Method of producing submicron particles of a labile agent and use thereof

Abstract

The present invention relates to a sustained release composition comprising micron particles of labile agent and a method of preparing and using the sustained release composition. The invention further relates to micron particles of a labile agent and a method of preparing the micron particles. The method of the invention for preparing a composition for the sustained release of a labile agent, comprises forming a suspension comprising the labile agent dispersed in a polymer solution comprising at least one biocompatible polymer and at least one polymer solvent. The suspension is then wet milled to achieve micron particles of the labile agent. The polymer solvent is then removed resulting in a solid polymer/labile agent matrix. The composition for sustained release of a labile agent is likewise prepared according to the method of the invention. The sustained release composition of the present invention can be used in a method for providing a therapeutically effective blood level of a labile agent, in a subject in need of treatment with said agent, for a sustained period comprising administering to the subject the sustained release composition described herein. The method for preparing micron particles of a labile agent comprises forming a suspension comprising the labile agent, dispersed in a polymer solution comprising at least one biocompatible polymer and at least one polymer solvent, and wet milling of the suspension. The submicron particles of labile agent, as described herein, are prepared according to this method.

What is claimed is:  
     
         1 . A method for preparing a composition for the sustained release of a labile agent, comprising the steps of: 
 a) forming a suspension comprising the labile agent dispersed in a polymer solution comprising at least one biocompatible polymer and at least one polymer solvent;    b) wet milling the suspension to achieve submicron particles of the labile agent; and    c) removing the polymer solvent thereby forming a solid polymer/labile agent matrix.    
     
     
         2 . The method of  claim 1  wherein the submicron particles have a volume median particle size of less than 1 micron, measured by laser diffraction.  
     
     
         3 . The method of  claim 1  wherein step (b) is conducted at a temperature of less than about 30° C.  
     
     
         4 . The method of  claim 3  wherein the temperature is less than about 10° C.  
     
     
         5 . The method of  claim 3  wherein the temperature is less than about 4° C.  
     
     
         6 . The method of  claim 1  wherein the labile agent is present in the suspension at a concentration of from about 0.01 to about 50% w/w of the combined weight of polymer and labile agent.  
     
     
         7 . The method of  claim 6  wherein the labile agent is present at a concentration of about 0.01 to 30% w/w of the combined weight of the polymer and labile agent.  
     
     
         8 . The method of  claim 1  wherein the labile agent is a protein, polypeptide or oligonucleotide.  
     
     
         9 . The method of  claim 1  wherein the labile agent is a protein.  
     
     
         10 . The method of  claim 8  wherein the labile agent is complexed to a stabilizing metal cation.  
     
     
         11 . The method of  claim 10  wherein said stabilizing metal cation is selected from the group consisting of Zn +2 , Ca +2 , Cu +2 , Mg +2 , K +  and any combination thereof.  
     
     
         12 . The method of  claim 11  wherein said stabilizing metal cation is Zn +2 .  
     
     
         13 . The method of  claim 10  wherein the labile agent is human growth hormone.  
     
     
         14 . The method of  claim 13  wherein the human growth hormone is complexed to Zn +2 .  
     
     
         15 . The method of  claim 1  wherein the biocompatible polymer is biodegradable.  
     
     
         16 . The method of  claim 15  wherein the biodegradable polymer is selected from the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-coglycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, poly(caprolactone), polycarbonates, polyesteramides, polyanhydrides, poly(amino acid)s, poly(ortho ester)s, polycyanoacrylates, polyamides, polyacetals, poly(ether ester)s, copolymers of poly(ethylene glycol) and poly(ortho ester)s, poly(dioxanone)s, poly(alkylene alkylate)s, biodegradable polyurethanes, blends and copolymers thereof.  
     
     
         17 . The method of  claim 16  wherein said polymer is poly(lactide-co-glycolide).  
     
     
         18 . The method of  claim 15  wherein the biocompatible polymer is non-biodegradable.  
     
     
         19 . The method of  claim 1  wherein the polymer solvent is methylene chloride, chloroform, acetone, ethyl acetate, methyl acetate, dimethylsulfoxide, hexafluoroisopropanol or any combinations thereof.  
     
