Stable pharmaceutical compositions

• US 7,595,293 B2
• Filed: 10/03/2005
• Issued: 09/29/2009
• Est. Priority Date: 04/11/2003
• Status: Active Grant

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Pedersen, Tina Bjeldskov, Bonde, Claude, Engelund, Dorthe Kot
• Primary Examiner(s): CARLSON, KAREN C
• Application Number:
  US11/244,497
• Publication Number:
  US 20060084605A1
• Time in Patent Office: 1,457 Days
• Field of Search: 530/350, 514/2
• US Class Current: 514/1.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/38 Albumins
• 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: C07K 14/605 Glucagons

Abstract

Pharmaceutical composition for parenteral administration comprising a glucagon-like peptide and human serum albumin or a variant thereof.

Claims

1. A pharmaceutical composition for parenteral administration, said composition comprising a glucagon-like peptide, human serum albumin or a variant thereof, a pharmaceutically acceptable buffer, a pharmaceutically acceptable preservative, and optionally an isotonicity agent and/or a stabilizer, wherein the pH of said pharmaceutical composition is from pH 7.2 to pH 8.0, and wherein the concentration of said glucagon-like peptide is from 3.0 mg/ml to 50 mg/ml.

2. The pharmaceutical composition according to claim 1, wherein the composition is a solution.

3. The pharmaceutical composition according to claim 1, wherein the composition is a suspension.

4. The pharmaceutical composition according to claim 1, which is a solid.

5. The pharmaceutical composition according to claim 4, which is to be reconstituted with water or another suitable solvent for injection.

6. The pharmaceutical composition according to claim 1, which is suitable for administration by injection or infusion.

7. The pharmaceutical composition according to claim 1, which is suitable for subcutaneous administration.

8. The pharmaceutical composition according to claim 1, which is suitable for intramuscular administration.

9. A pharmaceutical composition according to claim 1, which is suitable for intravenous administration.

10. The pharmaceutical composition according to claim 1, wherein said human serum albumin or a variant thereof is produced by recombinant DNA technology.

11. The pharmaceutical composition according to claim 1, wherein said human serum albumin or a variant thereof is a human serum albumin variant.

12. The pharmaceutical composition according to claim 11, wherein said human serum albumin variant has reduced binding affinities towards copper and nickel as compared to the corresponding binding affinities of human serum albumin towards copper and nickel.

13. The pharmaceutical composition according to claim 11, wherein said human serum albumin variant is a fragment of human serum albumin.

14. The pharmaceutical composition according to claim 11, wherein said human serum albumin variant comprises a modification of the Asp-Ala-His-Lys N-terminal sequence of human serum albumin.

15. The pharmaceutical composition according to claim 14, wherein said human serum albumin variant comprises at least one amino acid deletion among the three N-terminal amino acid residues Asp-Ala-His in the N-terminal of human serum albumin.

16. The pharmaceutical composition according to claim 14, wherein said modification of the Asp-Ala-His-Lys N-terminal sequence of human serum albumin is an N-terminal extension, such as Glu⁻

3, Ala<sup>−

2</sup>, Glu<sup>−

1</sup>, Phe⁰-HSA(1-585) or an N-terminal fragment thereof.

17. The pharmaceutical composition according to claim 14, wherein said human serum albumin variant is selected from the group consisting of HSA(2-585), HSA(3-585), HSA(4-585), Asp-Ala-HSA(4-585), Xaa3-HSA(1-585) where Xaa³ is an amino acid residue which has substituted the His residue occupying position 3 in native HSA, and fragments thereof.

18. The pharmaceutical composition according to claim 1, wherein the concentration of human serum albumin or a variant thereof is less than 10% w/v.

19. The pharmaceutical composition according to claim 1, wherein the isoelectric point of said glucagon-like peptide is from 3.0 to 7.0.

20. The pharmaceutical composition according to claim 1, wherein said glucagon-like peptide is GLP-1, a GLP-1 analogue, a derivative of GLP-1 or a derivative of a GLP-1 analogue.

21. The pharmaceutical composition according to claim 20, wherein said GLP-1 analogue is selected from the group consisting of:

Gly⁸-GLP-1(7-36)-amide,

Gly⁸-GLP-1(7-37),

Val⁸-GLP-1(7-36)-amide,

Val⁸-GLP-1(7-37),

Val⁸Asp²²-GLP-1(7-36)-amide,

Val⁸Asp²²-GLP-1(7-37),

Val⁸Glu²²-GLP-I(7-36)-amide,

Val⁸Glu²²-GLP-1(7-37),

Val⁸Lys²²-GLP-I(7-36)-amide,

Val⁸Lys²²-GLP-1(7-37),

Val⁸Arg²²-GLP-1(7-36)-amide,

Val⁸Arg²²-GLP-1(7-37),

Val⁸His²²-GLP-1(7-36)-amide,

Val⁸His²²-GLP-1(7-37),

Val⁸Trp¹⁹Glu²²-GLP-1(7-37),

Val⁸Glu²²Val²⁵-GLP-1(7-37),

Val⁸Tyr¹⁶Glu²²-GLP-1(7-37),

Val⁸Trp¹⁶Glu²²-GLP-1(7-37),

Val⁸Leu¹⁶Glu²²-GLP-1(7-37),

Val⁸Tyr¹⁸Glu²²-GLP-1(7-37),

Val⁸Glu²²His³⁷-GLP-1(7-37),

Val⁸Glu²²Ile³³-GLP-1(7-37),

Val⁸Trp¹⁶Glu²²Val²⁵Ile³³-GLP-1(7-37),

Val⁸Trp¹⁶Glu²²Ile³³-GLP-1(7-37),

Val⁸Glu²²Val²⁵Ile³³-GLP-1(7-37),

Val⁸Trp¹⁶Glu²²Val²⁵-GLP-1(7-37),

and analogues thereof and derivatives of any of these.

