Formulations for amylin agonist peptides

• US 6,410,511 B2
• Filed: 01/09/1998
• Issued: 06/25/2002
• Est. Priority Date: 01/08/1997
• Status: Expired due to Term

• Current Assignee: Astrazeneca Pharmaceuticals LP (Astrazeneca PLC)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Musunuri, Shankar, LʼItalien, James, Ruby, Kale
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): CHANNAVAJJALA, LAKSHMI SARADA
• Application Number:
  US09/005,262
• Publication Number:
  US 20010043934A1
• Time in Patent Office: 1,628 Days
• Field of Search: 514/2, 514/3, 514/4, 514/866, 514/884, 514/12, 424/400, 530/324
• US Class Current: 514/6.5
• 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 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 9/19 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

Abstract

The present invention is concerned with a pharmaceutical formulation in a container, for example, a vial, prefilled cartridge, prefilled syringe or disposable pen, comprising approximately 0.01 to about 0.5% (w/v) amylin agonist, preferably pramlintide, in an aqueous system along with approximately 0.02 to about 0.5% (w/v) of an acetate, phosphate, citrate, or glutamate buffer to a pH of the final composition of approximately 3.0 to about 6.0 as well as approximately 1.0 to 10% (w/v) of a carbohydrate or polyhydric alcohol tonicifier; and, optionally, approximately 0.005 to 1.0% (w/v) of a preservative selected from the group consisting of m-cresol, benzyl alcohol, parabens and phenol. These formulations maintain stability upon storage under refrigerated or room temperature conditions. Such formulations can be further combined with insulin in the same syringe for administration to a patient.

Claims

1. A liquid, pharmaceutical formulation comprising about 0.01 to about 0.5% (w/v) of an amylin agonist, about 1.0 to about 10% (w/v) of a carbohydrate or a polyhydric alcohol, and about 0.02 to about 0.5% (w/v) of an acetate, phosphate, citrate or glutamate buffer, and which has a pH of about 3.0 to about 6.0.

2. The liquid, pharmaceutical formulation of claim 1 which is substantially isotonic.

3. The liquid, pharmaceutical formulation of claim 1 which further comprises a preservative.

4. The liquid, pharmaceutical formulation of claim 3 wherein said preservative is selected from the group consisting of m-cresol, benzyl alcohol, methyl, ethyl, propyl and butyl parabens and phenol.

5. The liquid, pharmaceutical formulation of any of claims 1-4, wherein said amylin agonist is pramlintide.

6. The liquid, pharmaceutical formulation of any of claims 1-4, wherein said polyhydric alcohol is selected from the group consisting of mannitol, sorbitol, inositol, glycerol, xylitol, propylene/ethylene glycol copolymer, PEG 8000, PEG 400, PEG 4000, PEG 200, PEG 1450 or PEG 3350.

7. The liquid, pharmaceutical formulation of any of claims 1-4, wherein said polyhydric alcohol is mannitol.

8. The liquid, pharmaceutical formulation of any of claims 1-4, wherein said carbohydrate is selected from the group consisting of mannose, ribose, trehalose, maltose, glycerol, inositol and lactose.

9. The liquid, pharmaceutical formulation of any of claims 1-4, wherein said buffer is an acetate buffer.

10. The liquid, pharmaceutical formulation of any of claims 1-4, wherein the pH of said formulation is about 3.5 to about 5.0.

11. The liquid, pharmaceutical formulation of any of claims 1-4, wherein the pH of said formulation is about 3.8 to about 4.2.

12. The liquid, pharmaceutical formulation of any of claims 3-4, wherein said preservative is approximately at least about 0.15% (w/v) of m-cresol.

13. The liquid, pharmaceutical formulation of any of claims 3-4, wherein said preservative is approximately about 0.1 to about 0.3 (w/v) of m-cresol.

14. The liquid, pharmaceutical formulation of any of claims 1-4, wherein said formulation further comprises a surfactant.

15. The liquid, pharmaceutical formulation of claim 14, wherein said surfactant is selected from the group consisting of polyoxyethylene (20) sorbitan monooleate, 3-[(3-cholamidopropyl)dimethylammonio] 1-propanl sulfonate, polyoxyethylene (23) lauryl ether, poloxamer or a non-ionic surfactant.

