Long-acting formulations of insulin

• US 9,345,750 B2
• Filed: 03/20/2014
• Issued: 05/24/2016
• Est. Priority Date: 05/19/2010
• Status: Active Grant

• Current Assignee: Sanofi
• Original Assignee: Sanofi
• Inventors: Hahn, Annke, Becker, Reinhard, Boderke, Peter, Fuerst, Christiane, Mueller, Werner, Werner, Ulrich
• Primary Examiner(s): AUDET, MAURY A
• Application Number:
  US14/220,562
• Publication Number:
  US 20140206611A1
• Time in Patent Office: 796 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 38/2278 Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/02 Inorganic compounds
• 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 47/26 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: A61K 9/08 Solutions composition of solutions A61K47/00
• 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 5/48 of the pancreatic hormones
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin

Abstract

The application relates to an aqueous pharmaceutical formulation comprising 200-1000 U/mL [equimolar to 200-1000 IU human insulin] of insulin glargine.

Claims

1. An aqueous pharmaceutical formulation comprising 300 U/mL of insulin glargine [equimolar to 300 IU human insulin].

2. The aqueous pharmaceutical formulation of claim 1 further comprising at least one excipient selected from the group consisting of zinc, m-cresol, glycerol, and polysorbate 20.

3. The aqueous pharmaceutical formulation of claim 2 further comprising 90 μ

g/mL zinc, 2.7 mg/mL m-cresol, and 20 mg/mL glycerol 85%.

4. The aqueous pharmaceutical formulation of claim 3, wherein the zinc is present in the form of zinc chloride.

5. The aqueous pharmaceutical formulation of claim 2 further comprising 90 μ

g/mL zinc, 2.7 mg/mL m-cresol, 20 μ

g/mL polysorbate 20, and 20 mg/mL glycerol 85%.

6. The aqueous pharmaceutical formulation of claim 5, wherein the zinc is present in the form of zinc chloride.

7. The aqueous pharmaceutical formulation of claim 1, wherein the pH of the aqueous pharmaceutical formulation is between 3.4 and 4.6.

8. The aqueous pharmaceutical formulation of claim 7, wherein the pH of the aqueous pharmaceutical formulation is 4.0.

27. The aqueous pharmaceutical formulation of claim 1 further comprising an analogue of exendin-4.

28. The aqueous pharmaceutical formulation of claim 27, wherein the analogue of exendin-4 is selected from the group consisting of lixisenatide, exenatide, and liraglutide.

29. The aqueous pharmaceutical formulation of claim 28 comprising 0.1 μ

g to 10 μ

g lixisenatide per Unit insulin glargine.

30. The aqueous pharmaceutical formulation of claim 29 comprising 0.2 to 1 μ

g lixisenatide per Unit insulin glargine.

31. The aqueous pharmaceutical formulation of claim 30 comprising 0.25 μ

g to 0.7 μ

g lixisenatide per Unit insulin glargine.

9. An aqueous pharmaceutical formulation comprising 300 U/mL of insulin glargine [equimolar to 300 IU human insulin] wherein the pH of the aqueous pharmaceutical formulation is between 3.4 and 4.6.

10. The aqueous pharmaceutical formulation of claim 9, wherein the pH of the aqueous pharmaceutical formulation is 4.0.

11. The aqueous pharmaceutical formulation of claim 9 further comprising at least one excipient selected from the group consisting of zinc, m-cresol, glycerol, and polysorbate 20.

12. The aqueous pharmaceutical formulation of claim 11 further comprising 90 μ

g/mL zinc, 2.7 mg/mL m-cresol, and 20 mg/mL glycerol 85%.

13. The aqueous pharmaceutical formulation of claim 12, wherein the zinc is present in the form of zinc chloride.

14. The aqueous pharmaceutical formulation of claim 11 further comprising 90 μ

g/mL zinc, 2.7 mg/mL m-cresol, 20 μ

g/mL polysorbate 20, and 20 mg/mL glycerol 85%.

