Residual solvent extraction method and microparticles produced thereby

Abstract

Methods for preparing microparticles having reduced residual solvent levels. Microparticles are contacted with a non-aqueous washing system to reduce the level of residual solvent in the microparticles. Preferred non-aqueous washing systems include 100% ethanol and a blend of ethanol and heptane. A solvent blend of a hardening solvent and a washing solvent can be used to harden and wash microparticles in a single step, thereby eliminating the need for a post-hardening wash step.

1 . A method for preparing microparticles, comprising: 
 preparing an emulsion comprising an aqueous peptide solution and a biodegradable, biocompatible polymer dissolved in a halogenated solvent;    combining the emulsion with a coacervating agent that is free from solvents for the polymer to form a combined phase;    extracting the halogenated solvent from the combined phase with an extraction medium that is a non-solvent for the polymer and a solvent for the halogenated solvent and the coacervating agent, whereby microparticles precipitate out of the extraction medium;    drying the precipitated microparticles to form finished microparticles; and    after said drying step, washing the finished microparticles in a non-aqueous washing system that is either (1) 100% ethanol or (2) a blend of ethanol and heptane to thereby reduce a level of residual halogenated solvent.    
     
     
         2 . The method of  claim 1 , wherein the peptide is a luteinizing-hormone-releasing hormone (LHRH) analogue.  
     
     
         3 . The method of  claim 2 , wherein the halogenated solvent is methylene chloride.  
     
     
         4 . The method of  claim 1 , wherein the blend is a 3:1 ratio of ethanol to heptane.  
     
     
         5 . The method of  claim 1 , wherein the blend is a 1:1 ratio of ethanol to heptane.  
     
     
         6 . The method of  claim 1 , wherein a temperature of the washing system is between about 10° and about 26° C.  
     
     
         7 . The method of  claim 3 , wherein the coacervating agent is silicone oil.  
     
     
         8 . The method of  claim 1 , wherein the halogenated solvent is methylene chloride.  
     
     
         9 . The method of  claim 1 , wherein the coacervating agent is silicone oil.  
     
     
         10 . The method of  claim 7 , wherein the extraction medium is heptane.  
     
     
         11 . The method of  claim 1 , wherein the extraction medium is heptane.  
     
     
         12 . The method of  claim 1 , wherein the biodegradable, biocompatible 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.  
     
     
         13 . The method of  claim 3 , wherein the biodegradable, biocompatible 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.  
     
     
         14 . The method of  claim 1 , wherein the washing step is carried out until the level of residual halogenated solvent in the washed microparticles is less than about 0.06% by weight.  
     
     
         15 . The method of  claim 3 , wherein the washing step is carried out until the level of residual halogenated solvent in the washed microparticles is less than about 0.06% by weight.  
     
     
         16 . The method of  claim 1 , further comprising after said washing step: 
 final drying the washed microparticles.    
     
     
         17 . A method for processing microparticles, comprising: 
 contacting dried, finished microparticles comprising a biodegradable, biocompatible polymer matrix comprising a peptide and a halogenated solvent with a non-aqueous washing system to thereby reduce a level of residual halogenated solvent in the dried, finished microparticles to form washed microparticles, wherein the washing system is either (1) 100% ethanol or (2) a blend of ethanol and heptane; and    recovering the washed microparticles from the washing system.    
     
     
         18 . The method of  claim 17 , wherein the peptide is a luteinizing-hormone-releasing hormone (LHRH) analogue.  
     
     
         19 . The method of  claim 18 , wherein the halogenated solvent is methylene chloride.  
     
     
         20 . The method of  claim 17 , wherein the blend is a 3:1 ratio of ethanol to heptane.  
     
     
         21 . The method of  claim 17 , wherein the blend is a 1:1 ratio of ethanol to heptane.  
     
     
         22 . The method of  claim 17 , wherein a temperature of the washing system is between about 10° and 26° C.  
     
     
         23 . The method of  claim 17 , wherein the contacting step is carried out until the level of residual halogenated solvent in the recovered microparticles is less than about 0.06% by weight.  
     
     
         24 . Microparticles prepared by the method of  claim 1 .  
     
     
         25 . The microparticles of  claim 24 , wherein the peptide is a luteinizing-hormone-releasing hormone (LHRH) analogue.  
     