17. The formulation of claim 14, further comprising a preservative.

16. A formulation comprising an amylin agonist which is biologically active, has a reduced tendency to form aggregates in water or at a pressure of greater than 2 psi compared to human amylin, and has a reduced tendency to precipitate in the presence of NaCl compared to human amylin, admixed with one or more compounds which reduce loss of activity of said amylin agonist, in an amylin specific receptor binding assay or bioactivity assay or HPLC assay compared to a composition consisting of said amylin agonist in phosphate-buffered saline or saline, said compounds comprising a tonicity agent and a buffer, said tonicity agent being provided in an amount between 0.01% and 10% and said formulation having a pH of about 3.0 to about 6.0.

18. A method for treating a patient wit pramlintide, and insulin, said method comprising admixing a formulation of pramlintide with insulin and administering the mixture of said formulation and insulin to a patient in need of such treatment, wherein said formulation comprises a tonicifier, a buffer and a preservative, said tonicifier comprising approximately 1.0 to 10% (w/v) of a carbohydrate or a polyhydric alcohol, said buffer comprising approximately 0.02 to 0.5% (w/v) of an acetate, phosphate, citrate or glutamate buffer which allows a pH of the final formulation of approximately 3.0 to 6.0, and said preservative comprising a compound selected from the group consisting of m-cresol, benzyl alcohol, methyl, ethyl, propyl and butyl parabens and phenol, and wherein said pramlintide comprises about 0.01 to about 0.5% (w/v) of the formulation.

19. A commercial package containing a liquid pharmaceutical formulation containing pramlintide, for parenteral administration to a patient, said package comprising a borosilicate glass vial having an open end, a stopper intended for multiuse which is compatible with the amylin and/or amylin agonist, fixed in the open end of the vial, an aluminum band to retain the stopper in the far end of the vial wherein said liquid pharmaceutical formulation comprises a tonicifier, a buffer and a preservative, said tonicifier comprising 1.0 approximately to 1 0% (w/v) of a carbohydrate or a polyhydric alcohol, said buffer comprising approximately 0.02 to 0.5% (w/v) of an acetate, phosphate or glutamate buffer which allows a pH of the final formulation of approximately 3.0 to 6.0, and said preservative is selected from the group consisting of m-cresol, benzyl alcohol, methyl and ethyl parabens and phenol and said pramlintide is approximately 0.01 to 0.5% (w/v) of the formulation.

20. A commercial package containing a liquid pharmaceutical formulation containing pramlintide, for parenteral administration to a patient, said package comprising a cartridge suitable for use in a pen injector wherein said liquid pharmaceutical formulation comprises a tonicifier, a buffer and a preservative, said tonicifier comprising 1.0 approximately to 10% (w/v) of a carbohydrate or a polyhydric alcohol, said buffer comprising approximately 0.02 to 0.5% (w/v) of an acetate, phosphate, citrate or glutamate buffer which allows a pH of the final formulation of approximately 3.0 to 6.0, and said preservative is selected from the group consisting of m-cresol, benzyl alcohol, methyl and ethyl parabens and phenol and said pramlintide is approximately 0.01 to 0.5% (w/v) of the formulation.

21. A composition which comprises about 0.01 to about 0.5% (w/v) of pramlintide, about 1.0 to about 10% (w/v) of mannitol, and about 0.02 to about 0.5% (w/v) of an acetate buffer.

22. The composition of claim 21 which is a liquid.

23. The composition of claim 21 which further comprises about 0.1 to about 0.3% (w/v) of m-cresol.

24. The composition of claim 23 which is a liquid.

25. The composition of either of claims 22 or 24 which has a pH of from about 3.0 to about 6.0.

26. The composition of either of claims 22 or 24 which has a pH of from about 3.5 to about 5.0.

27. The composition of either of claims 22 or 24 which has a pH of from about 3.8 to about 4.2.

28. The composition of claim 21 which is lyophilized.

29. A composition which comprises about 0.01 to about 0.5% (w/v) of pramlintide and about 0.02 to about 0.5% (w/v) of an acetate buffer.

30. The composition of claim 29 which is a liquid.

31. The composition of claim 29 which is lyophilized.