Lyophilized Formulations of Exendins and Exendin Agonist Analogs

• US 20090215694A1
• Filed: 02/20/2009
• Published: 08/27/2009
• Est. Priority Date: 01/14/1999
• Status: Active Grant

• Current Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Young, Andrew A., Kolterman, Orville G., L'Italien, James J.
• Granted Patent: US 7,906,146 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• 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 lyophilized formulation comprising about 0.005% (w/v) to about 0.4% (w/v) exendin-4 and about 1.0% (w/v) to about 10% (w/v) mannitol.

2. A lyophilized formulation comprising about 0.005% (w/v) to about 0.4% (w/v) of an exendin or an exendin agonist analog and about 1.0% (w/v) to about 10% (w/v) of mannose, ribose, trehalose, maltose, glycerol, inositol, glucose, lactose, galactose, arabinose, sorbitol, mannitol, glycerol, xylitol, a polypropylene/ethylene glycol copolymer, a polyethylene glycol, or a combination thereof.

3. The lyophilized formulation of claim 2, wherein the exendin or the exendin agonist analog is exendin-3 or exendin-4.

4. The lyophilized formulation of claim 2, wherein the exendin or the exendin agonist analog is present in an amount of about 0.005% (w/v) to about 0.02% (w/v).

5. A lyophilized formulation comprising about 0.005% (w/v) to about 0.4% (w/v) of an exendin or an exendin agonist analog and about 1.0% (w/v) to about 10% (w/v) of a bulking agent.

6. The lyophilized formulation of claim 5, wherein the bulking agent is a carbohydrate, a polyhydric alcohol, or a combination thereof.

7. The lyophilized formulation of claim 6, wherein the carbohydrate is mannose, ribose, trehalose, maltose, glycerol, inositol, glucose, lactose, galactose, or arabinose.

8. The lyophilized formulation of claim 6, wherein the polyhydric alcohol is sorbitol, mannitol, glycerol, xylitol, a polypropylene/ethylene glycol copolymer, or a polyethylene glycol.

9. The lyophilized formulation of claim 5, wherein the bulking agent is mannitol.

10. The lyophilized formulation of claim 5, further comprising about 0.1% (w/v) to about 1.0% (w/v) of a surfactant.

11. The lyophilized formulation of claim 5, further comprising about 0.02% (w/v) to about 0.5% (w/v) of a buffer.

12. The lyophilized formulation of claim 11, wherein the buffer is an acetate buffer, a phosphate buffer, a citrate buffer, a glutamate buffer, or a combination of two or more thereof.

13. The lyophilized formulation of claim 5, further comprising about 0.005% (w/v) to about 1.0% (w/v) of an anti-microbial preservative.

14. The lyophilized formulation of claim 13, wherein the anti-microbial preservative is m-cresol, benzyl alcohol, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, or phenol.

15. The lyophilized formulation of claim 5, comprising about 0.005% (w/v) to about 0.02% (w/v) of an exendin or an exendin agonist analog.

16. The lyophilized formulation of claim 5, comprising about 0.005% (w/v) to about 0.05% (w/v) of an exendin or an exendin agonist analog.

17. The lyophilized formulation of claim 5, wherein the lyophilized formulation is a unit dosage formulation or a multi-unit dosage formulation.

18. The lyophilized formulation of claim 5, wherein the exendin or the exendin agonist analog comprises the amino acid sequence of any one of SEQ ID NOs:

4-239.

19. The lyophilized formulation of claim 5, wherein the exendin or the exendin agonist analog is exendin-3 or exendin-4.

20. The lyophilized formulation of claim 5, wherein the exendin or the exendin agonist analog is linked to a polyethylene glycol, an albumin, a polyamino acid, or a gelatin.