     
         26 . A method for processing microparticles, comprising: 
 contacting dried, finished microparticles comprising a biodegradable, biocompatible polymer matrix comprising goserelin and a halogenated solvent with a non-aqueous washing system to thereby reduce a level of residual halogenated solvent to less than about 0.06% by weight of the dried, finished microparticles to form washed microparticles, wherein the washing system is either (1) 100% ethanol or (2) a blend of ethanol and heptane; and    recovering the washed microparticles from the washing system.    
     
     
         27 . A method for preparing microparticles, comprising: 
 preparing a first phase comprising a biodegradable, biocompatible polymer and a halogenated solvent;    preparing an aqueous second phase comprising a peptide;    combining the first phase and the second phase under the influence of a mixer to form an emulsion;    combining the emulsion with a coacervating agent that is free from solvents for the polymer to form a combined phase;    extracting the halogenated solvent from the combined phase with an extraction medium that is a non-solvent for the polymer and a solvent for the halogenated solvent and the coacervating agent, whereby microparticles precipitate out of the extraction medium;    drying the precipitated microparticles to form finished microparticles; and    after said drying step, washing the finished microparticles in a non-aqueous washing system that is either (1) 100% ethanol or (2) a blend of ethanol and heptane to thereby reduce a level of residual halogenated solvent.    
     
     
         28 . The method of  claim 27 , wherein the mixer is a static mixer.  
     
     
         29 . The method of  claim 27 , wherein the peptide is a luteinizing-hormone-releasing hormone analogue.  
     
     
         30 . The method of  claim 29 , wherein the halogenated solvent is methylene chloride.  
     
     
         31 . The method of  claim 27 , wherein the blend is a 3:1 ratio of ethanol to heptane.  
     
     
         32 . The method of  claim 27 , wherein the blend is a 1:1 ratio of ethanol to heptane.  
     
     
         33 . The method of  claim 27 , wherein a temperature of the washing system is between about 10° and about 26° C.  
     
     
         34 . The method of  claim 30 , wherein the coacervating agent is silicone oil.  
     
     
         35 . The method of  claim 27 , wherein the halogenated solvent is methylene chloride.  
     
     
         36 . The method of  claim 27 , wherein the coacervating agent is silicone oil.  
     
     
         37 . The method of  claim 34 , wherein the extraction medium is heptane.  
     
     
         38 . The method of  claim 27 , wherein the extraction medium is heptane.  
     
     
         39 . The method of  claim 27 , wherein the biodegradable, biocompatible 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.  
     
     
         40 . The method of  claim 30 , wherein the biodegradable, biocompatible 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.  
     
     
         41 . The method of  claim 27 , wherein the washing step is carried out until the level of residual halogenated solvent in the washed microparticles is less than about 0.06% by weight.  
     
     
         42 . The method of  claim 30 , wherein the washing step is carried out until the level of residual halogenated solvent in the washed microparticles is less than about 0.06% by weight.  
     
     
         43 . The method of  claim 2 , wherein the LHRH analogue is goserelin.  
     
     
         44 . The method of  claim 18 , wherein the LHRH analogue is goserelin.  
     
     
         45 . The method of  claim 29 , wherein the LHRH analogue is goserelin.  
     
     
         46 . A method for preparing microparticles, comprising: 
 preparing an emulsion comprising an aqueous peptide solution and a biodegradable, biocompatible polymer dissolved in a halogenated solvent;    combining the emulsion with a coacervating agent that is free from solvents for the polymer to form a combined phase;    extracting the halogenated solvent from the combined phase with an extraction medium that is a non-solvent for the polymer and a solvent for the halogenated solvent and the coacervating agent, whereby microparticles precipitate out of the extraction medium;    drying the precipitated microparticles to form finished microparticles; and    after said drying step, washing the finished microparticles in a non-aqueous washing system that comprises ethanol.    
     
     
         47 . A method for processing microparticles, comprising: 
 contacting dried, finished microparticles comprising a biodegradable, biocompatible polymer matrix containing an active agent and an organic solvent with a non-aqueous washing system to thereby reduce a level of residual organic solvent in the dried, finished microparticles to form washed microparticles, wherein the non-aqueous washing system is either (1) 100% ethanol or (2) a blend of ethanol and heptane; and    recovering the washed microparticles from the non-aqueous washing system.    
     
     
         48 . The method of  claim 47 , wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.  
     
     
         49 . The method of  claim 47 , wherein the active agent is a peptide.  
     
