Preparation of microparticles having a selected release profile

Abstract

An improved method for preparing microparticles that exhibit controlled release of an effective amount of an active agent over an extended period of time. More particularly, a method is provided for preparing microparticles having a selected release profile for release of active agent contained in the microparticles. By adjusting the degree of drying that is performed during the preparation of the microparticles, the release profile can be controlled. By performing no intermediate drying, an initial burst and a substantially linear release profile is achieved. By performing substantially complete intermediate drying, an initial lag phase and a substantially sigmoidal release profile is achieved.

1 . A method for preparing microparticles having a selected release profile for release of active agent contained in the microparticles, comprising: 
 (a) dissolving a polymer in a first solvent to form a polymer solution;    (b) dissolving an active agent in a second solvent to form an active agent solution;    (c) combining the polymer solution and the active agent solution in a static mixer to form an emulsion;    (d) extracting at least a portion of the first and second solvents from the emulsion using an extraction liquid to form microparticles containing the active agent;    (e) selecting a degree of intermediate drying of the microparticles to be performed so that the selected release profile is achieved; and    (f) final drying the microparticles.    
     
     
         2 . The method of  claim 1 , wherein the selecting step (e) is carried out to select no intermediate drying, thereby resulting in microparticles having an initial burst and a substantially linear release profile.  
     
     
         3 . The method of  claim 1 , wherein the selecting step (e) is carried out to select substantially complete intermediate drying, thereby resulting in microparticles having an initial lag phase and a substantially sigmoidal release profile.  
     
     
         4 . The method of  claim 3 , further comprising after step (e) and prior to step (f): 
 (g) performing the selected degree of intermediate drying.    
     
     
         5 . The method of  claim 4 , wherein the substantially complete intermediate drying results in the microparticles having a moisture content of less than about 0.2% after step (g).  
     
     
         6 . The method of  claim 1 , wherein the first solvent is ethyl acetate.  
     
     
         7 . The method of  claim 1 , wherein the second solvent is benzyl alcohol.  
     
     
         8 . The method of  claim 6 , wherein the second solvent is benzyl alcohol.  
     
     
         9 . The method of  claim 1 , wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts of the foregoing.  
     
     
         10 . The method of  claim 8 , wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts of the foregoing.  
     
     
         11 . A microencapsulated active agent having a selected release profile prepared by a method for preparing microparticles, the method comprising: 
 (a) dissolving a polymer in a first solvent to form a polymer solution;    (b) dissolving an active agent in a second solvent to form an active agent solution;    (c) combining the polymer solution and the active agent solution in a static mixer to form an emulsion;    (d) extracting at least a portion of the first and second solvents from the emulsion to form microparticles containing the active agent;    (e) selecting a degree of intermediate drying of the microparticles to be performed so that the selected release profile is achieved; and    (f) final drying the microparticles.    
     
     
         12 . The microencapsulated active agent of  claim 11 , wherein the selecting step (e) is carried out to select no intermediate drying, thereby resulting in microparticles having an initial burst and a substantially linear release profile.  
     
     
         13 . The microencapsulated active agent of  claim 11 , wherein the selecting step (e) is carried out to select substantially complete intermediate drying, thereby resulting in microparticles having an initial lag phase and a substantially sigmoidal release profile.  
     
     
         14 . The microencapsulated active agent of  claim 11 , wherein the method further comprises after step (e) and prior to step (f): 
 (g) performing the selected degree of intermediate drying.    
     
     
         15 . The microencapsulated active agent of  claim 14 , wherein the substantially complete intermediate drying results in the microparticles having a moisture content of less than about 0.2% after step (g).  
     
     
         16 . The microencapsulated active agent of  claim 11 , wherein the first solvent is ethyl acetate and the second solvent is benzyl alcohol.  
     
     
         17 . The microencapsulated active agent of  claim 16 , wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts of the foregoing.  
     
     
         18 . Microparticles prepared by the method of  claim 1 .  
     
     
         19 . The microparticles of  claim 18 , wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts of the foregoing.  
     
     
         20 . The microparticles of  claim 18 , wherein the first solvent is ethyl acetate and the second solvent is benzyl alcohol.