Thermal Treatment Of An Implantable Medical Device

Abstract

A method of manufacturing an implantable medical device, such as a drug eluting stent, is disclosed. The method includes subjecting an implantable medical device that includes a polymer to a thermal condition. The thermal condition can result in reduction of the rate of release of an active agent from the device subsequent to the implantation of the device and/or improve the mechanical properties of a polymeric coating on the device.

1 . A method of applying a polymeric coating to an implantable medical device, comprising:
 applying to the implantable medical device a composition comprising a polymer and a solvent to form the polymeric coating on the implantable medical device, and   heating the polymer to a temperature equal to or greater than the glass transition temperature of the polymer and less than the melting temperature of the polymer for a duration of time, wherein the temperature is   (a) equal to the glass transition temperature of the polymer plus the melting temperature of the polymer, divided by 2;   (b) equal to 0.9 times the melting temperature of the polymer, wherein the melting temperature of the polymer is expressed in Kelvin;   (c) equal to or greater than the crystallization temperature of the polymer; or   (d) equal to the glass transition temperature of the polymer.   
     
     
         2 . The method of  claim 1 , wherein the temperature is equal to the glass transition temperature of the polymer. 
     
     
         3 . The method of  claim 2 , wherein the act of heating the polymer to the temperature is done concurrently with or subsequent to securing the implantable medical device onto a patient delivery device. 
     
     
         4 . The method of  claim 3 , wherein the implantable medical device is a stent, and the patient delivery device comprises a catheter. 
     
     
         5 . The method of  claim 1 , wherein the polymeric coating is free from any active agents. 
     
     
         6 . The method of  claim 1 , wherein the polymer comprises a crystalline component and an amorphous component such that the temperature is equal to the glass transition temperature of either of the components. 
     
     
         7 . The method of  claim 1 , wherein the glass transition temperature is above room temperature. 
     
     
         8 . The method of  claim 1 , wherein the polymer comprises a bioabsorbable polymer. 
     
     
         9 . The method of  claim 1 , wherein the polymer comprises poly(lactic acid). 
     
     
         10 . The method of  claim 1 , wherein the polymer comprises a block copolymer or a graft copolymer, and wherein a moiety of the block copolymer or the graft copolymer is poly(lactic acid). 
     
     
         11 . The method of  claim 1 , wherein the implantable medical device is a stent and wherein the act of heating the polymer to the temperature is done concurrently with or subsequent to securing the stent onto a patient delivery device. 
     
     
         12 . The method of  claim 1 , wherein the implantable medical device is a stent and wherein the act of heating the device to the temperature is done concurrently with crimping of the stent onto a catheter. 
     
     
         13 . The method of  claim 1 , wherein the composition additionally comprises rapamycin, everolimus or functional analogs or structural derivatives thereof. 
     
     
         14 . The method of  claim 1 , wherein the composition additionally comprises a drug. 
     
     
         15 . A method of manufacturing an implantable medical device, comprising:
 applying a semicrystalline polymer to the implantable medical device; and   heating the polymer to a temperature equal to the crystallization temperature of the polymer, or to a temperature greater than the melting temperature of the polymer for a duration of time.   
     
     
         16 . The method of  claim 15 , wherein the polymer comprises poly(lactic acid). 
     
     
         17 . The method of  claim 15 , wherein the polymer comprises a block copolymer or a graft copolymer, and wherein a moiety of the block copolymer or the graft copolymer is poly(lactic acid). 
     
     
         18 . A method of manufacturing an implantable medical device, comprising:
 applying a semicrystalline polymer to the implantable medical device; and   exposing the polymer to a temperature greater than the melting temperature of the polymer for a duration of time.   
     
     
         19 . A method of applying a polymeric coating to an implantable medical device, comprising:
 applying to the implantable medical device a composition comprising a polymer and a solvent to form the polymeric coating on the implantable medical device, and   heating the polymer to a temperature equal to or greater than the glass transition temperature of the polymer and less than the melting temperature of the polymer for a duration of time;   wherein the glass transition temperature is above room temperature.   
     
     
         20 . The method of  claim 19 , wherein the polymeric coating comprises a primer layer. 
     
     
         21 . The method of  claim 19 , wherein the polymer comprises a block copolymer or a graft copolymer, and wherein a moiety of the block copolymer or the graft copolymer is poly(lactic acid). 
     
