothilones, endostatin, angiostatin, lidocaine, bupivacaine and ropivacaine.  
     
     
         6 . The method of  claim 1 , wherein said organic solvent is selected from the group consisting of ethanol, isopropanol, chloroform, acetone, pentane, hexane, methylene chloride, and mixtures thereof.  
     
     
         7 . The method of  claim 6 , wherein said organic solvent further comprises water.  
     
     
         8 . The method of  claim 1 , wherein said step of applying a drug solution to said polymer includes the step of dipping said polymer into said drug solution.  
     
     
         9 . The method of  claim 1 , wherein said drug solution is applied to said polymer before said polymer is coated onto said medical device.  
     
     
         10 . The method of  claim 1 , wherein said drug solution is applied to said polymer after said polymer is coated onto said medical device.  
     
     
         11 . The method of  claim 1 , wherein said medical device is selected from catheters, guide wires, balloons, stents, vascular grafts, covered stents, stent grafts, filters, intraluminal paving systems, wire guides, cannulae, artificial limbs and artificial joints.  
     
     
         12 . The method of  claim 11 , wherein said medical device is a catheter comprising a shaft and an expandable portion mounted on said shaft, at least a portion of the exterior surface of the expandable portion being covered with said polymer coating.  
     
     
         13 . The method of  claim 1 , further comprising positioning said medical device at a desired location in a body lumen.  
     
     
         14 . The method of  claim 13 , wherein said medical device is a catheter comprising a shaft and an expandable portion mounted on said shaft, at least a portion of the exterior surface of the expandable portion being covered with said polymer coating.  
     
     
         15 . The method of  claim 14 , further comprising the step of expanding said expandable portion of said catheter.  
     
     
         16 . The method of  claim 15 , wherein said catheter comprises a sheath member which is extendable over said expandable portion.  
     
     
         17 . The method of  claim 16 , further comprising the steps of: 
 extending said sheath over said expandable portion prior to said positioning; and    exposing said expandable portion from said sheath prior to said expanding.    
     
     
         18 . The method of  claim 1 , wherein said step of coating comprises the step of applying multiple layers of said polymer to said medical device.  
     
     
         19 . The method of  claim 1 , wherein said medical device is a stent.  
     
     
         20 . The method of  claim 1 , wherein said drug is paclitaxel.  
     
     
         21 . The method of  claim 1 , wherein said medical device is a stent and said drug is paclitaxel.  
     
     
         22 . The method of  claim 21 , wherein said stent is a patterned stent.  
     
     
         23 . The method of  claim 22 , wherein said polymer is a copolymer of polylactic acid and polycaprolactone.  
     
     
         24 . A medical device for delivering a substantially water-insoluble drug at a desired location within a body, comprising: 
 a medical device adapted for insertion in a body; and    a polymer coating containing at least one substantially water-insoluble drug provided on at least a portion of said medical device, wherein said substantially water-insoluble drug has a water-solubility no greater than 1 part drug to 30 parts water.    
     
     
         25 . The medical device of  claim 24 , wherein said drug has a water solubility no greater than 1 part drug to 1,000 parts water.  
     
     
         26 . The medical device of  claim 24 , wherein said medical device is a catheter for delivering substantially water-insoluble drugs to a desired location within a body lumen, said catheter comprising: 
 a shaft;    an expandable portion mounted on said shaft; and    a polymer coating on at least a portion of said expandable portion of said catheter, said polymer coating being impregnated with at least one substantially water-insoluble drug.    
     
     
         27 . The medical device of  claim 26 , wherein said expandable portion includes an inflatable balloon.  
     
     
         28 . The medical device of  claim 27 , further comprising a sheath member extendable over said expandable portion.  
     
     
         29 . The medical device of  claim 24 , wherein said polymer is selected from the group consisting of polycarboxylic acids, cellulosic polymers, gelatin, polyvinylpyrrolidone, maleic anhydride polymers, polyamides, polyvinyl alcohols, polyethylene oxides, glycosaminoglycans, polysaccharides, polyesters, polyacrylamides, polyethers, polyurethane dispersions, acrylic latex dispersions, polyalkylenes, proteins, polypeptides, silicones, siloxanes, copolymers of vinyl monomers, polyvinyl ethers, polylactic acid, polycaprolactone, and mixtures and copolymers thereof.  
     
     
         30 . The medical device of  claim 29 , wherein said polymer is polyacrylic acid.  
     
     
         31 . The medical device of  claim 24 , wherein said at least one substantially water-insoluble drug is selected from the group consisting of dexamethasone, molsidomine, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, mesalamine, paclitaxel, cisplatin, vinblastine, vincristine, epothilones, endostatin, angiostatin, lidocaine, bupivacaine and ropivacaine.  
     
     
         32 . The medical device of  claim 27 , wherein said expandable portion includes a stent.  
     
     
         33 . The medical device of  claim 24 , wherein said polymer coating is layered.  
     
     
         34 . The medical device of  claim 24 , wherein said polymer is polyurethane.  
     
     
         35 . The medical device of  claim 24 , wherein said medical device is a stent.  
     
     
         36 . The medical device of  claim 24 , wherein said drug is paclitaxel.  
     
     
         37 . The medical device of  claim 24 , wherein said medical device is a stent and said drug is paclitaxel.  
     