15. The aqueous pharmaceutical formulation of claim 14, wherein the zinc is present in the form of zinc chloride.

16. An aqueous pharmaceutical formulation comprising 300 U/mL of insulin glargine [equimolar to 300 IU human insulin], 90 μ

g/mL zinc chloride, 2.7 mg/mL m-cresol, and 20 mg/mL glycerol 85%, wherein the pH of the aqueous pharmaceutical formulation is 4.0.

17. An aqueous pharmaceutical formulation comprising 300 U/mL of insulin glargine [equimolar to 300 IU human insulin], 90 μ

g/mL zinc chloride, 2.7 mg/mL m-cresol, 20 μ

g/mL polysorbate 20, and 20 mg/mL glycerol 85%, wherein the pH of the aqueous pharmaceutical formulation is 4.0.

18. An aqueous pharmaceutical formulation comprising 300 U/mL of insulin glargine [equimolar to 300 IU human insulin], wherein the pharmacokinetic profile and the pharmacodynamic profile of the 300 U/mL aqueous pharmaceutical formulation are flatter than the pharmacokinetic profile and the pharmacodynamic profile of an aqueous pharmaceutical formulation comprising 100 U/mL of insulin glargine, and wherein the pH of the 300 U/mL aqueous pharmaceutical formulation is between 3.4 and 4.6.

19. The aqueous pharmaceutical formulation of claim 18, wherein the pH of the aqueous pharmaceutical formulation is 4.0.

20. The aqueous pharmaceutical formulation of claim 18 further comprising at least one excipient selected from the group consisting of zinc, m-cresol, glycerol, and polysorbate 20.

21. The aqueous pharmaceutical formulation of claim 20 further comprising 90 μ

g/mL zinc, 2.7 mg/mL m-cresol, and 20 mg/mL glycerol 85%.

22. The aqueous pharmaceutical formulation of claim 21, wherein the zinc is present in the form of zinc chloride.

23. The aqueous pharmaceutical formulation of claim 20 further comprising 90 μ

g/mL zinc, 2.7 mg/mL m-cresol, 20 μ

g/mL polysorbate 20, and 20 mg/mL glycerol 85%.

24. The aqueous pharmaceutical formulation of claim 23, wherein the zinc is present in the form of zinc chloride.

25. An aqueous pharmaceutical formulation comprising 300 U/mL of insulin glargine [equimolar to 300 IU human insulin] providing a peakless long acting basal insulin, wherein the pH of the aqueous pharmaceutical formulation is between 3.4 and 4.6.

26. An aqueous pharmaceutical formulation comprising 300 U/mL of insulin glargine [equimolar to 300 IU human insulin] exhibiting an extended duration of exposure of insulin glargine than an aqueous pharmaceutical formulation comprising 100 U/mL insulin glargine, wherein the pH of the U300 U/mL aqueous formulation is between 3.4 and 4.6.

32. A method of treating Type I or Type II Diabetes Mellitus in a patient in need thereof comprising subcutaneously administering to the patient an aqueous pharmaceutical formulation comprising 300 U/mL of insulin glargine [equimolar to 300 IU human insulin].

33. The method of claim 32, wherein the aqueous pharmaceutical formulation further comprises at least one excipient selected from the group consisting of zinc, m-cresol, glycerol, and polysorbate 20.

40. The method of any one of claim 32, 34, 36, or 38, wherein the aqueous pharmaceutical formulation is administered once daily.

41. The method of any one of claim 33, 35, 37, or 39, wherein the aqueous pharmaceutical formulation further comprises 90 μ

g/mL zinc, 2.7 mg/mL m-cresol, and 20 mg/mL glycerol 85%.

42. The method of any one of claim 33, 35, 37, or 39, wherein the aqueous pharmaceutical formulation further comprises 90 μ

g/mL zinc, 2.7 mg/mL m-cresol, 20 μ

g/mL polysorbate 20, and 20 mg/mL glycerol 85%.

43. The method of any one of claim 33, 35, 37, or 39, wherein the zinc in the aqueous pharmaceutical formulation is present in the form of zinc chloride.

44. The method of any one of claim 32, 34, 36, or 38, wherein the pH of aqueous pharmaceutical formulation is between 3.4 and 4.6.