     
         22 . The method of  claim 19 , wherein the polymer is selected from the group consisting of ethylene vinyl alcohol copolymer, poly(n-butyl methacrylate), poly(ethylene-co-vinyl acetate), poly(ethylene terephthalate), poly(vinylidene fluoride), poly(p-phenylene sulfide), poly(6-aminocaproic acid), poly(methyl methacrylate), poly(vinyl alcohol), poly(epsilon caprolactone), random and block copolymers of α-methylstyrene and vinyl acetate, random and block copolymers of α-methylstyrene and vinyl chloride, random and block copolymers of α-methylstyrene and styrene, random and block copolymers of styrene and butyl methacrylate, random and block copolymers of styrene and methyl methacrylate, random and block copolymers of styrene and ethylene oxide, random and block copolymers of styrene and isoprene, random and block copolymers of styrene and isobutylene, random and block copolymers of methyl methacrylate and ethyl acrylate, random and block copolymers of methyl methacrylate and vinyl acetate, random and block copolymers of methyl methacrylate and ethyl methacrylate, and any combination thereof. 
     
     
         23 . The method of  claim 22 , wherein the polymer is selected from the group consisting of ethylene vinyl alcohol copolymer, poly(n-butyl methacrylate), poly(ethylene-co-vinyl acetate), poly(ethylene terephthalate), poly(vinylidene fluoride), poly(p-phenylene sulfide), poly(6-aminocaproic acid), poly(methyl methacrylate), poly(vinyl alcohol), poly(epsilon carpolactone), and any combination thereof. 
     
     
         24 . The method of  claim 19 , wherein the polymer exhibits more than one glass transition temperature, and the heating temperature is above the highest of the glass transition temperatures. 
     
     
         25 . The method of  claim 19 , wherein the polymer exhibits more than one glass transition temperature, and the heating temperature is above the lowest of the glass transition temperatures. 
     
     
         26 . The method of  claim 19 , wherein the polymer comprises a bioabsorbable polymer; and wherein the bioabsorbable polymer is selected from the group consisting of poly(hydroxybutyrate) (PHB), poly(hydroxyvalerate) (PHV), poly(hydroxybutyrate-co-valerate), poly(caprolactone) (PCL), poly(lactide-co-glycolide) (PLGA), poly(lactic acid), poly(glycerol-sebacate) (PGS), poly(ester amide), collagen, elastin, silk, AB and ABA block-copolymers of PEG with poly(butylene terephthalate) (PBT), poly(ethylene-glycol)-block-poly(butylene terephthalate) (PEG-PBT), poly(ethylene-glycol)-block-poly (butylene terephthalate)-block-poly(ethylene-glycol) (PEG-PBT-PEG), poly(butylene terephthalate)-block-poly(ethylene-glycol)-block poly(butylene terephthalate) (PBT-PEG-PBT), AB and ABA block-copolymers of PEG with PCL, poly(ethylene-glycol)-block-poly(caprolactone) (PEG-PCL), poly(ethylene-glycol)-block-poly(caprolactone)-block-poly(ethylene-glycol) (PEG-PCL-PEG), poly(caprolactone)-block-poly(ethylene-glycol)block-poly(caprolactone) (PCL-PEG-PCL), and any combination thereof. 
     
     
         27 . The method of  claim 19 , wherein the duration of time is sufficient to improve the mechanical properties of the coating. 
     
     
         28 . A method of applying a polymeric coating to an implantable medical device, comprising:
 applying to the implantable medical device a composition comprising a polymer and a solvent to form the polymeric coating on the implantable medical device, and   heating the polymer to a temperature equal to or greater than the glass transition temperature of the polymer and less than the melting temperature of the polymer for a duration of time;   wherein during the act of heating the polymer to the temperature, the temperature is changed to another temperature between the glass transition temperature and the melting temperature.   
     
     
         29 . The method of  claim 28 , wherein the polymer is selected from the group consisting of ethylene vinyl alcohol copolymer, poly(n-butyl methacrylate), poly(ethylene-co-vinyl acetate), poly(ethylene terephthalate), poly(vinylidene fluoride), poly(p-phenylene sulfide), poly(6-aminocaproic acid), poly(methyl methacrylate), poly(vinyl alcohol), poly(epsilon caprolactone), random and block copolymers of α-methylstyrene and vinyl acetate, random and block copolymers of α-methylstyrene and vinyl chloride, random and block copolymers of α-methylstyrene and styrene, random and block copolymers of styrene and butyl methacrylate, random and block copolymers of styrene and methyl methacrylate, random and block copolymers of styrene and ethylene oxide, random and block copolymers of styrene and isoprene, random and block copolymers of styrene and isobutylene, random and block copolymers of methyl methacrylate and ethyl acrylate, random and block copolymers of methyl methacrylate and vinyl acetate, random and block copolymers of methyl methacrylate and ethyl methacrylate, and any combination thereof. 
     