     
         50 . The method of  claim 48 , wherein the organic solvent is a solvent blend comprising ethyl acetate and benzyl alcohol.  
     
     
         51 . The method of  claim 49 , wherein the non-aqueous washing system is 100% ethanol.  
     
     
         52 . The method of  claim 47 , further comprising prior to said contacting step: 
 preparing an emulsion that comprises the active agent, the biodegradable, biocompatible polymer, and the organic solvent; and    extracting the organic solvent from the emulsion using an extraction liquid to thereby form microparticles containing the active agent.    
     
     
         53 . The method of  claim 47 , further comprising prior to said contacting step: 
 preparing a first phase that comprises the active agent, the biodegradable, biocompatible polymer, and the organic solvent, wherein the organic solvent is a solvent for the biodegradable, biocompatible polymer;    preparing a second phase that is free from solvents for the biodegradable, biocompatible polymer;    combining the first phase and the second phase to form an emulsion;    extracting the organic solvent from the emulsion using an extraction medium, whereby microparticles precipitate out of the extraction medium.    
     
     
         54 . The method of  claim 53 , wherein the extraction medium is a non-solvent for the biodegradable, biocompatible polymer and a solvent for the organic solvent.  
     
     
         55 . The method of  claim 49 , wherein the peptide is goserelin.  
     
     
         56 . The method of  claim 53 , wherein the second phase comprises silicone oil.  
     
     
         57 . A method for preparing microparticles, comprising: 
 preparing a first phase, the first phase comprising an active agent, a biodegradable, biocompatible polymer, and a solvent;    preparing a second phase, wherein the first phase is substantially immiscible with the second phase;    combining the first phase and the second phase to form an emulsion;    extracting solvent from the emulsion using an extraction liquid to thereby form microparticles containing the active agent;    drying the microparticles to form finished microparticles; and    after said drying step, washing the finished microparticles with a non-aqueous washing system to thereby reduce the level of residual solvent in the microparticles, wherein the non-aqueous washing system comprises ethanol.    
     
     
         58 . The method of  claim 57 , wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.  
     
     
         59 . The method of  claim 58 , wherein the solvent is a solvent blend comprising ethyl acetate and benzyl alcohol.  
     
     
         60 . A method for preparing microparticles, comprising: 
 preparing an emulsion comprising an aqueous peptide solution and a biodegradable, biocompatible polymer dissolved in a solvent;    combining the emulsion with a coacervating agent that is free from solvents for the polymer to form a combined phase;    extracting solvent from the combined phase in an extraction medium that is a non-solvent for the polymer and a solvent for the solvent and the coacervating agent, whereby microparticles precipitate out of the extraction medium;    drying the precipitated microparticles to form finished microparticles; and    after said drying step, washing the finished microparticles in 100% ethanol.    
     
     
         61 . The method of  claim 60 , wherein the peptide is goserelin.  
     
     
         62 . The method of  claim 60 , wherein the coacervating agent is silicone oil.  
     
     
         63 . The method of  claim 60 , wherein the extraction medium is heptane.  
     
     
         64 . The method of  claim 60 , wherein the washing step is carried out until the level of solvent in the microparticles is less than about 0.06% by weight.  
     
     
         65 . The method of  claim 57 , wherein the non-aqueous washing system is 100% ethanol.  
     
     
         66 . The method of  claim 47 , wherein the contacting step is carried out until the level of residual organic solvent is less than about 0.2% by weight.  
     
     
         67 . The method of  claim 50 , wherein the contacting step is carried out until the level of ethyl acetate is less than about 0.2% by weight and the level of benzyl alcohol is less than about 0.2% by weight.  
     
     
         68 . A method for processing microparticles, comprising: 
 contacting dried, finished microparticles comprising a biodegradable, biocompatible polymer matrix containing an active agent and an organic solvent with a non-aqueous washing system to thereby reduce a level of residual organic solvent in the dried, finished microparticles to form washed microparticles, wherein the non-aqueous washing system is either (1) 100% alcohol or (2) a blend of alcohol and a liquid alkane; and    recovering the washed microparticles from the non-aqueous washing system.    
     
     
         69 . The method of  claim 68 , wherein the active agent is a peptide.  
     
     
         70 . The method of  claim 69 , wherein the non-aqueous washing system is the blend of alcohol and a liquid alkane.