Non-aqueous single phase vehicles and formulations utilizing such vehicles

• US 20050276856A1
• Filed: 07/18/2005
• Published: 12/15/2005
• Est. Priority Date: 03/31/2003
• Status: Active Grant

• Current Assignee: DURECT Corporation
• Original Assignee: DURECT Corporation
• Inventors: Zlatkova-Karaslavova, Ekaterina S., Berry, Stephen A., Fereira, Pamela J., Rohloff, Catherine M., Desjardin, Michael A.
• Granted Patent: US 8,496,943 B2
• Time in Patent Office: Days
• US Class Current: 424/486
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas

Abstract

The present invention is related to materials and methods for forming polymeric delivery vehicles that reduces risk of oxidative degradation of a carried drug and the resulting compositions.

Claims

1. A method for reducing the level of peroxide in a biocompatible polymer preparation capable of forming a drug delivery vehicle comprising adding methionine to the biocompatible polymer preparation.

2. The method of claim 1, wherein the weight ratio of methionine to polymer following the addition of the methionine to the biocompatible polymer preparation is from 1 to 50 to 1 to 2.

3. The method of claim 1, wherein the polymer is water soluble.

4. The method of claim 3, further comprising solubilizing the water soluble polymer in water to form an aqueous solution.

5. The method of claim 4, wherein the aqueous solution comprises from 0.5% to 40% by unit weight of the water soluble polymer per unit volume of the aqueous solution.

6. The method of claim 4, wherein the weight ratio of methionine to polymer is from 1 to 50 to 1 to 2.

7. The method of claim 4, further comprising removing the methionine from the aqueous solution.

8. The method of claim 7, wherein the removing step comprises diafiltrating, dialyzing, or precipitating.

9. The method of claim 7, further comprising removing substantially all of the water from the aqueous solution following removal of the methionine.

10. The method of claim 9, wherein the removing substantially all step comprises lyophilizing, spray drying, drum drying, or fluid bed processing.

11. The method of claim 1, wherein the biocompatible polymer preparation comprises a polyvinylpyrrolidone, polyethylene glycol, or methyl cellulose.

12. The method of claim 1, wherein the polymer preparation comprises polyvinylpyrrolidone.

13. The method of claim 1, wherein the methionine is L-methionine.

14. The method of claim 1, wherein the biocompatible polymer preparation further comprises a solvent and forms a stable nonaqueous drug formulation comprising a drug, wherein the drug is insoluble in one or more components of the drug formulation and the drug is stable at 37°

C. for at least two months.

15. The method of claim 14, wherein about less than 35% of the drug is degraded by chemical pathways.

16. The method of claim 14, wherein about less than 15% of the drug is degraded through aggregation.

17. The method of claim 14, wherein the drug comprises a particulate material.

18. The method of claim 14, wherein the drug comprises medicines, vitamins, nutrients, or food supplements.

19. The method of claim 14, wherein the drug comprises a peptide or protein.

20. The method of claim 14, wherein the drug is selected from the group comprising an adrenocorticotropic hormone, angiotensin I and II, atrial natriuretic peptide, bombesin, bradykinin, calcitonin, cerebellin, dynorphin N, alpha and beta endorphin, endothelin, enkephalin, epidermal growth factor, fertirelin, follicular gonadotropin releasing peptide, galanin, glucagon, GLP-1, gonadorelin, gonadotropin, goserelin, growth hormone releasing peptide, histrelin, human growth hormone, insulin, interferons, leuprolide, LHRH, motilin, nafarerlin, neurotensin, oxytocin, relaxin, somatostatin, substance P, tumor necrosis factor, triptorelin, vasopressin, growth hormone, nerve growth factor, blood clotting factors, ribozymes, or antisense oligonucleotides, or combinations thereof.

21. The method of claim 14, wherein the biocompatible polymer preparation comprises a polyester, pyrrolidone, polyethylene glycol, methyl cellulose, ester of unsaturated alcohols, ether of unsaturated alcohols, or polyoxyethylene/polyoxypropylene block copolymer, or combinations thereof.

22. The method of claim 14, wherein the solvent is selected from the group comprising glycofurol, tetraglycol, n-methylpyrrolidone, glycerol formal, glycerine, or propylene glycol, or combinations thereof.

23. The method of claim 14, wherein the drug formulation exhibits peroxide levels below 5 ppm.

24. The method of claim 14, wherein the drug is dispersed within the drug delivery vehicle as a suspension.

25. An aqueous solution comprising:

a biocompatible polymer, and

methionine, which is added to the biocompatible polymer in an amount that yields a weight ratio of methionine to polymer from 1 to 50 to 1 to 2;

wherein the biocompatible polymer comprises polyvinylpyrrolidone, polyethylene glycol, or methyl cellulose.

26. The aqueous solution of claim 25 further comprising a drug.

27. The aqueous solution of claim 25, wherein the biocompatible polymer is from 0.5% to 40% unit weight per unit volume of the aqueous solution.

28. The aqueous solution of claim 25, wherein the methionine is L-methionine.

29. The aqueous solution of claim 25, wherein the biocompatible polymer comprises polyvinylpyrrolidone.

30. A stable nonaqueous drug formulation comprising:

a biocompatible polymer;

a solvent;

methionine, provided that the weight ratio of methionine to polymer is from 1 to 50 to 1 to 2; and

a drug;

wherein the drug is insoluble in the polymer or the solvent and the drug formulation is stable at 37°

C. for at least two months.

31. The drug formulation of claim 30, wherein the biocompatible polymer comprises polyvinylpyrrolidone, polyethylene glycol, or methyl cellulose.

32. The drug formulation of claim 30, wherein less than about 35% of the drug is degraded by chemical pathways.

33. The drug formulation of claim 30, wherein less than about 15% of the drug is degraded through aggregation.

34. The drug formulation of claim 30, wherein the drug comprises a particulate material.

35. The drug formulation of claim 30, wherein the drug comprises medicines, vitamins, nutrients, or food supplements.

36. The drug formulation of claim 30, wherein the drug comprises a peptide or protein.

37. The drug formulation of claim 30, wherein the drug is selected from the group consisting of adrenocorticotropic hormone, angiotensin I and II, atrial natriuretic peptide, bombesin, bradykinin, calcitonin, cerebellin, dynorphin N, alpha and beta endorphin, endothelin, enkephalin, epidermal growth factor, fertirelin, follicular gonadotropin releasing peptide, galanin, glucagon, GLP-1, gonadorelin, gonadotropin, goserelin, growth hormone releasing peptide, histrelin, human growth hormone, insulin, interferons, leuprolide, LHRH, motilin, nafarerlin, neurotensin, oxytocin, relaxin, somatostatin, substance P, tumor necrosis factor, triptorelin, vasopressin, growth hormone, nerve growth factor, blood clotting factors, ribozymes, and antisense oligonucleotides.

38. The drug formulation of claim 30, wherein the solvent is comprises glycofurol, tetraglycol, n-methylpyrrolidone, glycerol formal, glycerine, or propylene glycol, or combinations thereof.

39. The drug formulation of claim 30, wherein the drug formulation is delivered via an implantable device.

40. The drug formulation of claim 39, wherein the drug formulation is delivered over an extended period of time.

41. The drug formulation of claim 40, wherein the extended period of time is from about one week to about one year.