     
         30 . The method of  claim 28 , wherein the polymer is selected from the group consisting of ethylene vinyl alcohol copolymer, poly(n-butyl methacrylate), poly(ethylene-co-vinyl acetate), poly(ethylene terephthalate), poly(vinylidene fluoride), poly(p-phenylene sulfide), poly(6-aminocaproic acid), poly(methyl methacrylate), poly(vinyl alcohol), poly(epsilon caprolactone), and any combination thereof. 
     
     
         31 . The method of  claim 28 , wherein the polymer exhibits more than one glass transition temperature, and the heating temperature is above the lowest of the glass transition temperatures. 
     
     
         32 . The method of  claim 28 , wherein the polymer exhibits more than one glass transition temperature, and the heating temperature is above the highest of the glass transition temperatures. 
     
     
         33 . The method of  claim 28 , wherein the composition additionally comprises a second polymer such that the coating formed comprises a polymer blend, and the heating temperature is above the lowest of the glass transition temperatures if the polymer blend exhibits more than one glass transition temperature. 
     
     
         34 . The method of  claim 33 , wherein the heating temperature is less than the lowest melting temperature if the polymer blend exhibits more than one melting temperature. 
     
     
         35 . The method of  claim 28 , wherein the composition additionally comprises a second polymer such that the coating formed comprises a polymer blend, and the heating temperature is above the highest of the glass transition temperatures if the polymer blend exhibits more than one glass transition temperature. 
     
     
         36 . The method of  claim 35 , wherein the heating temperature is less than the lowest melting temperature if the polymer blend exhibits more than one melting temperature. 
     
     
         37 . The method of  claim 28 , wherein the polymeric coating is free from any active agents and the polymeric coating comprises a primer layer. 
     
     
         38 . The method of  claim 37 , wherein the implantable medical device is made of a metal, a metallic material, or a metal alloy. 
     
     
         39 . The method of  claim 37 , wherein the duration of time is sufficient to improve the mechanical properties of the primer layer. 
     
     
         40 . A method of coating an implantable medical device, comprising:
 applying a first layer to the device comprising a first polymer having a first glass transition temperature;   applying a second layer over the first layer, the second layer comprising a second polymer having a second glass transition temperature; and   heating the first polymer or the second polymer to a temperature between the first glass transition temperature and the second glass transition temperature.   
     
     
         41 . The method of  claim 40 , wherein the first glass transition temperature is higher than the second glass transition temperature. 
     
     
         42 . The method of  claim 40 , wherein the first glass transition temperature is lower than the second glass transition temperature. 
     
     
         43 . The method of  claim 40 , wherein at least one of the layers comprises a drug. 
     
     
         44 . The method of  claim 40 , wherein the first and the second polymers are independently selected from the group consisting of ethylene vinyl alcohol copolymer, poly(n-butyl methacrylate), poly(ethylene-co-vinyl acetate), poly(ethylene terephthalate), poly(vinylidene fluoride), poly(p-phenylene sulfide), poly(6-aminocaproic acid), poly(methyl methacrylate), poly(vinyl alcohol), poly(epsilon caprolactone), poly(lactic acid), random and block copolymers of α-methylstyrene and vinyl acetate, random and block copolymers of α-methylstyrene and vinyl chloride, random and block copolymers of α-methylstyrene and styrene, random and block copolymers of styrene and butyl methacrylate, random and block copolymers of styrene and methyl methacrylate, random and block copolymers of styrene and ethylene oxide, random and block copolymers of styrene and isoprene, random and block copolymers of styrene and isobutylene, random and block copolymers of methyl methacrylate and ethyl acrylate, random and block copolymers of methyl methacrylate and vinyl acetate, random and block copolymers of methyl methacrylate and ethyl methacrylate, and any combination thereof. 
     
