Technology for preparation of macromolecular microspheres

Abstract

Microspheres are produced by contacting an aqueous solution of a protein or other macromolecule with an organic solvent and a counterion, and chilling the solution. The microspheres are useful for preparing pharmaceuticals of defined dimensions.

1 - 141 . (canceled) 
     
     
         142 . Microparticles comprising a polypeptide comprising SEQ ID NO:17, prepared by a process comprising:
 a) adding a counterion selected from the group consisting of sodium citrate, sodium sulfate, calcium sulfate, potassium sulfate and magnesium sulfate to an aqueous solution comprising a polypeptide comprising SEQ ID NO:17, whereby an aqueous composition is formed;   b) adding isopropanol to the aqueous composition of (a) whereby a second aqueous composition is formed; and   c) cooling the second aqueous composition of (b) at a rate of 0.1° C./min to 10° C./min to a temperature between 4° C. and −45° C., whereby microparticles comprising a polypeptide compromising SEQ ID NO: 17 are formed.   
     
     
         143 . The microparticles of  claim 142  wherein step c) of the method comprises cooling the second aqueous composition of (b) at a rate of 0.5° C./min to 2° C./min. 
     
     
         144 . The microparticles of  claim 142  wherein step c) of the method comprises cooling the second aqueous composition of (b) at a rate of 0.5° C./min to 1° C./min. 
     
     
         145 . The microparticles of  claim 142  wherein the counterion is sodium sulfate. 
     
     
         146 . The microparticles of  claim 142  wherein the counterion is magnesium sulfate. 
     
     
         147 . The microparticles of  claim 142  wherein the method further comprises cooling the composition containing microparticles comprising a polypeptide compromising SEQ ID NO: 17 to a temperature of between about −45° C. and about −80° C. 
     
     
         148 . The microparticles of  claim 142  wherein step c) of the method comprises cooling the second aqueous composition of (b) to a temperature between 2° C. and −20° C. degrees. 
     
     
         149 . The microparticles of  claim 142  wherein step b) of the method comprises adding isopropanol to about 10% v/v. 
     
     
         150 . The microparticles of  claim 142  wherein step b) of the method comprises adding isopropanol to about 20% v/v. 
     
     
         151 . The microparticles of  claim 142  wherein step b) of the method comprises adding isopropanol to about 30% v/v. 
     
     
         152 . The microparticles of  claim 142  wherein the method further comprises lyophilizing the composition containing microparticles to obtain a dry powder. 
     
     
         153 . The microparticles of  claim 142  wherein the microparticles comprise a counterion selected from the group consisting of: sodium citrate, sodium sulfate, calcium sulfate, potassium sulfate and magnesium sulfate. 
     
     
         154 . A pharmaceutical composition comprising the microparticles of  claim 142  and a pharmaceutically acceptable carrier or excipient. 
     
     
         155 . Microparticles comprising a protein comprising SEQ ID NO:17 and a counterion selected from the group consisting of: sodium citrate, sodium sulfate, calcium sulfate, potassium sulfate and magnesium sulfate. 
     
     
         156 . The microparticles of  claim 155  further comprising a sugar selected from the group consisting of: sorbitol, mannitol, trehalose and sucrose. 
     
     
         157 . The microparticles of  claim 155  having an average diameter, as determined by laser diffraction, between 1 and 5 microns.