Insulin molecule having protracted time action

• US 20050014679A1
• Filed: 12/12/2002
• Published: 01/20/2005
• Est. Priority Date: 12/20/2001
• Status: Abandoned Application

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Myers, Sharon Ruth, Zhang, Lianshan, Kohn, Wayne David, Beals, John Michael, Micanovic, Radmila, Ng, Kingman, DiMarchi, Richard Dennis, DeFelippis, Michael Rosario
• Application Number:
  US10/496,847
• Publication Number:
  US 20050014679A1
• Time in Patent Office: Days
• US Class Current: 530/303
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/62 Insulins

Abstract

The present invention provides an insulin molecule that provides a protracted, even basal duration of action. The insulin molecule comprises a modification at the N-terminus of the A-chain, optionally a modification at the N-terminus of the B-chain, a modification at a B-chain lysine, and optionally a modification at the C-terminus of the A-chain. The present invention also provides a method of treating diabetes mellitus comprising administering the insulin molecule.

Claims

1. An insulin molecule having

(a) an A-chain of Formula I,

A-1 A0 

View Dependent Claims (2, 3, 4, 5, 6, 8, 9, 11, 13, 14, 15, 16, 17, 19, 20, 23, 24, 33)

2. The insulin molecule of claim 1, wherein the ε

-amino group of Lys at position B28 or B29 is covalently bound to the α

-carboxyl group of Arg to form Lys-Nε

-Arg.

3. The insulin molecule of claim 1, wherein the ε

-amino group of Lys at position B28 or B29 is covalently bound to the α

-carboxyl group of Lys to form Lys-Nε

-Lys.

4. The insulin molecule of claim 1, wherein Xaa at position A-1 and Xaa at position B-1 are absent.

5. The insulin molecule of claim 1, wherein Xaa at position B-1 and Xaa at position B0 are absent.

6. The insulin molecule of claim 1, wherein Xaa at position A-1, Xaa at position B-1 and Xaa at position B0 are absent.

8. The insulin molecule of claim 6, wherein Xaa at position A0 is Arg.

9. The insulin molecule of claim 4,

wherein Xaa at position A0 is Arg;

and

Xaa at position B0 is Arg.

11. A composition comprising the insulin molecule of claim 1.

13. The composition of claim 11, further comprising one or more pharmaceutically acceptable excipients.

14. The composition of claim 13, further comprising a divalent metal cation.

15. The composition of claim 14, wherein the divalent metal cation is zinc.

16. The composition of claim 11, further comprising human insulin.

17. The composition of claim 11, further comprising a rapid-acting insulin analog.

19. A microcrystal comprising the insulin molecule of claim 11 and a divalent metal cation, wherein the microcrystal does not contain protamine.

20. The microcrystal of claim 19, wherein the divalent metal cation is zinc.

23. A process for preparing the microcrystal of claim 19, comprising contacting ingredients comprising the insulin molecule, and a divalent metal cation in aqueous solvent at a pH that permits formation of hexamers of the insulin molecule.

24. The process of claim 23, wherein the divalent metal cation is zinc.

33. A method of treating hyperglycemia, the method comprising administering the composition of claim 11 to a subject in an amount sufficient to regulate blood glucose concentration in the subject.

7. (Cancelled)

10. (Cancelled)

12. (Cancelled)

18. (Cancelled)

21. (Cancelled)

22. (Cancelled)

25. (Canceled)

26. (Cancelled)

27. A method of making an insulin molecule, the method comprising:

(a) acylating each free amino group of an insulin template with a protected amino acid or a protected amino acid derivative to form an acylated insulin molecule;

(b) purifying the acylated insulin molecule;

(c) removing the protecting group from each protected amino acid or protected amino acid derivative to form a deprotected acylated insulin molecule; and

(d) purifying the deprotected acylated insulin molecule.

28. (Canceled)

29. (Canceled)

30. (Canceled)

31. (Canceled)

32. (Canceled)

34. (Canceled)

35. (Canceled)

36. An insulin molecule having

(a) an A-chain of Formula I,

A-1 A0 

View Dependent Claims (37, 38, 39, 40, 41, 42, 43, 47, 50)

37. The insulin molecule of claim 36, wherein

Xaa at position A-1 is absent;

and

Xaa at position B-1 is absent.

38. The insulin molecule of claim 37, wherein

Xaa at position A0 is Arg or Lys;

and

Xaa at position B0 is Arg or Lys.

39. The insulin molecule of claim 38, wherein

Xaa at position A0 is Arg;

and

Xaa at position B0 is Arg.

40. A microcrystal comprising the insulin molecule of claim 36 and a divalent cation.

41. The microcrystal of claim 40, wherein the divalent metal cation is zinc.

42. The microcrystal of claim 40, further comprising protamine.

43. A composition comprising the insulin molecule of claim 36.

47. The composition of claim 43, further comprising one or more pharmaceutically acceptable excipients.

50. A method of treating hyperglycemia, the method comprising administering the composition of claim 43 to a subject in an amount sufficient to regulate blood glucose concentration in the subject.

44. (Canceled)

45. (Canceled)

46. (Canceled)

48. (Canceled)

49. (Canceled)

51. (Canceled)

52. (Canceled)

53. (Canceled)