     
         45 . The method of  claim 44 , wherein at least one of the first and the second polymers is selected from the group consisting of ethylene vinyl alcohol copolymer, poly(n-butyl methacrylate), poly(ethylene-co-vinyl acetate), poly(ethylene terephthalate), poly(vinylidene fluoride), poly(p-phenylene sulfide), poly(6-aminocaproic acid), poly(methyl methacrylate), poly(vinyl alcohol), poly(epsilon caprolactone-), and any combination thereof. 
     
     
         46 . The method of  claim 40 , wherein both the first and second glass transition temperatures are above room temperature. 
     
     
         47 . A method of coating an implantable medical device, comprising:
 applying a coating to the device, the coating comprising a polymer; and   heating the coating to a temperature so as to modify % crystallinity of the polymer;   wherein the temperature is sufficient to increase the crystallinity of the polymer in at least a portion of the coating by 5% to 30%.   
     
     
         48 . A method of applying a polymeric coating to a stent comprising:
 applying to the stent a composition comprising a polymer and a solvent to form the polymeric coating on the stent, and   heating the polymer to a temperature equal to or greater than the glass transition temperature of the polymer and less than the melting temperature of the polymer for a duration of time, wherein the act of heating the polymer to the temperature is done concurrently with or subsequent to securing the stent onto a patient delivery device; and   wherein the polymer is selected from the group consisting of ethylene vinyl alcohol copolymer, poly(n-butyl methacrylate), poly(ethylene-co-vinyl acetate), poly(ethylene terephthalate), poly(vinylidene fluoride), poly(p-phenylene sulfide), poly(6-aminocaproic acid), poly(methyl methacrylate), poly(vinyl alcohol), poly(epsilon caprolactone), poly(lactic acid), random and block copolymers of α-methylstyrene and vinyl acetate, random and block copolymers of α-methylstyrene and vinyl chloride, random and block copolymers of α-methylstyrene and styrene, random and block copolymers of styrene and butyl methacrylate, random and block copolymers of styrene and methyl methacrylate, random and block copolymers of styrene and ethylene oxide, random and block copolymers of styrene and isoprene, random and block copolymers of styrene and isobutylene, random and block copolymers of methyl methacrylate and ethyl acrylate, random and block copolymers of methyl methacrylate and vinyl acetate, random and block copolymers of methyl methacrylate and ethyl methacrylate, and any combination thereof.   
     
     
         49 . The method of  claim 48 , wherein the patient delivery device comprises a catheter. 
     
     
         50 . The method of  claim 48 , wherein the polymer is selected from the group consisting of ethylene vinyl alcohol copolymer, poly(n-butyl methacrylate), poly(ethylene-co-vinyl acetate), poly(ethylene terephthalate), poly(vinylidene fluoride), poly(p-phenylene sulfide), poly(6-aminocaproic acid), poly(methyl methacrylate), poly(vinyl alcohol), poly(epsilon caprolactone), and any combination thereof. 
     
     
         51 . A method of applying a polymeric coating to an implantable medical device, comprising:
 applying to the implantable medical device a composition comprising a first polymer, a second polymer, and a solvent to form the polymeric coating on the implantable medical device, the coating formed comprising a polymer blend; and   heating the polymer blend to a temperature greater than the glass transition temperature of the polymer blend and less than the melting temperature of the polymer blend for a duration of time;   wherein the glass transition temperature is above room temperature.   
     
     
         52 . The method of  claim 51 , wherein the heating temperature is above the lowest of the glass transition temperatures if the polymer blend exhibits more than one glass transition temperature. 
     
     
         53 . The method of  claim 52 , wherein the heating temperature is less than the lowest melting temperature if the polymer blend exhibits more than one melting temperature. 
     
     
         54 . The method of  claim 51 , wherein the heating temperature is above the highest of the glass transition temperatures if the polymer blend exhibits more than one glass transition temperature. 
     
     
         55 . The method of  claim 54 , wherein the heating temperature is less than the lowest melting temperature if the polymer blend exhibits more than one melting temperature. 
     
     
         56 . A method of coating implantable medical devices, comprising:
 applying a composition to a set of implantable medical devices, the composition comprising a polymer and a drug; and   subjecting the implantable medical devices to a temperature treatment based on the type of polymer and the type of drug such that the standard deviation of the mean release rate of the drug in a 24 hour period is decreased as compared to the standard deviation of the mean release rate for a base line group of devices which have not been subjected to the temperature treatment.