Implantable medical device with beneficial agent concentration gradient

Abstract

The implantable medical devices are configured to release at least one therapeutic agent from a matrix affixed to the implantable body with a release profile which is programmable to the agent and treatment. The matrix is formed such that the concentration of the therapeutic agent in the matrix varies as a gradient relative to a surface of the implantable body. The change in the concentration gradient of the agent in the matrix directly controls the rate of elution of the agent from the matrix. The therapeutic agent matrix can be disposed in the stent or on surfaces of the stent in various configurations, including within volumes defined by the stent, such as openings, holes, or concave surfaces, as a reservoir of agent, and alternatively as a coating on all or a portion of the surfaces of the stent structure.

1 . A method of forming an implantable medical device configured to release at least one therapeutic agent therefrom, the method comprising:
 providing an implantable medical device having a body, a luminal surface, a mural surface and at least one recess in the body;   forming a first homogeneous solution comprising the at least one therapeutic agent mixed with a polymeric binder;   introducing the first homogeneous solution into the at least one recess in the body of the implantable medical device;   solidifying the first homogeneous solution, thereby forming a first portion of a matrix, wherein a concentration of the at least one therapeutic agent in the matrix varies as a continuous gradient relative to a surface of the body of the implantable medical device;   forming a second homogeneous solution comprising the polymeric binder;   applying the second homogeneous solution to the first portion of the matrix, thereby at least partially liquifying the first portion of the matrix; and   solidifying the second homogeneous solution, thereby forming a second portion of the matrix, wherein the concentration of the at least one therapeutic agent in the matrix is higher at the luminal surface of the implantable body than at the mural surface of the implantable body.   
     
     
         2 . The method of  claim 1 , wherein the first and second homogenous solutions include a solvent and the first and second homogenous solutions are solidified by evaporation of the solvent. 
     
     
         3 . The method of  claim 2 , wherein the solvent comprises a miscible organic solvent. 
     
     
         4 . The method of  claim 3 , wherein the miscible organic solvent is selected from the group consisting of dimethyl sulfoxide, N-methyl pyrrolidone, ethyl lactate, and simple alcohols. 
     
     
         5 . The method of  claim 2 , wherein the solvent and the polymeric binder are both non-water soluble. 
     
     
         6 . The method of  claim 5 , wherein the non-water soluble solvent is selected from the group consisting of a poly(lactide-co-glycolide) polymer, N-methyl pyrrolidone, ethyl lactate, anisole, chloroform, tetrahydrofuran, xylene, and methylene chloride. 
     
     
         7 . The method of  claim 1 , further comprising:
 applying successive homogeneous solutions to the matrix; and   solidifying the successive homogeneous solutions, thereby forming additional portions of the matrix, wherein the concentration of the therapeutic agent in the matrix is different in the successive portions of the matrix.   
     
     
         8 . The method of  claim 1 , wherein said at least one recess extends through the body of the implantable medical device. 
     
     
         9 . The method of  claim 1 , wherein the polymeric binder of the first homogeneous solution is water soluble. 
     
     
         10 . The method of  claim 1 , wherein the therapeutic agent is selected from the group consisting of antithrombotic agents, antiproliferative agents, and antirestenotic agents. 
     
     
         11 . The method of  claim 1 , wherein the matrix is selected from the group consisting of poly(lactide-co-glycolide) (PLGA) and Poly vinylpyrrolidone (PVP). 
     
     
         12 . The method of  claim 1 , further comprising:
 applying a solution of a barrier material prior to applying introducing the first homogenous solution, the barrier material forming a barrier to the passage of the therapeutic agent in the first homogenous solution to one side of the body of the implantable medical device.   
     
     
         13 . The method of  claim 1 , wherein the second homogenous solution contains no therapeutic agent. 
     
     
         14 . The method of  claim 1 , wherein the second homogeneous solution comprises the at least one therapeutic agent, and wherein a concentration of the at least one therapeutic agent in the second homogeneous solution is different from a concentration of the at least one therapeutic agent in the first homogeneous solution. 
     
     
         15 . The method of  claim 1 , wherein the implantable medical device is a stent. 
     
     
         16 . The method of  claim 14 , further comprising:
 applying successive homogeneous solutions to the matrix; and   solidifying the successive homogeneous solutions, thereby forming additional portions of the matrix, wherein the concentration of the at least one therapeutic agent in the matrix is different in the successive portions of the matrix.   
     
     
         17 . A method of forming an implantable medical device configured to release at least one therapeutic agent therefrom, the method comprising:
 providing an implantable medical device having a substantially cylindrical body, a luminal surface, a mural surface and a plurality of struts;   forming a homogeneous solution comprising a polymeric binder and a solvent;   evaporating the solvent in the homogeneous solution, thereby forming a matrix;   exposing the matrix to a solution comprising the therapeutic agent for a time sufficient to produce a partial diffusion of the therapeutic agent into the matrix wherein a concentration of the at least one therapeutic agent in the matrix varies as a continuous gradient; and   affixing the matrix to the body of the implantable medical device body such that the matrix is disposed in the plurality of holes passing through at least some of the struts in the implantable body; and   coating the matrix with a barrier layer at the luminal surface, wherein the therapeutic agent has a maximum concentration substantially adjacent to the barrier layer and a minimum concentration substantially adjacent to the mural surface of the implantable body.   
     
     
         18 . The method of  claim 17 , wherein the matrix is affixed to the implantable medical device body by placing the matrix into the body prior to immersing the matrix in the solution comprising the therapeutic agent. 
     
     
         19 . The method of  claim 17 , wherein the matrix is affixed to the implantable medical device body by disposing the homogeneous solution comprising a polymeric binder and a solvent into the plurality of openings and then evaporating the solvent. 
     
     
         20 . The method of  claim 17 , wherein the implantable medical device is a stent.