Claims
- 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.
RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser. No. 09/501,934, filed Feb. 10, 2000. The entire teachings of the above application are incorporated herein by reference.
Continuations (1)
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Number |
Date |
Country |
Parent |
09501934 |
Feb 2000 |
US |
Child |
10217953 |
Aug 2002 |
US |