     
         38 . The medical device of  claim 37 , wherein said stent is a patterned stent.  
     
     
         39 . The medical device of  claim 38 , wherein said polymer is a copolymer of polylactic acid and polycaprolactone.  
     
     
         40 . The medical device of  claim 38  wherein the at least one water-insoluble drug comprises a combination of paclitaxel and an agent selected from the group consisting of anticoagulants, antimitotics, antithrombogenics, thrombolytics, anti-inflammatory agents, antioxidants, growth factors, modulators of vascular homeostasis, cytocidal agents, and cytostatic agents.  
     
     
         41 . The medical device of  claim 37 , wherein the paclitaxel is released from said device over a time frame effective to inhibit proliferative disease when said stent is positioned at a site of injury to thereby prevent or inhibit undesired cellular proliferation.  
     
     
         42 . The medical device of  claim 40 , wherein the time frame is at least about 7 days.  
     
     
         43 . The medical device of  claim 40 , wherein the time frame is at least about 28 days.  
     
     
         44 . The medical device of  claim 40 , wherein the paclitaxel is released at a rate in the range of from about 0.2 to about 7 μg paclitaxel per day.  
     
     
         45 . The medical device of  claim 40 , wherein the paclitaxel is released at a rate in the range of from about 0.5 to about 5 μg per day.  
     
     
         46 . The medical device of  claim 37 , wherein the device inhibits neointimal proliferation when placed at the site of injury in a blood vessel.  
     
     
         47 . A polymer containing at least one substantially water-insoluble drug.  
     
     
         48 . The polymer of  claim 45 , wherein said polymer is selected from the group consisting of polycarboxylic acids, cellulosic polymers, gelatin, polyvinylpyrrolidone, maleic anhydride polymers, polyamides, polyvinyl alcohols, polyethylene oxides, glycosaminoglycans, polysaccharides and derivatives thereof, polyesters, polyacrylamides, polyethers, polyurethane dispersions, acrylic latex dispersions, polyalkylenes, proteins, polypeptides, silicones, siloxanes, copolymers of vinyl monomers, polyvinyl ethers, polylactic acid, polycaprolactone, and mixtures and copolymers thereof.  
     
     
         49 . The polymer of  claim 46 , wherein said polymer is polyacrylic acid.  
     
     
         50 . The polymer of  claim 45 , wherein said at least one substantially water-insoluble drug is selected from the group consisting of dexamethasone, molsidomine, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, mesalamine, paclitaxel, cisplatin, vinblastine, vincristine, epothilones, endostatin, angiostatin, lidocaine, bupivacaine and ropivacaine.  
     
     
         51 . The polymer of  claim 45 , wherein said polymer is polyurethane.  
     
     
         52 . The polymer of  claim 40 , wherein said polymer is a copolymer of polylactic acid and polycaprolactone.  
     
     
         53 . The polymer of  claim 45 , wherein said drug is paclitaxel.  
     
     
         54 . The polymer of  claim 45 , wherein said polymer is polyurethane and said drug is paclitaxel.  
     
     
         55 . The polymer of  claim 45 , wherein said polymer is a copolymer of polylactic acid and polycaprolactone and said drug is paclitaxel.  
     
     
         56 . A method of preventing or inhibiting proliferative disease at a site of blood vessel injury in a patient comprising implanting a patterned stent comprising an outer coating of polymer/paclitaxel at the site of injury, wherein the paclitaxel is released from the outer coating at a release rate and for a period of time sufficient to inhibit or prevent cellular proliferation at the site of injury.  
     
     
         57 . The method of  claim 56 , wherein the paclitaxel is released from the outer coating for a period of time from about 7 to about 28 days.  
     
     
         58 . The method of  claim 56 , wherein the paclitaxel is released from the outer coating at a release rate of from about 0.2 to about 7 μg/day.  
     
     
         59 . The method of  claim 56 , wherein the paclitaxel is released from the outer coating at a release rate and for a period of time sufficient to inhibit or prevent neointima formation at the site of injury.  
     
     
         60 . The method of  claim 56 , wherein the proliferative disease is restenosis.  
     
     
         61 . The method of  claim 56 , wherein the stent comprises an outer coating of a polylactic acid/polycaprolactone copolymer and paclitaxel.  
     
     
         62 . A method of preventing or inhibiting proliferative disease in a patient comprising 
 implanting a patterned stent comprising an outer coating of polymer/paclitaxel at a site of cellular proliferation, wherein the paclitaxel is released from the outer coating at a release rate and for a period of time sufficient to inhibit or prevent cellular proliferation at the site.    
     
     
         63 . The method of  claim 62 , wherein the paclitaxel is released from the outer coating for a period of time from about 7 to about 28 days.  
     
     
         64 . The method of  claim 62 , wherein the palclitaxel is released from the outer coating at a release rate of from about 0.2 to about 7 μg/day.  
     
     
         65 . The method of  claim 62 , wherein the paclitaxel is released from the outer coating at a release rate and for a period of time sufficient to inhibit or prevent neointima formation at the site.  
     
     
         66 . The method of  claim 62 , wherein the proliferative disease is restenosis.  
     
     
         67 . The method of  claim 62 , wherein the stent comprises an outer coating of a polylactic acid/polycaprolactone copolymer and paclitaxel.