Formulations for amylin agonist peptides

• US 20030092606A1
• Filed: 05/31/2002
• Published: 05/15/2003
• Est. Priority Date: 01/08/1997
• Status: Active Grant

• Current Assignee: Astrazeneca Pharmaceuticals LP (Astrazeneca PLC)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: LʼItalien, James, Stetsko, Gregg
• Granted Patent: US 7,312,196 B2
• Time in Patent Office: Days
• US Class Current: 514/5.9
• 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 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• 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: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention is concerned with a pharmaceutical formulation comprising an amylin agonist and optionally a buffer, a tonicifier or stabilizer, and a preservative in a container, for example, a vial, prefilled cartridge, prefilled syringe or disposable pen. This formulation may be in liquid, gel, solid or powdered form for delivery, for example, via nasal, pulmonary, oral, sublingual, buccal, transdermal, or parenteral routes. Formulation with biocompatible polymers and release modifiers, such as sugars, can facilitate controlled release after injection, minimizing the number of administrations to a patient. These formulations maintain stability upon storage under refrigerated or room temperature conditions. Such formulations can be further combined with insulin for administration to a patient.

Claims

1. A liquid pharmaceutical formulation comprising

about 0.5 to 1.0% (w/v) of an amylin agonist, and a pharmaceutically acceptable excipient.

2. The formulation of claim 1, further comprising about 1.0 to 10% (w/v) of a carbohydrate or a polyhydric alcohol, and

about 0.02 to 0.5% (w/v) of an acetate, phosphate, citrate or glutamate buffer.

3. The formulation of claim 1, further comprising a liquid vehicle which comprises water or an aqueous/organic solvent mixture or suspension, and wherein the formulation has a pH of about 3.0 to about 7.0.

4. The formulation of claim 3, wherein the pH of said formulation is about 3.5 to about 5.0.

5. The formulation of claim 3, wherein the pH of said formulation is about 3.8 to about 4.2.

6. The formulation of claim 3 which i s substantially isotonic.

7. The formulation of claim 1 which further comprises a preservative.

8. The formulation of claim 7 wherein said preservative is selected from the group consisting of m-cresol, benzyl alcohol, methyl, ethyl, propyl and butyl parabens and phenol.

9. The formulation of claim 7, wherein said preservative is between about 0.1 to 0.3% (w/v) of m-cresol.

10. The formulation of claim 7, wherein said preservative is at least 0.15% (w/v) of m-cresol.

11. The formulation of claim 1, wherein said amylin agonist is pramlintide.

12. The formulation of claim 2, wherein said polyhydric alcohol is mannitol, sorbitol, inositol, glycerol, xylitol, propylene/ethylene glycol copolymer, PEG 8000, PEG 400, PEG 4000, PEG 200, PEG 1450 or PEG 3350.

13. The formulation of claim 2, wherein said polyhydric alcohol is mannitol.

14. The formulation of claim 2, wherein said carbohydrate is mannose, ribose, trehalose, maltose, glycerol, inositol, lactose, sucrose, fructose, galactose, or arabinose.

15. A formulation mixture comprising a mixture of the formulation of claim 1 and insulin.

16. The formulation mixture of claim 15 for use with an insulin pump device.

17. The formulation of claim 1, wherein said formulation further comprises a surfactant.

18. The formulation of claim 17, wherein said surfactant is polyoxyethylene (20) sorbitan monooleate, 3-[(3-cholamidopropyl) dimethylanmonio] 1-propanl sulfonate, polyoxyethylene (23) lauryl ether, poloxamer or a non-ionic surfactant.

19. The formulation of claim 17, further comprising a preservative.

23. A method for treating a diabetic patient in need of such treatment comprising administering a therapeutically effective amount of the formulation of claim 1 to the patient in need of such treatment.

24. The method of claim 23 wherein insulin is admixed with said formulation.

25. The method of claim 24 wherein the admixing step is simultaneous, or concerted and sequential.

36. The formulation of claim 1 for administration to a subject, wherein the formulation is administered in the form selected from the group consisting of a parenteral controlled release delivery, oral delivery, a microcapsule delivery, an implant delivery, and a polymer matrix delivery.

39. The formulation of claim 1 formulated for nasal or pulmonary delivery.

42. The formulation of claim 1 formulated for controlled release injectable delivery.

43. The formulation of claim 1 formulated for transdermal delivery.

20. A formulation which comprises about 80% to 90% (w/w) of an amylin agonist and about 10% to 20% (w/w) of a pharmaceutically acceptable excipient.

21. The formulation of claim 20 which is a liquid, gel or semi-solid.

22. The formulation of claim 20 which is lyophilized.

26. A method for treating a diabetic patient in need of such treatment comprising administering a therapeutically effective amount of the formulation of claim 20 to the patient in need of such treatment.

27. The method of claim 26 wherein insulin is admixed with said formulation.

28. The method of claim 26 wherein the admixing step is simultaneous, or concerted and sequential.

29. The formulation of claim 20 for nasal, pulmonary or buccal delivery.

30. The formulation of claim 29 further comprising a penetration enhancer, or a stabilizer.

31. The formulation of claim 29 further comprising a polymer.

32. The formulation of claim 29 further comprising a preservative.

37. The formulation of claim 20 for administration to a subject, wherein the formulation is administered in the form selected from the group consisting of oral delivery, a microcapsule delivery, an implant delivery, and a polymer matrix delivery.

40. The formulation of claim 20 formulated in tablets or capsules for oral, sublingual or buccal delivery.

41. The formulation of claim 20 formulated in powder form for nasal or pulmonary delivery.

44. The formulation of claim 20 formulated for transdermal delivery.

33. A solid formulation for oral administration comprising an amylin agonist which comprises about 1 to 98% (w/w) of the formulation, a powdered excipient which comprises about 1.0 to 20% (w/w) of the formulation, and a penetration enhancer or stabilizer.

34. The formulation of claim 33 wherein the formulation is encapsulated within a polymeric coating.

35. The formulation of claim 33, wherein the powdered excipient is lactose.

38. A liquid suspension formulation comprising

about 0.5 to 90% (w/v) of an amylin agonist,

about 1.0 to 10% (w/v) of a carbohydrate or a polyhydric alcohol, and

about 0.02 to 0.5% (w/v) of an acetate, phosphate, citrate or glutamate buffer, and a liquid vehicle,

wherein the formulation has a pH of about 3.0 to 7.0.

45. A formulation comprising about 0.5 to 1.0% (w/v) of an amylin agonist and a pharmaceutically acceptable emulsifier.

46. The formulation of claim 45, wherein the emulsifier is an oil.