Soluble, Stable Insulin-Containing Formulations with a Protamine Salt

• US 20110046049A1
• Filed: 11/21/2005
• Published: 02/24/2011
• Est. Priority Date: 11/22/2004
• Status: Active Grant

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Olsen, Helle Birk, Kaarsholm, Niels Christian, Balschmidt, Per
• Granted Patent: US 8,263,551 B2
• Time in Patent Office: Days
• US Class Current: 514/5.9
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• 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 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

The present invention relates to pharmaceutical formulations comprising insulin, an insulin analog, an insulin derivative, or a combination of any of the foregoing, and a salt of protamine, to methods of preparing such formulations, and to uses of such formulations in the treatment of diseases and conditions for which use of the insulin peptide(s) contained in such formulations is indicated. The present invention further relates to methods for increasing the stability and/or solubility of insulin in insulin-containing formulations at a pH less than 7.0 by adding a salt of protamine to the insulin-containing formulations.

Claims

1. A pharmaceutical formulation which is a solution comprising an insulin, an insulin analog or an insulin derivative or a mixture thereof and a protamine salt, wherein said protamine salt is present in said formulation in a concentration of greater than 0.25 mM and wherein said formulation has a pH of less than about 7.0.

2. The formulation according to claim 1, wherein the molar ratio of protamine salt to insulin is from about 0.5 to about 100.

3. The formulation according to claim 2, wherein the molar ratio of protamine salt to insulin is from about 0.5 to about 10.

4. The formulation according to claim 3, wherein the molar ratio of protamine salt to insulin is from about 0.5 to 5.

5. The formulation according to claim 1, wherein the pH of said formulation is from about 4.0 to about 7.0.

6. The formulation according to claim 5, wherein the pH of said formulation is from about 4.0 to about 6.5.

7. The formulation according to claim 6, wherein the pH of said formulation is from about 4.5 to about 6.0.

8. The formulation according to claim 1, further comprising a preservative.

9. The formulation according to claim 8, wherein the preservative is m-cresol.

10. The formulation according to claim 1, further comprising an isotonicity agent.

11. The formulation according to claim 10, wherein the isotonicity agent is glycerol.

12. The formulation according to claim 1, further comprising a divalent metal ion.

13. The formulation according to claim 12, wherein the divalent metal ion is zinc.

14. The formulation according to claim 1, further comprising a surfactant.

15. The formulation according to claim 14, wherein the surfactant is TWEEN®

20.

16. The formulation according to claim 1, wherein said insulin is human insulin.

17. The formulation according to claim 1, wherein said insulin is a human insulin analog.

18. The formulation according to claim 1, wherein said insulin is a human insulin derivative.

19. A method of treating type 1 or type 2 diabetes, said method comprising administering to a patient in need of such treatment an effective amount of a formulation according to claim 1.

20. The formulation according to claim 1, wherein the protamine salt is selected from the group consisting of propionate, lactate, formiate, nitrate and acetate salts of protamine.

21. The formulation according to claim 20, wherein the protamine salt is protamine acetate.

22. The formulation according to claim 20, wherein the insulin is human insulin.

23. The formulation according to claim 20, further comprising a divalent metal ion.

24. The formulation according to claim 20, further comprising a preservative.

25. The formulation according to claim 20, further comprising an isotonicity agent.

26. The formulation according to claim 20, further comprising a surfactant.

27. The formulation according to claim 1, wherein said formulation is soluble at a pH of less than about 7.0.

28. A method of treating type 1 or type 2 diabetes, said method comprising administering to a patient in need of such treatment an effective amount of a formulation according to claim 20.

30. The formulation according to claim 20, wherein said formulation is soluble at a pH of less than about 7.0.

29. (canceled)