US2003138491A1PendingUtilityA1

Microencapsulation and sustained release of biologically active acid-stable or free sulfhydryl-containing proteins

56
Assignee: ALKERMES INCPriority: Feb 10, 2000Filed: Aug 13, 2002Published: Jul 24, 2003
Est. expiryFeb 10, 2020(expired)· nominal 20-yr term from priority
Inventors:Mark TracyKevin L. WardDavid S. ScherJ. Keith Johnson
A61K 47/34A61K 9/1647A61K 38/215
56
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Claims

Abstract

This invention relates to sustained release compositions, and methods of forming and using said compositions, for the sustained release of biologically active acid-stable or free sulfhydryl-containing proteins, in particular β-IFN. The sustained release composition of this invention comprises a biocompatible polymer having dispersed therein a stabilized biologically active acid-stable or free sulfhydryl-containing protein formulation and a nonionic polymer surfactant. The method of the invention, for forming a composition for the sustained release of biologically active acid-stable or free sulfhydryl-containing protein, in particular β-IFN, includes dissolving a polymer in a polymer solvent to form a polymer solution, adding a stabilized biologically active acid-stable or free sulfhydryl-containing protein formulation and a nonionic surfactant to the polymer solution, and then solidifying the polymer to form a polymer matrix containing the stabilized biologically active acid-stable or free sulfhydryl-containing protein formulation, and a nonionic surfactant. The method of using the sustained release composition of the present invention comprises providing a therapeutically effective blood level of biologically active acid-stable or free sulfhydryl-containing protein in a subject for a sustained period by administering to the subject a dose of the sustained release composition described herein.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . A composition for the sustained release of biologically active acid-stable or free sulfhydryl-containing protein comprising: 
 a) a biocompatible polymer;    b) a stabilized biologically active acid-stable or free sulfhydryl-containing protein formulation comprising at least one biologically active acid-stable or free sulfhydryl-containing protein, at least one disaccharide and at least one acidic excipient; and    c) surfactant    wherein said biologically active protein formulation and said surfactant are dispersed within the biocompatible polymer.    
     
     
         2 . The sustained release composition of  claim 1  wherein the biologically active acid-stable or free sulfhydryl-containing protein is β-IFN.  
     
     
         3 . The sustained release composition of  claim 2  wherein the β-IFN is present in the stabilized formulation from about 0.5% (w/w) to about 50% (w/w) of the dry weight of the formulation.  
     
     
         4 . The sustained release composition of  claim 3  wherein the β-IFN is present in a range from about 0.5% (w/w) to about 30% (w/w) of the dry weight of the formulation.  
     
     
         5 . The sustained release composition of  claim 1  wherein the acidic excipient is an organic acid.  
     
     
         6 . The sustained release composition of  claim 5  wherein the organic acid is selected form the group consisting of: citric acid, ascorbic acid, acetic acid, ethylenediaminetetraacetic acid, saturated fatty acids, dicarboxylic acids, bile acids, amino acids and combinations thereof.  
     
     
         7 . The sustained release composition of  claim 6  wherein the organic acid is an acidic amino acid.  
     
     
         8 . The sustained release composition of  claim 7  wherein the acidic amino acid is glutamic acid, aspartic acid or a combination thereof.  
     
     
         9 . The sustained release composition of  claim 1  wherein the disaccharide is selected from the group consisting of: sucrose, trehalose and combinations thereof.  
     
     
         10 . The sustained release composition of  claim 1  wherein the surfactant is selected from the group consisting of: poloxamers, polysorbates, polyethyleneglycols, polyoxyethlene fatty acid esters, bile salts, benzalkonium chloride, polyoxyethylene (40) monostearate and combinations thereof.  
     
     
         11 . The sustained release composition of  claim 1  further comprising an acidic excipient which is separately dispersed within the biocompatible polymer.  
     
     
         12 . The sustained release composition of  claim 10  wherein the poloxamer is selected from the group consisting of: poloxamer 407, poloxamer 188, and combinations thereof.  
     
     
         13 . The sustained release composition of  claim 10  wherein the polysorbate is selected from the group consisting of: polysorbate 80, polysorbate 20 and combinations thereof.  
     
     
         14 . The sustained release composition of  claim 1  wherein the biologically active protein is present from about 0.01%(w/w) to about 30% (w/w) of the total weight of the sustained release composition.  
     
     
         15 . The sustained release composition of  claim 14  wherein the protein is present from about 0.5% (w/w) to about 5% (w/w) of the total weight of the sustained release composition.  
     
     
         16 . The sustained release composition of  claim 1  wherein the stabilized biologically active acid-stable or free sulfhydryl-containing protein formulation further comprises a water soluble polymer.  
     
     
         17 . The sustained release composition of  claim 16  wherein the water soluble polymer is a polysaccharide.  
     
     
         18 . The sustained release composition of  claim 17  wherein the polysaccharide is selected from the group consisting of: methyl cellulose, ethylcellulose, ficoll, and combinations thereof.  
     
     
         19 . The sustained release composition of  claim 16  wherein the water soluble polymer is a polymer surfactant.  
     
     
         20 . The sustained release composition of  claim 19  wherein the polymer surfactant is nonionic.  
     
     
         21 . The sustained release composition of  claim 20  wherein the nonionic surfactant is selected from the group consisting of: poloxamers, polysorbates, polyethyleneglycol, polyoxyethlene fatty acid esters and combinations thereof.  
     
