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

• US 7,205,276 B2
• Filed: 12/09/2004
• Issued: 04/17/2007
• Est. Priority Date: 03/23/2001
• Status: Expired due to Term

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Sanofi-Aventis Deutschland Gmb
• Inventors: Boderke, Peter
• Primary Examiner(s): Chism; B. Dell
• Application Number:
  US11/007,154
• Publication Number:
  US 20050187142A1
• Time in Patent Office: 859 Days
• Field of Search: None
• US Class Current: 514/6.3
• 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. An aqueous liquid formulation comprising

at least one insulin derivative;

at least one surfactant;

optionally at least one preservative; and

optionally at least one of an isotonicizing agent, a buffer, and an excipient, wherein the formulation is stable and free from or contains less than 0.2% by weight of zinc based on the insulin content of the formulation.

2. The formulation as claimed in claim 1, wherein the at least one surfactant is selected from at least one of alkali metal soaps, amine soaps, alkaline earth metal soaps, alkylsulfates, alkylsulfonates, natural surfactants, cationic surfactants, fatty alcohols, fatty acids, esters of polyhydric alcohols, ethers of polyhydric alcohols, and polyols.

3. The formulation as claimed in claim 1, wherein the surfactant comprises a soap selected from at least one of a stearate, a palmitate, an oleate, and a ricinoleate.

4. The formulation as claimed in claim 2, wherein the alkylsulfates are selected from at least one of sodium laurylsulfate, sodium cetylsulfate, and sodium stearylsulfate.

5. The formulation as claimed in claim 2, wherein the natural surfactants are selected from at least one of bile acid salts, saponins, gum arabic, and lecithins.

6. The formulation as claimed in claim 2, wherein the cationic surfactants are selected from at least one of alkonium halides, cetylpyridinium chloride, and alkyltrimethylammonium bromide.

7. The formulation as claimed in claim 2, wherein the fatty alcohols are selected from at least one of cetyl alcohol, stearyl alcohol, and cholesterol.

8. The formulation as claimed in claim 2, wherein the esters of polyhydric alcohols are selected from at least one of esters of sorbitol, glycerol, sucrose, and polyethylene glycol.

9. The formulation as claimed in claim 2, wherein the esters of polyhydric alcohols are fatty acid esters.

10. The formulation as claimed in claim 2, wherein the ethers of polyhydric alcohols are selected from at least one of ethers of sorbitol, glycerol, sucrose, and polyethylene glycol.

11. The formulation as claimed in claim 1, wherein the surfactant comprises at least one of a polysorbate, a sorbitan ester, a polyoxyethylene stearate, a polyoxyethylene ether, and a polyethylene glycol ether.

12. The formulation as claimed in claim 2, wherein the polyols are selected from at least one of polypropylene glycols, polyethylene glycols, poloxamers, Pluronics, and Tetronics.

13. The formulation as claimed in claim 1, wherein the preservative is selected from at least one of phenol, cresol, chlorocresol, benzyl alcohol, and parabens.

14. The formulation as claimed in claim 1, wherein the isotonicizing agent is selected from at least one of mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, and glycerol.

15. The formulation as claimed in claim 1, wherein the excipient is selected from at least one of a buffer substance, an acid, an alkali, a salt, protamine, arginine, and amino quinurid.

16. The formulation as claimed in claim 15, wherein the buffer substance is selected from TRIS, phosphate, citrate, acetate, and glycylglycine.

17. The formulation as claimed in claim 1, wherein the at least one insulin derivative is selected from at least one of B29-N-myristoyl-des(B30) human insulin;

B29-N-palmitoyl-des(B30) human insulin;

B29-N-myristoyl human insulin;

B29-N-palmitoyl human insulin;

B28-N-myristoyl Lys^B28Pro^B29 human insulin;

B28-N-palmitoyl-Lys^B28Pro^B29 human insulin;

B30-N-myristoyl-Thr^B29Lys^B30 human insulin;

B30-N-palmitoyl-Thr^B29Lys^B30 human insulin;

B29-N-(N-palmitoyl-γ

-glutamyl)-des(B39) human insulin;

B29-N-(N-lithocholyl-γ

-glutamyl)-des(B30) human insulin;

B29-N-(ω

-carboxyheptadecanoyl)-des(B30) human insulin; and

B29-N-(ω

-carboxyheptadecanoyl) human insulin.

18. The formulation as claimed in claim 1, in which the at least one insulin derivative is present in a concentration of 60–

6000 nmol/ml.

19. The formulation as claimed in claim 18, wherein the at least one insulin derivative is present in a concentration of 240–

3000 nmol/ml.

20. The formulation as claimed in claim 1,in which the at least one surfactant is present in a concentration of 0.1–

10000 μ

g/ml.

21. The formulation as claimed in claim 20, in which the surfactant is present in a concentration of 1–

1000 μ

g/ml.

22. The formulation as claimed in claim 1, in which the surfactant and/or isotonicizing agent comprises at least one of glycerol and mannitol in a concentration of 100–

250 mM.

23. The formulation as claimed in claim 22, further comprising chloride as a buffer substance and/or isotonicizing agent in a concentration of up to 150 mM.

24. The formulation as claimed in claim 1, in which a buffer substance is present in a concentration of 5–

250 mM.

25. A process for the production of the formulation as claimed in claim 1, wherein the components are mixed together in the form of aqueous solutions, the pH is adjusted to a desired level, and the mixture is made up to the final volume with water.

26. The formulation of claim 1 wherein the surfactant comprises polysorbate 20, and the formulation further comprises cresol, trometamol and NaCl.

