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.

What is claimed is: 
     
         1 . Microparticles comprising a polypeptide comprising the amino acid of SEQ ID NO:17 prepared by a method 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 the amino acid sequence of 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 a composition containing polypeptide microparticles comprising the polypeptide is formed.   
     
     
         2 . The microparticles of  claim 1 , wherein the cooling rate is 0.5° C./min to 2° C./min. 
     
     
         3 . The microparticles of  claim 1 , wherein the cooling rate is 0.5° C./min to 1° C./min. 
     
     
         4 . The microparticles of  claim 1 , wherein the counterion is sodium citrate. 
     
     
         5 . The microparticles of  claim 1 , wherein the counterion is magnesium sulfate. 
     
     
         6 . The microparticles of  claim 1 , wherein the method of making further comprises cooling the composition containing polypeptide microparticles comprising the polypeptide to a temperature of between about −45° C. and about −80° C. 
     
     
         7 . The microparticles of  claim 1 , wherein step c) comprises cooling the second aqueous composition of (b) to a temperature between 2° C. and −20° C. degrees. 
     
     
         8 . The microparticles of  claim 1 , wherein step b) comprises adding isopropanol to about 10% v/v. 
     
     
         9 . The microparticles of  claim 1 , wherein step b) comprises adding isopropanol to about 20% v/v. 
     
     
         10 . The microparticles of  claim 1 , wherein wherein step b) comprises adding isopropanol to about 30% v/v. 
     
     
         11 . The microparticles of  claim 1 , wherein the method of making further comprises lyophilizing the composition containing polypeptide microparticles to obtain a dry powder. 
     
     
         12 . The microparticles of  claim 1 , wherein the diameter of the microparticles is between 0.5 μm and 10 μm. 
     
     
         13 . The composition of  claim 12 , wherein the diameter of the microparticles is between 0.5 μm or and 5.0 μm. 
     
     
         14 . A composition comprising microparticles of a polypeptide comprising the amino acid sequence of SEQ ID NO:17 and magnesium sulfate or sodium sulfate, wherein the microparticles have a diameter 
     
     
         15 . The microparticles of  claim 14 , wherein the diameter of the microparticles is between 0.5 μm and 10 μm. 
     
     
         16 . The composition of  claim 15 , wherein the diameter of the microparticles is between 0.5 μm or and 5.0 μm.