Zinc-free and low-zinc insulin preparations having improved stability

• US 7,696,162 B2
• Filed: 10/06/2008
• Issued: 04/13/2010
• Est. Priority Date: 03/23/2001
• Status: Expired due to Term

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Inventors: Boderke, Peter
• Primary Examiner(s): Russel; Jeffrey E
• Application Number:
  US12/285,464
• Publication Number:
  US 20090186807A1
• Time in Patent Office: 554 Days
• Field of Search: None
• US Class Current: 514/1.1
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• 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 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/48 of the pancreatic hormones

Abstract

The invention relates to a formulation comprising a polypeptide selected from at least one of insulin, an insulin metabolite, an insulin analog, and an insulin derivative; at least one surfactant; optionally at least one preservative; and optionally at least one of an isotonicizing agent, a buffer or an excipient, wherein the formulation is free from or low in zinc. The invention also relates to the production of such insulin preparations and their use as pharmaceutical formulations.

Claims

1. A formulation comprising:

Lys(B3),Glu(B29) human insulin;

a compound chosen from polysorbate 20, polysorbate 80, and poloxamer 171; and

water,

wherein the formulation is free from zinc or contains less than 0.2% by weight of zinc based on the insulin content of the formulation.

2. The formulation according to claim 1, wherein the pH is in a range from 6 to 8.5.

3. The formulation according to claim 1, wherein the formulation further comprises tromethamine.

4. The formulation according to claim 1, wherein the formulation further comprises NaCl.

5. The formulation according to claim 1, wherein the formulation further comprises cresol.

6. The formulation according to claim 5, wherein the formulation further comprises tromethamine.

7. The formulation according to claim 6, wherein the formulation further comprises NaCl.

8. The formulation according to claim 1, wherein the compound is polysorbate 20.

9. A method of treating diabetes mellitus comprising administering a formulation comprising:

Lys(B3),Glu(B29) human insulin;

a compound chosen from polysorbate 20, polysorbate 80, and poloxamer 171; and

water,

wherein the formulation is free from zinc or contains less than 0.2% by weight of zinc based on the insulin content of the formulation.

10. The method according to claim 9, wherein the pH is in a range from 6 to 8.5.

11. The method according to claim 9, wherein the formulation further comprises tromethamine.

12. The method according to claim 9, wherein the formulation further comprises NaCl.

13. The method according to claim 9, wherein the formulation further comprises cresol.

14. The method according to claim 13, wherein the formulation further comprises tromethamine.

15. The method according to claim 14, wherein the formulation further comprises NaCl.

16. The method according to claim 9, wherein the compound is polysorbate 20.

17. A method of making a formulation comprising Lys(B3),Glu(B29) human insulin;

a compound chosen from polysorbate 20, polysorbate 80, and poloxamer 171; and

water, wherein the formulation is free from zinc or contains less than 0.2% by weight of zinc based on the insulin content of the formulation;

said method comprising;

dissolving the Lys(B3),Glu(B29) human insulin in the water, adding the compound chosen from polysorbate 20, polysorbate 80, and poloxamer 171, and optionally adding a final volume of water.

18. The method according to claim 17, wherein the formulation comprises a pH in a range from 6 to 8.5, and the method comprises:

dissolving the Lys(B3),Glu(B29) human insulin in the water, adjusting the pH, adding the compound chosen from polysorbate 20, polysorbate 80, and poloxamer 171, and optionally adding a final volume of water.

19. The method according to claim 17, wherein the compound is polysorbate 20.