22. The pharmaceutical composition according to claim 20, wherein said glucagon-like peptide has from 31 to 43 amino acid residues.

23. The pharmaceutical composition according to claim 1, wherein said derivative of GLP-1 or a derivative of a GLP-1 analogue has a lysine residue, wherein a lipophilic substituent optionally via a spacer is attached to the epsilon amino group of said lysine.

24. The pharmaceutical composition according to claim 23, wherein said lipophilic substituent has from 8 to 40 carbon atoms.

25. The pharmaceutical composition according to claim 23, wherein said spacer is present and is selected from an amino acid selected from the group consisting of beta-Ala, L-Glu, and aminobutyroyl.

26. The pharmaceutical composition according to claim 23, wherein said derivative of a GLP-1 analogue is Arg^34, Lys²⁶(N^e-(5,γ

-Glu(N^a-hexadecanoyl)))-GLP⁻

1(7-37).

27. The pharmaceutical composition according to claim 1, wherein said glucagon-like peptide is a DPPIV-protected glucagon-like peptide.

28. The pharmaceutical composition according to any claim 1, wherein said glucagon-like peptide is a plasma stable glucagon-like peptide.

29. The pharmaceutical composition according to claim 1, wherein said glucagon-like peptide is GLP-2, a GLP-2 analogue, a derivative of GLP-2 or a derivative of a GLP-2 analogue.

30. The pharmaceutical composition according to claim 29, wherein said derivative of GLP-2 or a derivative of a GLP-2 analogue has a lysine residue, such as one lysine, wherein a lipophilic substituent optionally via a spacer is attached to the epsilon amino group of said lysine.

31. The pharmaceutical composition according to claim 30, wherein said lipophilic substituent has from 8 to 40 carbon atoms.

32. The pharmaceutical composition according to claim 30, wherein said spacer is present and is selected from an amino acid selected from the group consisting of beta-Ala, L-Glu, and aminobutyroyl.

33. The pharmaceutical composition according to claim 29, wherein said glucagon-like peptide has from 27 to 39 amino acid residues.

34. The pharmaceutical composition according to claim 29, wherein the concentration of said glucagon-like peptide is from 0.1 mg/ml to 100 mg/ml.

35. The pharmaceutical composition according to claim 1, wherein said glucagon-like peptide is exendin-4, an exendin-4 analogue, a derivative of exendin-4, or a derivative of an exendin-4 analogue.

36. The pharmaceutical composition according to claim 35, wherein said glucagon-like peptide is exendin-4.

37. The pharmaceutical composition according to claim 35, wherein said derivative of exendin-4 or derivative of an exendin-4 analogue is acylated or pegylated.

38. The pharmaceutical composition according to claim 35, wherein said derivative of exendin-4 or derivative of an exendin-4 analogue has a lysine residue, such as one lysine, wherein a lipophilic substituent optionally via a spacer is attached to the epsilon amino group of said lysine.

39. The pharmaceutical composition according to claim 38, wherein said lipophilic substituent has from 8 to 40 carbon atoms.

40. The pharmaceutical composition according to claim 38, wherein said spacer is present and is selected from an amino acid selected from the group consisting of beta-Ala, L-Glu, and aminobutyroyl.

41. The pharmaceutical composition according to claim 35, wherein said glucagon-like peptide has from 30 to 48 amino acid residues.

42. The pharmaceutical composition according to claim 35, wherein the concentration of said glucagon-like peptide is from 5 μ

g/ml to 10 mg/ml.

43. The pharmaceutical composition according to claim 1, wherein said glucagon- like peptide is glucagon, a glucagon analogue or a derivative thereof.

44. The pharmaceutical composition according to claim 1, wherein said glucagon-like peptide is Arg^34, Lys²⁶(N^e-(5,γ

-Glu(N^a-hexadecanoyl)))-GLP-I(7-37) and said human serum albumin or a variant thereof is recombinant human serum albumin.

45. The pharmaceutical composition according to claim 44, wherein the concentration of Arg^34, Lys²⁶(N^e-(5, γ

-Glu(N^a-hexadecanoyl)))-GLP-1(7-37) is in the range from 3 mg/ml to 8 mg/ml and the concentration of recombinant human serum albumin is in the range from 0.001% w/v to 10% w/v.

46. The pharmaceutical composition according to claim 1, wherein said buffer is ortho-phosphate, TRIS, glycine, N-glycylglycine, citrate sodium acetate, sodium carbonate, glycylglycine, histidine, lysine, arginine, sodium phosphate, and sodium citrate or mixtures thereof.

47. The pharmaceutical composition according to claim 1, wherein said preservative is phenol, m-cresol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, 2-phenoxyethanol, butyl p-hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, or mixtures thereof.

48. The pharmaceutical composition according to claim 1, wherein said isotonicity agent is present.

49. The pharmaceutical composition according to claim 48, wherein said isotonicity agent is sodium chloride, xylitol, mannitol, sorbitol, glycerol, glucose, maltose, sucrose, L-glycine, L-histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine, polyethyleneglycol, propylene glycol or mixtures thereof.

50. The pharmaceutical composition according to claim 1, which further comprises a stabiliser.

51. The pharmaceutical composition according to claim 1, which further comprises a surfactant.

52. A method for treatment of hyperglycemia comprising parenteral administration of an effective amount of the pharmaceutical composition according to claim 1.