Method for preparing microparticles having a selected polymer molecular weight

Abstract

A method for preparing microparticles having a selected polymer molecular weight. The hold time and temperature of a solution containing a nucleophilic compound and a polymer having a starting molecular weight are controlled in order to control the molecular weight of the polymer in the finished microparticle product. In this manner, a selected polymer molecular weight in the finished microparticle product can be achieved from a variety of starting material molecular weights.

What Is claimed is:  
     
         1 . A method of preparing microparticles having a selected microparticle polymer molecular weight, comprising: 
 (a) combining a first phase comprising a nucleophilic compound, a polymer having a starting molecular weight, and a solvent for the polymer, with a second phase to form an emulsion;    (b) extracting solvent from the emulsion, thereby forming microparticles; and    (c) maintaining the first phase at a hold temperature for a hold period prior to step (a), the hold period of sufficient duration to allow the starting molecular weight of the polymer to reduce so that the selected microparticle polymer molecular weight is achieved.    
     
     
         2 . The method of  claim 1 , further comprising: 
 (d) increasing the hold temperature, thereby increasing molecular weight decay of the polymer to reduce a duration of the hold period.    
     
     
         3 . The method of  claim 1 , further comprising: 
 (d) decreasing the hold temperature, thereby decreasing molecular weight decay of the polymer to increase a duration of the hold period.    
     
     
         4 . The method of  claim 1 , wherein the starting molecular weight is in the range of from about 50 kD to about 250 kD.  
     
     
         5 . The method of  claim 1 , wherein the hold period is in the range of from about 0.05 hour to about 6 hours.  
     
     
         6 . The method of  claim 1 , wherein the hold temperature is in the range of from about 15° C. to about 35° C.  
     
     
         7 . The method of  claim 1 , wherein step (b) comprises combining the emulsion and an extraction medium.  
     
     
         8 . The method of  claim 1 , wherein the nucleophilic compound is selected from the group consisting of risperidone,  9  -hydroxyrisperidone, and pharmaceutically acceptable salts thereof.  
     
     
         9 . The method of  claim 8 , wherein the solvent comprises benzyl alcohol and ethyl acetate.  
     
     
         10 . The method of  claim 1 , wherein the polymer is selected from the group consisting of poly(glycolic acid), poly-d,l-lactic acid, poly-l-lactic acid, and copolymers of the foregoing.  
     
     
         11 . The method of  claim 10 , wherein the polymer is poly(d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide in the range of from about 100:0 to about 50:50.  
     
     
         12 . The method of  claim 1 , further comprising: 
 (d) mixing the first phase during the hold period.    
     
     
         13 . The method of  claim 1 , wherein the selected microparticle polymer molecular weight is in the range of from about 10 kD to about 185.0 kD.  
     
     
         14 . The method of  claim 4 , wherein the selected microparticle polymer molecular weight is in the range of from about 10 kD to about 185.0 kD.  
     
     
         15 . The method of  claim 1 , wherein the starting molecular weight reduces by an amount in the range of from about 10% to about 50% to reach the selected microparticle polymer molecular weight.  
     
     
         16 . The method of  claim 4 , wherein the starting molecular weight reduces by an amount in the range of from about 10% to about 50% to reach the selected microparticle polymer molecular weight.  
     
     
         17 . The method of  claim 13 , wherein the starting molecular weight reduces by an amount in the range of from about 10% to about 50% to reach the selected microparticle polymer molecular weight.  
     
     
         18 . The method of  claim 1 , further comprising: 
 (d) adding an inactive agent to the first phase.    
     
     
         19 . The method of  claim 1 , wherein the nucleophilic compound is an active agent.  
     
     
         20 . The method of  claim 1 , wherein the nucleophilic compound is an inactive agent.  
     
     
         21 . The method of  claim 1 , wherein the nucleophilic compound is basic.  
     
     
         22 . The method of  claim 1 , wherein the nucleophilic compound is naltrexone.  
     
     
         23 . The method of  claim 1 , wherein the nucleophilic compound is oxybutynin.  
     
     
         24 . Microparticles having a selected microparticle polymer molecular weight prepared by the method of  claim 1 .  
     
     
         25 . Microparticles having a selected microparticle polymer molecular weight prepared by the method of  claim 8 .  
     
     
         26 . Microparticles having a selected microparticle polymer molecular weight prepared by the method of  claim 10 .  
     
     
         27 . Microparticles having a selected microparticle polymer molecular weight prepared by the method of  claim 22.