Non-aqueous polar aprotic peptide formulations

• US 6,235,712 B1
• Filed: 02/28/2000
• Issued: 05/22/2001
• Est. Priority Date: 07/03/1996
• Status: Expired due to Term

• Current Assignee: Horatio Washington Depot Technologies, LLC
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Stevenson, Cynthia L., Prestrelski, Steven J.
• Primary Examiner(s): DAVENPORT, AVIS MICHELLE
• Application Number:
  US09/514,951
• Time in Patent Office: 449 Days
• Field of Search: 514/11, 514/12, 530/300, 530/313, 530/317, 530/324
• US Class Current: 424/422
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 7/23 Luteinising hormone-releasing hormone [LHRH]; Related peptides

Abstract

This invention relates to stable non-aqueous polar aprotic formulations of peptide compounds. These stable formulations comprise peptide in non-aqueous polar aprotic solvent. They may be stored at elevated temperatures for long periods of time and are especially useful in implantable delivery devices for long term delivery of drug.

Claims

1. A method for preparing a stable non-aqueous formulation of an LHRH-related peptide compound, said compound comprising at least one LHRH-related peptide compound and at least one polar aprotic solvent, said method comprising dissolving at least one LHRH-related peptide compound in at least one polar aprotic solvent.

2. The method of claim 1, wherein at least about 10% (w/w) peptide compound is dissolved.

3. The method of claim 1 wherein at least about 30% (w/w) peptide compound is dissolved.

4. The method of claim 1 wherein said peptide compound is selected from the group consisting of leuprolide, LHRH, nafarelin and goserelin.

5. The method of claim 1 further comprising the step of adding a non-aqueous protic solvent.

6. The method of claim 1 wherein about 30% to about 50% (w/w) of the LHRH-related compound leuprolide acetate is dissolved in DMSO.

7. The method of claim 1 wherein 370 mg leuprolide is dissolved in 1 ml DMSO.

8. The method of claim 1 wherein said administration is parenteral administration.

9. The method of claim 1 wherein said administration is long-term continuous administration.

10. The method of claim 9 wherein said administration is accomplished by use of an implantable drug delivery device.

11. The method of claim 1 wherein said condition is prostatic cancer and said peptide compound is leuprolide.

12. The method of claim 11 wherein at least about 80 micrograms of leuprolide is administered daily.

13. The method of claim 12 wherein said daily administration continues for a period selected from the group consisting of 3 months, 6 months and 12 months.

14. The method of claim 13 wherein said daily administration for said period is continuous administration accomplished using an implantable drug delivery system.

16. The method of claim 1 wherein no components containing added water are added to the formulation.

17. The method of claim 1 which is conducted in an atmosphere of inert gas.

18. The method of claim 1 wherein said atmosphere is dry nitrogen.

19. The method of claim 1 wherein no conventional bacteriostatic, bactericidal or sporicidal agent is added to the formulation.

15. A method for treating a subject suffering from prostatic cancer by administration of an LHRH antagonist, said method comprising administering to said subject an effective amount of a stable non-aqueous formulation of an LHRH antagonist and at least one polar aprotic solvent.