Exendin analog formulations

• US 7,399,489 B2
• Filed: 11/10/2005
• Issued: 07/15/2008
• 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., L'Italien, James J.
• Primary Examiner(s): Bragdon; Kathleen Kerr
• Assistant Examiner(s): LIU, SAMUEL W
• Application Number:
  US11/272,488
• Publication Number:
  US 20060069029A1
• Time in Patent Office: 978 Days
• Field of Search: 530/308, 530/322, 530/300, 424/278.1, 424/489, 514/2, 514/3, 514/12
• US Class Current: 424/489
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/16 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: C07K 14/57563 Vasoactive intestinal peptide [VIP]; Related peptides
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

Novel formulations containing exendins, exendin agonists and/or exendin analogs are provided.

Claims

1. A pharmaceutical formulation which is a liquid dosage form suitable for multi-use administration comprising about 0.005% (w/v) to about 0.4% (w/v) of an exendin, an exendin analog or a combination thereof, 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, benzyl 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 and said exendin is not exendin-4.

2. The pharmaceutical formulation of claim 1, where said exendin is exendin-3.

3. The pharmaceutical formulation of claim 1, where said exendin analog comprises SEQ ID NO:

41.

4. The pharmaceutical formulation of claim 1, where said exendin analog comprises SEQ ID NO:

42.

5. The pharmaceutical formulation of claim 1, where said exendin analog comprises SEQ ID NO:

43.

6. The pharmaceutical formulation of claim 1, where said exendin analog comprises SEQ ID NO:

44.

7. The pharmaceutical formulation of claim 1, where said exendin analog comprises SEQ ID NO:

45.

8. The pharmaceutical formulation of claim 1, where said exendin analog comprises SEQ ID NO:

46.

9. The pharmaceutical formulation of claim 1, where said exendin analog comprises SEQ ID NO:

47.

10. The pharmaceutical formulation of claim 1, where said exendin analog comprises SEQ ID NO:

48.

11. The pharmaceutical formulation of claim 1, where said exendin analog is selected from at least one of the group consisting of SEQ ID NOs:

6-189.

12. The pharmaceutical formulation of claim 1, wherein said exendin analog is selected from at least one of the group consisting of SEQ ID NOs:

6, 7, 8, 9, 40 and 41.

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

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

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

16. 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.

17. The formulation of claim 1, wherein said buffer is at a concentration between about 0.02% (w/v) and about 0.5% (w/v).

18. 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% (w/v) and 10% (w/v).

19. The formulation of claim 18, wherein said polyhydric alcohol is selected from the group consisting of sorbitol, mannitol, inositol, glycerol, xylitol, polyethylene glycols, and any combination thereof.

20. The formulation of claim 18, wherein said carbohydrate is selected from the group consisting of galactose, arabinose, lactose, and any combination thereof.

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

22. The formulation of claim 1, wherein said preservative is m-cresol, phenol or a combination thereof.

23. 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 or exendin analog.

24. 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 or exendin analog.

25. 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 or exendin analog.

26. A pharmaceutical formulation which is a liquid dosage form suitable for multi-use administration comprising an exendin, an exendin analog or a combination thereof, a buffer, an iso-osmolality modifier, and about 0.005% (w/v) to about 1.0% (w/v) of a preservative selected from the group consisting of m-cresol, phenol, benzyl 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 and said exendin is not exendin-4.

27. The formulation of claim 26, wherein said formulation is suitable for a route of administration selected from the group consisting of:

oral administration to achieve a dose of from about 500 μ

g/day to about 12,000 μ

g/day of said exendin or exendin analog in a single or divided dose;

pulmonary administration to achieve a dose from about 100 μ

g/day to about 12,000 μ

g/day of said exendin or exendin analog in a single or divided dose;

sublingual administration to achieve a dose from about 10 μ

g/day to about 8,000 μ

g/day of said exendin or exendin analog in a single or divided dose;

nasal administration to achieve a dose from about 10 μ

g/day to about 12,000 μ

g/day of said exendin or exendin analog in a single or divided dose; and

buccal administration to achieve a dose from about 100 μ

g/day to about 12,000 μ

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

28. The formulation of claim 26, said formulation having a pH of between about 4.0 and about 6.0.

29. The formulation of claim 26, wherein said pH is between about 4.0 and about 5.0.

30. The formulation of claim 26, 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 26, wherein said buffer is at a concentration between about 0.02% (w/v) and about 0.5% (w/v).

32. The formulation of claim 26, 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% (w/v) and 10% (w/v).

33. The formulation of claim 26, wherein said polyhydric alcohol is selected from the group consisting of sorbitol, mannitol, inositol, glycerol, xylitol, polyethylene glycols, and any combination thereof.

34. The formulation of claim 26, wherein said carbohydrate is selected from the group consisting of galactose, arabinose, lactose, and any combination thereof.

35. The formulation of claim 26, wherein said iso-osmolality modifier is mannitol, sorbitol, or a combination thereof.

36. The formulation of claim 26, wherein said preservative is m-cresol, phenol or a combination thereof.