Exendin agonist formulations and methods of administration thereof

• US 6,902,744 B1
• Filed: 01/14/2000
• Issued: 06/07/2005
• Est. Priority Date: 01/14/1999
• Status: Expired due to Term

• Current Assignee: Astrazeneca Pharmaceuticals LP (Astrazeneca PLC)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Young, Andrew A., Kolterman, Orville G.
• Primary Examiner(s): Carlson, Karen Cochrane
• Assistant Examiner(s): LIU, SAMUEL W
• Application Number:
  US09/889,330
• Time in Patent Office: 1,971 Days
• Field of Search: 424/489, 424/278.1, 514/2, 514/3, 514/4, 514/12, 514/866, 530/300
• US Class Current: 424/489
• CPC Class Codes: A61K 38/2278 Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin

Abstract

Novel exendin and exendin agonist compound formulations and dosages and methods of administration thereof are provided. These compositions and methods are useful in treating diabetes and conditions that would be benefited by lowering plasma glucose or delaying and/or slowing gastric emptying or inhibiting food intake.

Claims

1. A pharmaceutical formulation which is a liquid dosage form suitable for multi-use administration comprising about 0.005% to about 0.4% (w/v) of exendin-4, a buffer, an iso-osmolality modifier, and about 0.005% to about 1.0% (w/v) of a preservative selected from the group consisting of m-cresol, phenol, alcohol, methyl-, ethyl-, propyl- and butyl-paraben and any combination thereof, wherein said formulation has a pH of between about 3.0 and about 7.0.

2. The formulation of claim 1, said formulation having a pH of between about 4.0 and about 6.0.

3. The formulation of claim 1, wherein said exendin-4 is present at a concentration of between about 0.005% and about 0.05% (w/v).

4. The formulation of claim 1, wherein said buffer is selected from the group consisting of an acetate buffer, a glutamate buffer, a citrate buffer, a phosphate buffer, and any combination thereof.

5. The formulation of claim 1, wherein said buffer comprises an acetate buffer.

6. The formulation of claim 1, wherein said buffer comprises a glutamate buffer.

7. The formulation of claim 1, wherein said buffer comprises a citrate buffer.

8. The formulation of claim 1, wherein said buffer is at a concentration between about 0.002% and about 0.5% (w/v).

9. The formulation of claim 1, wherein said pH is between about 4.0 and about 5.0.

10. The formulation of claim 1, wherein said iso-osmolality modifier is a carbohydrate, a polyhydric alcohol, or a combination thereof, and said iso-osmolality modifier is at a concentration between about 1% and 10% (w/v).

11. The formulation of claim 10, wherein said polyhydric alcohol is selected from the group consisting of sorbitol, mannitol, inositol, glycerol, xylitol, polyethylene glycols, and any combination thereof.

12. The formulation of claim 10, wherein said carbohydrate is selected from the group consisting of galactose, arabinose, lactose, and any combination thereof.

13. The formulation of claim 1, wherein said iso-osmolality modifier is mannitol, sorbitol, or a combination thereof.

14. The formulation of claim 1, wherein said iso-osmolality modifier comprises mannitol.

15. The formulation of claim 1, wherein said iso-osmolality modifier comprises sorbitol.

16. The formulation of claim 1, wherein said preservative comprises m-cresol.

17. The formulation of claim 1, wherein said preservative comprises phenol.

18. The formulation of claim 1, wherein said formulation is suitable for administration via injection to achieve a dose of from about 0.1 μ

g/kg to about 0.5 μ

g/kg of said exendin-4.

19. The formulation of claim 1, wherein said formulation is suitable for administration via injection to achieve a dose of from about 0.005 μ

g/kg to about 0.2 μ

g/kg of said exendin-4.

20. The formulation of claim 1, wherein said formulation is suitable for administration via injection to achieve a dose of from about 1 μ

g/day to about 1 mg/day of said exendin-4.

21. A pharmaceutical formulation which is a liquid dosage form suitable for multi-use administration comprising 0.025% (w/v) of exendin-4, 0.159% (w/v) of an acetate buffer, 4.3% (w/v) mannitol, and 0.22% (w/v) m-cresol, wherein said formulation has a pH of 4.5.

22. A pharmaceutical formulation which is a liquid dosage form suitable for multi-use administration comprising exendin-4, a buffer, an iso-osmolality modifier, and about 0.005% to about 1.0% (w/v) of a preservative selected from the group consisting of m-cresol, phenol, alcohol, methyl-, ethyl-, propyl- and butyl-paraben and any combination thereof, wherein said formulation has a pH of between about 3.0 and about 6.0.

23. The formulation of claim 22, wherein said formulation is suitable for oral administration to achieve a dose of from about 500 μ

g/day to about 12,000 μ

g/day of said exendin-4 in a single or divided dose.

24. The formulation of claim 22, wherein said formulation is suitable for pulmonary administration to achieve a dose from about 100 μ

g/day to about 12,000 μ

g/day of said exendin-4 in a single or divided dose.

25. The formulation of claim 22, wherein said formulation is suitable for nasal administration to achieve a dose from about 10 μ

g/day to about 12,000 μ

g/day of said exendin-4 in a single or divided dose.

26. The formulation of claim 22, wherein said formulation is suitable for buccal administration to achieve a dose from about 100 μ

g/day to about 12,000 μ

g/day of said exendin-4 in a single or divided dose.

27. The formulation of claim 22, wherein said formulation is suitable for sublingual administration to achieve a dose from about 10 μ

g/day to about 8,000 μ

g/day of said exendin-4 in a single or divided dose.

28. The formulation of claim 22, said formulation having a pH of between about 4.0 and about 6.0.

29. The formulation of claim 22, wherein said pH is between about 4.0 and about 5.0.

30. The formulation of claim 22, wherein said buffer is selected from the group consisting of an acetate buffer, a glutamate buffer, a citrate buffer, a phosphate buffer, and any combination thereof.

31. The formulation of claim 22, wherein said buffer comprises an acetate buffer.

32. The formulation of claim 22, wherein said buffer comprises a glutamate buffer.

33. The formulation of claim 22, wherein said buffer comprises a citrate buffer.

34. The formulation of claim 22, wherein said buffer is at a concentration between about 0.02% and about 0.5% (w/v).

35. The formulation of claim 22, wherein said iso-osmolality modifier is a carbohydrate, a polyhydric alcohol, or a combination thereof, and said iso-osmolality modifier is at a concentration between about 1% and 10% (w/v).

36. The formulation of claim 35, wherein said polyhydric alcohol is selected from the group consisting of sorbitol, mannitol, inositol, glycerol, xylitol, polyethylene glycols, and any combination thereof.

37. The formulation of claim 35, wherein said carbohydrate is selected from the group consisting of galactose, arabinose, lactose, and any combination thereof.

38. The formulation of claim 22, wherein said iso-osmolality modifier is mannitol, sorbitol, or a combination thereof.

39. The formulation of claim 22, wherein said iso-osmolality modifier comprises mannitol.

40. The formulation of claim 22, wherein said iso-osmolality modifier comprises sorbitol.

41. The formulation of claim 22, wherein said preservative comprises m-cresol.

42. The formulation of claim 22, wherein said preservative comprises phenol.