Preparation of biodegradable, biocompatible microparticles containing a biologically active agent

Abstract

A method for preparing biodegradable, biocompatible microparticles. A first phase is prepared that includes a biodegradable, biocompatible polymer, an active agent, and a solvent. A second phase is prepared. The first and second phases are combined to form an emulsion in which the first phase is discontinuous and the second phase is continuous. The discontinuous first phase is separated from the continuous second phase. The residual level of solvent in the discontinuous first phase is reduced to less than about 2% by weight.

1 . A method for preparing microparticles, comprising: 
 (A) preparing a first phase comprising a biodegradable and biocompatible polymer, a psychotherapeutic agent, and a solvent;    (B) preparing an aqueous phase;    (C) combining said first phase and said aqueous phase to form an emulsion in which said first phase is discontinuous and said aqueous phase is continuous;    (D) separating said discontinuous first phase from said continuous aqueous phase; and    (E) reducing a residual level of said solvent in said discontinuous first phase to less than about 2% by weight.    
   
   
       2 . The method of  claim 1 , wherein step (E) comprises: 
 washing said discontinuous first phase with an aqueous solution at a temperature in the range of from about 25° C. to about 40° C.    
   
   
       3 . The method of  claim 1 , wherein step (E) comprises: 
 washing said discontinuous first phase with an aqueous solvent system comprising water and a second solvent for said solvent.    
   
   
       4 . The method of  claim 1 , wherein said solvent is a solvent blend of at least two mutually miscible organic solvents.  
   
   
       5 . The method of  claim 2 , wherein said aqueous solution comprises water and a C 1 -C 4  alcohol.  
   
   
       6 . The method of  claim 5 , wherein said C 1 -C 4  alcohol is ethanol.  
   
   
       7 . The method of  claim 2 , wherein said aqueous solution is water.  
   
   
       8 . The method of  claim 3 , wherein said aqueous solvent system further comprises a C 1 -C 4  alcohol.  
   
   
       9 . The method of  claim 8 , wherein said C 1 -C 4  alcohol is ethanol.  
   
   
       10 . The method of  claim 1 , wherein step (C) is carried out using a static mixer.  
   
   
       11 . Microparticles prepared by the method of  claim 1 .  
   
   
       12 . Microparticles prepared by the method of  claim 1 , wherein said psychotherapeutic agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts of the foregoing.  
   
   
       13 . Microparticles prepared by the method of  claim 10 .  
   
   
       14 . The method of  claim 10 , wherein said psychotherapeutic agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts of the foregoing.  
   
   
       15 . Microparticles prepared by the method of  claim 14 .  
   
   
       16 . Microparticles prepared by the method of  claim 1 , wherein said 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.  
   
   
       17 . Microparticles prepared by the method of  claim 12 , wherein said 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.  
   
   
       18 . A method for preparing microparticles, comprising: 
 combining an organic phase and an aqueous phase in a static mixer to form an emulsion, wherein said organic phase comprises a biodegradable and biocompatible polymer, an active agent, and a solvent;    separating said organic phase from said aqueous phase; and    washing said organic phase with an ethanol wash to thereby reduce a residual level of said solvent in said organic phase to less than about 2% by weight.    
   
   
       19 . Microparticles prepared by the method of  claim 18 .  
   
   
       20 . Microparticles prepared by the method of  claim 18 , wherein said active agent comprises a basic moiety.  
   
   
       21 . Microparticles prepared by the method of  claim 18 , wherein said solvent is free from halogenated hydrocarbons.  
   
   
       22 . Microparticles prepared by the method of  claim 18 , wherein said solvent is a blend of ethyl acetate and benzyl alcohol.  
   
   
       23 . Microparticles prepared by the method of  claim 18 , wherein said solvent comprises ethyl acetate.  
   
   
       24 . Microparticles prepared by the method of  claim 18 , wherein said ethanol wash is an aqueous solution of 25% ethanol.  
   
   
       25 . Microparticles prepared by the method of  claim 18 , wherein said 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.