27. An aqueous liquid formulation obtainable by the process as claimed in claim 25.

28. A method of treating diabetes mellitus comprising administering the formulation as claimed in claim 1 to a patient in need thereof.

29. The formulation of claim 1 further comprising at least one insulin, insulin derivative, or active insulin metabolite.

30. An aqueous liquid formulation comprising

at least one insulin derivative;

at least one surfactant;

optionally at least one preservative; and

optionally at least one of an isotonicizing agent, a buffer, and an excipient, wherein the formulation is stable and free from zinc or contains less than a 2;

6 ratio of zinc to insulin.

31. The formulation as claimed in claim 30, wherein the at least one surfactant is selected from at least one of alkali metal soaps, amine soaps, alkaline earth metal soaps, alkylsulfates, alkylsulfonates, natural surfactants, cationic surfactants, fatty alcohols, fatty acids, esters of polyhydric alcohols, ethers of polyhydric alcohols, and polyols.

32. The formulation as claimed in claim 30, wherein the surfactant comprises a soap selected from at least one of a stearate, a palmitate, an oleate, and a ricinoleate.

33. The formulation as claimed in claim 31, wherein the alkylsulfates are selected from at least one of sodium laurylsulfate, sodium cetylsulfate, and sodium stearylsulfate.

34. The formulation as claimed in claim 31, wherein the natural surfactants are selected from at least one of bile acid salts, saponins, gum arabic, and lecithins.

35. The formulation as claimed in claim 31, wherein the cationic surfactants are selected from at least one of alkonium halides, cetylpyridinium chloride, and alkyltrimethylammonium bromide.

36. The formulation as claimed in claim 31, wherein the fatty alcohols are selected from at least one of cetyl alcohol, stearyl alcohol, and cholesterol.

37. The formulation as claimed in claim 31, wherein the esters of polyhydric alcohols are selected from at least one of esters of sorbitol, glycerol, sucrose, and polyethylene glycol.

38. The formulation as claimed in claim 31, wherein the esters of polyhydric alcohols are fatty acid esters.

39. The formulation as claimed in claim 31, wherein the ethers of polyhydric alcohols are selected from at least one of ethers of sorbitol, glycerol, sucrose, and polyethylene glycol.

40. The formulation as claimed in claim 30, wherein the surfactant comprises at least one of a polysorbate, a sorbitan ester, a polyoxyethylene stearate, a polyoxyethylene ether, and a polyethylene glycol ether.

41. The formulation as claimed in claim 31, wherein the polyols are selected from at least one of polypropylene glycols, polyethylene glycols, poloxamers, Pluronics, and Tetronics.

42. The formulation as claimed in claim 30, wherein the preservative is selected from at least one of phenol, cresol, chlorocresol, benzyl alcohol, and parabens.

43. The formulation as claimed in claim 30, wherein the isotonicizing agent is selected from at least one of mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, and glycerol.

44. The formulation as claimed in claim 30, wherein the excipient is selected from at least one of a buffer substance, an acid, an alkali, a salt, protamine, arginine, and amino quinurid.

45. The formulation as claimed in claim 44, wherein the buffer substance is selected from TRIS, phosphate, citrate, acetate, and glycylglycine.

46. The formulation as claimed in claim 30, wherein the at least one insulin derivative is selected from at least one of B29-N-myristoyl-des(B30) human insulin;

B29-N-palmitoyl-des(B30) human insulin;

B29-N-myristoyl human insulin;

B29-N-palmitoyl human insulin;

B28-N-myristoyl Lys^B28Pro^B29 human insulin;

B28-N-palmitoyl-Lys^B28Pro^B29 human insulin;

B30-N-myristoyl-Thr⁸²⁹Lys⁸³⁰ human insulin;

B30-N-palmitoyl-Thr^B29Lys^B30 human insulin;

B29-N-(N-palmitoyl-γ

-glutamyl)-des(B39) human insulin;

B29-N-(N-lithocholyl-γ

-glutamyl)-des(B30) human insulin;

B29-N-(ω

-carboxyheptadecanoyl)-des(B30) human insulin; and

B29-N-(ω

-carboxyheptadecanoyl) human insulin.

47. The formulation as claimed in claim 30, in which the at least one insulin derivative is present in a concentration of 60–

6000 nmol/ml.

48. The formulation as claimed in claim 47, wherein the at least one insulin derivative is present in a concentration of 240–

3000 nmol/ml.

49. The formulation as claimed in claim 30, in which the at least one surfactant is present in a concentration of 0.1–

10000 μ

g/ml.

50. The formulation as claimed in claim 49, in which the surfactant is present in a concentration of 1–

1000 μ

g/ml.

51. The formulation as claimed in claim 30, in which the surfactant and/or isotonicizing agent comprises at least one of glycerol and mannitol in a concentration of 100–

250 mM.

52. The formulation as claimed in claim 51, further comprising chloride as a buffer substance and/or isotonicizing agent in a concentration of up to 150 mM.

53. The formulation as claimed in claim 30, in which a buffer substance is present in a concentration of 5–

250 mM.

54. A process for the production of the formulation as claimed in claim 30, wherein the components are mixed together in the form of aqueous solutions, the pH is adjusted to a desired level, and the mixture is made up to the final volume with water.

55. The formulation of claim 30 wherein the surfactant comprises polysorbate 20, and the formulation further comprises cresol, trometamol and NaCl.

56. An aqueous liquid formulation obtainable by the process as claimed in claim 54.

57. A method of treating diabetes mellitus comprising administering the formulation as claimed in claim 30 to a patient in need thereof.

58. The formulation of claim 30 further comprising at least one insulin, insulin derivative, or active insulin metabolite.