     
         22 . The sustained release composition of  claim 21  wherein the poloxamer is selected from the group consisting of: poloxamer 188, poloxamer 407 and combinations thereof.  
     
     
         23 . The sustained release composition of  claim 21  wherein the polysorbate is selected from the group consisting of: polysorbate 80, polysorbate 20 and combinations thereof.  
     
     
         24 . The sustained release composition of  claim 1  wherein the biocompatible polymer is selected from the group consisting of poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polycyanoacrylates, poly(p-dioxanone), poly(alkylene oxalate)s, biodegradable polyurethanes, blends thereof and copolymers thereof.  
     
     
         25 . The sustained release composition of  claim 24  wherein said polymer comprises poly(lactide-co-glycolide).  
     
     
         26 . The sustained release composition of  claim 1  further comprising a multivalent metal cation component dispersed within the biocompatible polymer.  
     
     
         27 . A method for providing a therapeutically effective amount of a biologically active acid-stable or free sulfhydryl-containing protein in a subject for a sustained period comprising administering to the subject a dose of the sustained release composition of  claim 1 .  
     
     
         28 . A method for forming a composition for the sustained release of a biologically active acid-stable or free sulfhydryl-containing protein, comprising the steps of: 
 a) dissolving a biocompatible polymer in a polymer solvent to form a polymer solution;    b) adding at least one surfactant and a stabilized biologically active acid-stable or free sulfhydryl-containing protein formulation comprising: at least one biologically active acid-stable or free sulfhydryl-containing protein; at least one disaccharide; and at least one acidic excipient, to the polymer solution; and    c) solidifying the biocompatible polymer to form a polymer matrix containing the stabilized biologically active protein formulation and the surfactant dispersed therein.    
     
     
         29 . The method of  claim 28  wherein the biologically active acid-stable or free sulfhydryl-containing protein is β-IFN.  
     
     
         30 . The method of  claim 29  wherein the β-IFN is present in the stabilized formulation from about 0.5% (w/w) to about 50% (w/w) of the dry weight of the formulation.  
     
     
         31 . The method of  claim 30  wherein the β-IFN is present in a range from about 0.5% (w/w) to 30% (w/w) of the dry weight of the formulation.  
     
     
         32 . The method of  claim 28  wherein the acidic excipient is an organic acid.  
     
     
         33 . The method of  claim 32  wherein the organic acid is selected form the group consisting of: citric acid, ascorbic acid, acetic acid, ethylenediaminetetraacetic acid, saturated fatty acids, dicarboxylic acids, bile acids, and combinations thereof.  
     
     
         34 . The method of  claim 33  wherein the organic acid is an acidic amino acid.  
     
     
         35 . The method of  claim 34  wherein the acidic amino acid is glutamic acid, aspartic acid or a combination thereof.  
     
     
         36 . The method of  claim 28  wherein the disaccharide is selected from the group consisting of: sucrose, trehalose and combinations thereof.  
     
     
         37 . The method of  claim 28  wherein the surfactant is selected from the group consisting of: poloxamers, polysorbates, polyethylene glycol, polyoxyethlene fatty acid esters, bile salts, benzalkonium chloride and combinations thereof.  
     
     
         38 . The method of  claim 37  wherein the poloxamer is selected from the group consisting of: poloxamer 407, poloxamer 188 and combinations thereof.  
     
     
         39 . The method of  claim 37  wherein the polysorbate is selected from the group consisting of: polysorbate 80, polysorbate 20 and combinations thereof.  
     
     
         40 . The method of  claim 28  wherein the biologically active acid-stable or free sulfhydryl-containing protein is present from about 0.01%(w/w) to about 30% (w/w) of the total weight of the sustained release composition.  
     
     
         41 . The method of  claim 40  wherein the protein is present from about 0.5% (w/w) to about 5% (w/w) of the total weight of the composition.  
     
     
         42 . The method of  claim 30  wherein the stabilized biologically active β-IFN formulation further comprises a water soluble polymer.  
     
     
         43 . The method of  claim 42  wherein the water soluble polymer is a polysaccharide.  
     
     
         44 . The method of  claim 43  wherein the polysaccharide is selected from the group consisting of: methyl cellulose, ethyl cellulose, ficoll and combinations thereof.  
     
     
         45 . The method of  claim 42  wherein the water soluble polymer is a polymer surfactant.  
     
     
         46 . The method of  claim 45  wherein the polymer surfactant is nonionic.  
     
     
         47 . The method of  claim 46  wherein the nonionic surfactant is selected from the group consisting of: poloxamers, polysorbates, polyethyleneglycol, polyoxyethylene fatty acid esters, and combinations thereof.  
     
     
         48 . The method of  claim 47  wherein the poloxamer is selected from the group consisting of: poloxamer 407, poloxamer 188, and combinations thereof.  
     
     
         49 . The method of  claim 47  wherein the polysorbate is selected from the group consisting of: polysorbate 80, polysorbate 20, and combinations thereof.  
     
     
         50 . The method of  claim 28  wherein the biocompatible polymer is selected from the group consisting of poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polycyanoacrylates, poly(p-dioxanone), poly(alkylene oxalate)s, biodegradable polyurethanes, blends thereof and copolymers thereof.  
     
     
         51 . The method of  claim 50  wherein said polymer comprises poly(lactide-co-glycolide).  
     
     
         52 . The method of  claim 28  further comprising the step of adding a multivalent metal cation component to the polymer solution.

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