Non-aqueous single phase vehicles and formulations utilizing such vehicles

• US 8,496,943 B2
• Filed: 07/18/2005
• Issued: 07/30/2013
• Est. Priority Date: 03/31/2003
• Status: Expired due to Fees

• Current Assignee: DURECT Corporation
• Original Assignee: DURECT Corporation
• Inventors: Fereira, Pamela J., Desjardin, Michael A., Rohloff, Catherine M., Berry, Stephen A., Zlatkova-Karaslavova, Ekaterina S.
• Primary Examiner(s): BREDEFELD, RACHAEL EVA
• Application Number:
  US11/183,477
• Publication Number:
  US 20050276856A1
• Time in Patent Office: 2,934 Days
• Field of Search: 424/400, 424/486, 424/489
• US Class Current: 424/400
• 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 present in a biocompatible polymer and forming a drug delivery formulation, said method comprising:

solubilizing the biocompatible polymer in water to form an aqueous solution, wherein the biocompatible polymer is water soluble;

combining methionine with the aqueous solution comprising the biocompatible polymer to obtain a polymer preparation having a reduced level of peroxide;

removing substantially all of the water from the polymer preparation;

combining the polymer preparation with a solvent to form a drug delivery vehicle solution;

combining the drug delivery vehicle solution with a drug to form a drug delivery formulation comprising the drug suspended in the drug delivery vehicle solution and wherein the drug delivery formulation is nonaqueous.

2. The method of claim 1, wherein about less than 35% of the drug in the drug delivery formulation is degraded by oxidation, deamidation, and hydrolysis after maintenance of the formulation at 37°

C. for a period of two months.

3. The method of claim 1, wherein about less than 15% of the drug in the drug delivery formulation is degraded through aggregation after maintenance of the formulation at 37°

C. for a period of two months.

4. The method of claim 1, wherein the drug is a particulate material.

5. The method of claim 1, wherein the drug is medicines, vitamins, nutrients, or food supplements.

6. The method of claim 1, wherein the drug is a peptide or protein.

7. The method of claim 1, wherein the drug is at least one member selected from adrenocorticotropic hormone, angiotensin I, angiotension II, atrial natriuretic peptide, bombesin, bradykinin, calcitonin, cerebellin, dynorphin, alpha endorphin, beta endorphin, endothelin, enkephalin, epidermal growth factor, fertirelin, follicular gonadotropin releasing peptide, galanin, glucagon, glucagon-like-peptide-1 (GLP-1), gonadorelin, gonadotropin, goserelin, growth hormone releasing peptide, histrelin, human growth hormone, insulin, interferons, leuprolide, luteinizing hormone-releasing hormone (LHRH), motilin, nafarelin, neurotensin, oxytocin, relaxin, somatostatin, substance P, tumor necrosis factor, triptorelin, vasopressin, growth hormone, nerve growth factor, blood clotting factors, ribozymes, and antisense oligonucleotides.

8. The method of claim 1, wherein the biocompatible polymer is selected from a polyester, pyrrolidone, ester of unsaturated alcohols, ether of unsaturated alcohols, polyoxyethylenepolyoxypropylene block copolymer, or combinations thereof.

9. The method of claim 1, wherein the solvent is at least one member selected from glycofurol, tetraglycol, n-methylpyrrolidone, glycerol formal, glycerine, and propylene glycol.

10. The method of claim 1, wherein the drug formulation exhibits peroxide levels below 5 ppm.

11. The method of claim 1, further comprising removing the methionine before removing substantially all of the water from the polymer preparation.

12. The method of claim 11, wherein the removing step of methionine comprises diafiltrating.

13. The method of claim 1, wherein removing substantially all of the water from the polymer preparation comprises lyophilizing.

14. The method of claim 1, wherein the polymer is polyvinylpyrrolidone.

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

16. The method of claim 1, wherein the drug delivery vehicle solution has a viscosity ranging from about 1000 poise to about 10,000,000 poise.

17. The method of claim 1, wherein the polymer ranges from about 40 wt % to about 80 wt %, based on the drug delivery vehicle solution.

18. The method of claim 1, wherein the solvent ranges from about 20 wt % to about 60 wt %, based on the drug delivery vehicle solution.

19. The method of claim 1, wherein the drug is stable in the drug delivery formulation at 37°

C. for at least two months.