     
         20 . The method of  claim 1  wherein the composition for sustained release further comprises a metal cation component dispersed within the polymer wherein said metal cation component is added to the suspension after step (b) and before step (c), and which modulates the release of the labile agent.  
     
     
         21 . The method of  claim 20  wherein the metal cation component is selected from the group consisting of Mg(OH) 2 , MgCO 3 , CaCO 3 , ZnCO 3 , Mg(OAc) 2 , Zn(OAc) 2 , ZnSO 4 , MgCl 2 , ZnCl 2 , MgSO 4 , zinc citrate and magnesium citrate.  
     
     
         22 . A composition for the sustained release of a labile agent prepared by the method comprising the steps of: 
 a) forming a suspension comprising the labile agent dispersed in a polymer solution comprising at least one biocompatible polymer and at least one polymer solvent;    b) wet milling the suspension to achieve submicron particles of the labile agent; and    c) removing the polymer solvent thereby forming a solid polymer/labile agent matrix.    
     
     
         23 . The composition of  claim 22  wherein the submicron particles have a volume median particle size of less than 1 micron, measured by laser diffraction.  
     
     
         24 . The composition of  claim 22  wherein step (b) is conducted at a temperature of less than about 30° C.  
     
     
         25 . The composition of  claim 24  wherein the temperature is less than about 10° C.  
     
     
         26 . The composition of  claim 24  wherein the temperature is less than about 4° C.  
     
     
         27 . The composition of  claim 22  wherein the labile agent is present in the suspension at a concentration of from about 0.01 to about 50% w/w of the combined weight of polymer and labile agent.  
     
     
         28 . The composition of  claim 27  wherein the labile agent is present at a concentration of about 0.01 to 30% w/w of the combined weight of the polymer and labile agent.  
     
     
         29 . The composition of  claim 22  wherein the labile agent is a protein, polypeptide or oligonucleotide.  
     
     
         30 . The composition of  claim 22  wherein the labile agent is a protein.  
     
     
         31 . The composition of  claim 29  wherein the labile agent is complexed to a stabilizing metal cation.  
     
     
         32 . The composition of  claim 31  wherein said stabilizing metal cation is selected from the group consisting of Zn +2 , Ca +2 , Cu +2 , Mg +2 , K +  and any combination thereof.  
     
     
         33 . The composition of  claim 32  wherein said stabilizing metal cation is Zn +2 .  
     
     
         34 . The composition of  claim 31  wherein the labile agent is human growth hormone.  
     
     
         35 . The composition of  claim 34  wherein the human growth hormone is complexed to Zn +2 .  
     
     
         36 . The composition of  claim 22  wherein the biocompatible polymer is biodegradable.  
     
     
         37 . The composition of  claim 36  wherein the biodegradable polymer is selected from the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-coglycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, poly(caprolactone), polycarbonates, polyesteramides, polyanhydrides, poly(amino acid)s, poly(ortho ester)s, polycyanoacrylates, polyamides, polyacetals, poly(ether ester)s, copolymers of poly(ethylene glycol) and poly(ortho ester)s, poly(dioxanone)s, poly(alkylene alkylate)s, biodegradable polyurethanes, blends and copolymers thereof.  
     
     
         38 . The composition of  claim 37  wherein said polymer is poly(lactide-co-glycolide).  
     
     
         39 . The composition of  claim 22  wherein the biocompatible polymer is non-biodegradable.  
     
     
         40 . The composition of  claim 22  wherein the polymer solvent is methylene chloride, chloroform, acetone, ethyl acetate, methyl acetate, dimethylsulfoxide, hexafluoroisopropanol or any combinations thereof.  
     
     
         41 . The composition of  claim 41  wherein the metal cation component is selected from the group consisting of Mg(OH) 2 , MgCO 3 , CaCO 3 , ZnCO 3 , Mg(OAc) 2 , Zn(OAc) 2 , ZnSO 4 , MgCl 2 , ZnCl 2 , MgSO 4 , zinc citrate and magnesium citrate.