Sustained-release microspheres and methods of making and using same

Abstract

Provided, among other things, are compositions and methods for making sustained-release microspheres, as well as a microsphere delivery system for the sustained release of an active agent. The microsphere delivery system comprises a homogenous mixture of biodegradable polymer, active agent, and a so-called release-modifying agent (including a pH-stabilizing agent), and provides protected and sustained release of active agents from the microsphere delivery system. According to the invention, the microspheres preferably are produced by an oil-in-water emulsion method that involves the production of a homogeneous oil phase prepared by mixing active agent and a release-modifying agent, such as arginine, with biodegradable polymer, each dissolved in organic solvent. The homogeneous oil phase desirably is then dispersed in an aqueous phase containing an emulsifying agent, followed by solvent removal, to produce the microspheres in which the active agent and release-modifying agent are distributed homogeneously throughout the biodegradable polymer matrix.

1 - 42 . (canceled) 
     
     
         43 . A microsphere delivery system prepared by a process comprising:
 (a) dissolving a biodegradable polymer in a first organic solvent that is immiscible with water to produce a first mixture;   (b) dissolving an active agent in a second organic solvent that is miscible with water to produce a second mixture, wherein the active agent is a protein or a peptide;   (c) producing a third mixture by separately dissolving a basic amino acid in either (i) a third organic solvent that is miscible with water, or (ii) a mixture of said second organic solvent and said third organic solvent, wherein said basic amino acid is selected from the group consisting of arginine, lysine, and histidine, and wherein said second organic solvent and said third organic solvent are different;   (d) mixing together said first mixture, said second mixture and said third mixture to prepare a homogeneous organic dispersed phase;   (e) emulsifying said homogeneous organic dispersed phase to produce microdroplets; and   (f) removing said first organic solvent, said second organic solvent, and said third organic solvent from said microdroplets to produce said microspheres,   thereby producing said microsphere delivery system.   
     
     
         44 . The delivery system according to  claim 43 , wherein said first solvent comprises dichloromethane or chloroform. 
     
     
         45 . The delivery system according to  claim 43 , wherein said second solvent comprises methanol or ethanol. 
     
     
         46 . The delivery system according to  claim 43 , wherein said third solvent comprises acetic acid and methanol. 
     
     
         47 . The delivery system according to  claim 43 , wherein step (c) further comprises dissolving an organic acid in the third organic solvent or the mixture of said second organic solvent and said third organic solvent. 
     
     
         48 . The delivery system according to  claim 43 , wherein step (c) further comprises dissolving glacial acetic acid in the third organic solvent or the mixture of said second organic solvent and said third organic solvent. 
     
     
         49 . The delivery system according to  claim 43 , wherein the emulsification is done in an aqueous continuous phase comprising a surfactant. 
     
     
         50 . The delivery system according to  claim 43 , wherein the emulsification is done in an aqueous continuous phase comprising polyvinyl alcohol in water. 
     
     
         51 . The delivery system according to  claim 43 , wherein said first organic solvent, said second organic solvent, and said third organic solvent are removed by extraction and evaporation. 
     
     
         52 . The delivery system according to  claim 43 , wherein said first organic solvent, said second organic solvent, and said third organic solvent are removed by increasing the temperature of said microdroplets to from about 30° C. to about 45° C., and stirring for from about 30 minutes to about 360 minutes. 
     
     
         53 . The delivery system according to  claim 43 , wherein said biodegradable polymer is selected from the group consisting of polylactic acid, polyglycolic acid, and copolymers of lactic acid and glycolic acid. 
     
     
         54 . The delivery system according to  claim 43 , wherein the amount of said basic amino acid comprises from about 0.1 to 1.0% (w/w) of said microsphere delivery system. 
     
     
         55 . The delivery system according to  claim 43 , wherein said basic amino acid is L-arginine. 
     
     
         56 . The delivery system according to  claim 43 , further comprising recovering said microspheres. 
     
     
         57 . The delivery system according to  claim 56 , wherein said microspheres are recovered by filtration. 
     
     
         58 . A pharmaceutical formulation comprising the delivery system according to claim  1  and a pharmaceutically acceptable carrier therefor. 
     
     
         59 . The pharmaceutical formulation according to  claim 58 , wherein said active agent is selected from the group consisting of hormones, antibiotics, antineoplastics, anesthetics, anti-psychotics, anticoagulants, vasoactive agents, neuroactive agents, immunomodulating agents, antivirals, antibodies, and antigens. 
     
     
         60 . The pharmaceutical formulation according to  claim 58 , wherein said active agent is selected from the group consisting of goserelin, salmon calcitonin, leuprolide, and octreotide. 
     
     
         61 . A microsphere delivery system for sustained release of an active agent, said delivery system comprising a biodegradable polymer, an active agent, and a release-modifying agent wherein said active agent and release modifying agent are evenly distributed in and throughout said polymer's matrix, and wherein said release-modifying agent stabilizes said active agent and enhances its sustained release. 
     
     
         62 . A process for preparing a microsphere delivery system comprising: (a) dissolving a biodegradable polymer in a first organic solvent that is immiscible with water to produce a first mixture; (b) dissolving an active agent in a second organic solvent that is miscible with water to produce a second mixture; (c) producing a third mixture by separately dissolving a release-modifying agent in either (i) a third organic solvent that is miscible with water, or (ii) a mixture of said second organic solvent and said third organic solvent; (d) mixing together said first mixture, said second mixture and said third mixture to prepare a homogeneous organic dispersed phase; (e) emulsifying said homogeneous organic dispersed phase to produce microdroplets; and (f) removing said first organic solvent, said second organic solvent, and said third organic solvent from said microdroplets to produce said microspheres.