45. The method of claim 44, wherein the pH of the aqueous pharmaceutical formulation is 4.0.

46. The method of any one of claim 33, 35, 37, or 39, wherein the aqueous pharmaceutical formulation further comprises 90 μ

g/mL zinc chloride, 2.7 mg/mL m-cresol, and 20 mg/mL glycerol 85%, and wherein the pH of the aqueous pharmaceutical formulation is 4.0.

47. The method of any one of claim 32, 34, 36, or 38, wherein the pharmacokinetic profile and pharmacodynamic profile of the 300 U/mL aqueous pharmaceutical formulation are flatter than the pharmacokinetic profile and pharmacodynamic profile of an aqueous pharmaceutical formulation comprising 100 U/mL of insulin glargine, and wherein the pH of the 300 U/mL aqueous pharmaceutical formulation is between 3.4 and 4.6.

55. The method of any one of claim 32, 34, 36, 38, or 48, wherein the aqueous pharmaceutical formulation further comprises an analogue of exendin-4.

56. The method of claim 55, wherein the analogue of exendin-4 is selected from the group consisting of lixisenatide, exenatide and liraglutide.

57. The method of claim 56, wherein the aqueous formulation comprises 0.1 μ

g to 10 μ

g lixisenatide per Unit insulin glargine.

58. The method of claim 57, wherein the aqueous formulation comprises 0.2 to 1 μ

g lixisenatide per Unit insulin glargine.

59. The method of claim 58, wherein the aqueous formulation comprises 0.25 μ

g to 0.7 μ

g lixisenatide per Unit insulin glargine.

34. A method of extending the duration of exposure of a long acting insulin in the treatment of Type I or Type II Diabetes Mellitus in a patient in need thereof comprising subcutaneously administering to the patient an aqueous pharmaceutical formulation comprising 300 U/mL insulin glargine [equimolar to 300 IU human insulin].

35. The method of claim 34, wherein the aqueous pharmaceutical formulation further comprises at least one excipient selected from the group consisting of zinc, m-cresol, glycerol, and polysorbate 20.

36. A method of reducing the incidence of hypoglycaemia in the treatment of Type I or Type II Diabetes Mellitus in a patient in need thereof comprising subcutaneously administering to the patient an aqueous pharmaceutical formulation comprising 300 U/mL insulin glargine [equimolar to 300 IU human insulin].

37. The method of claim 36, wherein the aqueous pharmaceutical formulation further comprises at least one excipient selected from the group consisting of zinc, m-cresol, glycerol, and polysorbate 20.

38. A method of providing a peakless long acting basal insulin in the treatment of Type I or Type II Diabetes Mellitus in a patient in need thereof comprising subcutaneously administering to the patient an aqueous pharmaceutical formulation comprising 300 U/mL insulin glargine [equimolar to 300 IU human insulin].

39. The method of claim 38, wherein the aqueous pharmaceutical formulation further comprises at least one excipient selected from the group consisting of zinc, m-cresol, glycerol, and polysorbate 20.

48. A method of treating Type I or Type II Diabetes Mellitus in a patient in need thereof comprising subcutaneously administering to the patient an aqueous pharmaceutical formulation comprising 300 U/mL of insulin glargine [equimolar to 300 IU human insulin], wherein the pH of the aqueous pharmaceutical formulation is between 3.4 and 4.6.

49. The method of claim 48, wherein the pH of the aqueous pharmaceutical formulation is 4.0.

50. The method of claim 48, wherein the aqueous pharmaceutical formulation further comprises at least one excipient selected from the group consisting of zinc, m-cresol, glycerol, and polysorbate 20.

51. The method of claim 50, wherein the aqueous pharmaceutical formulation further comprises 90 μ

g/mL zinc, 2.7 mg/mL m-cresol, and 20 mg/mL glycerol 85%.

52. The method of claim 51, wherein the zinc is present in the form of zinc chloride.

53. The method of claim 50, wherein the aqueous pharmaceutical formulation further comprises 90 μ

g/mL zinc, 2.7 mg/mL m-cresol, 20 μ

g/mL polysorbate 20, and 20 mg/mL glycerol 85%.

54. The method of claim 53, wherein the zinc is present in the form of zinc chloride.