Human serum albumin-free stabilized interferon liquid formulations

• US 20070059285A1
• Filed: 04/29/2004
• Published: 03/15/2007
• Est. Priority Date: 05/01/2003
• Status: Active Grant

• Current Assignee: Ares Trading SA (Merck & Co., Inc.)
• Original Assignee: Ares Trading SA (Merck & Co., Inc.)
• Inventors: Del Rio, Alessandra, Samaritani, Fabrizio
• Granted Patent: US 8,309,069 B2
• Time in Patent Office: Days
• US Class Current: 424/85.500
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 38/215 IFN-beta
• 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 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• 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 9/0019 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 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/12 Keratolytics, e.g. wart or anti-corn preparations
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A stabilized HSA-free liquid pharmaceutical composition is described, which comprises an interferon (IFN), wherein said formulation is a solution that comprises a buffer, a surfactant, an isotonicity agent and an antioxidant. Preferably the interferon is human recombinant IFN-beta.

Claims

1. A stabilized HSA-free liquid pharmaceutical composition comprising an interferon (IFN), wherein said composition is a solution that comprises a buffer, a surfactant, an isotonicity agent and an anti-oxidant.

2. The composition of claim 1, wherein said interferon is IFN-beta.

3. The composition of claim 1, wherein said IFN-beta is human recombinant IFN-beta.

4. The composition of claims claim 1, wherein said buffer is present in an amount sufficient to maintain the pH of said composition within plus or minus 0.5 units of a specified pH, where the specified pH is about 3.0 to about 5.0.

5. The composition of claim 4, wherein said pH is 3.5±

.0.2.

6. The composition of claim 4, wherein said pH is 4.5±

.0.2.

7. The composition of claim 1, wherein said buffer is present at a concentration of about 5 mM to 500 mM.

8. The composition of claim 1, wherein said buffer is present at a concentration of about 10 mM.

9. The composition of claim 1 wherein the buffer is acetate buffer.

10. The composition of claim 1, wherein said isotonicity agent is mannitol.

11. The composition of claim 1, wherein said isotonicity agent is present at a concentration of about 0.5 mg/ml to about 500 mg/ml.

12. The composition of claim 1, wherein said isotonicity agent is present at a concentration of about 55 mg/ml.

13. The composition of claim 1, wherein said surfactant is selected from Pluronic®

F77, Pluronic®

F87, Pluronic®

F88 and Pluronic®

F68.

14. The composition of claim 1, wherein said surfactant is Pluronic®

F68.

15. The composition of claim 1, wherein said surfactant is present at a concentration of about 0.01 mg/ml to about 10 mg/ml.

16. The composition of claim 1, wherein said surfactant is present at a concentration of about 1 mg/ml.

17. The composition of claim 1, wherein said antioxidant is methionine.

18. The composition of claim 1, wherein said antioxidant is present at a concentration of about 0.01 to about 5.0 mg/ml.

19. The composition of claim 1, wherein said antioxidant is present at a concentration of about 0.1 mg/ml.

20. The composition of claim 1, wherein said interferon is present at a concentration of about 10 μ

g/ml to about 800 μ

g/ml.

21. The composition of claim 1, wherein said interferon is present at a concentration of about 22, 44, 88 or 264 μ

g/ml.

22. The composition of claim 1, wherein said composition is an aqueous solution.

23. The composition of claim 1, further comprising a bacteriostatic agent.

24. The composition of claim 23, wherein said bacteriostatic agent is benzyl alcohol.

25. The composition of claim 23, wherein said bacteriostatic agent is present at a concentration of about 0.1% to about 2.0%.

26. The composition of claim 23, wherein said bacteriostatic agent is present at a concentration of about 0.2 or 0.3%.

27. A method for preparing a stabilized HSA-free liquid pharmaceutical composition according to claim 1, wherein said method comprises adding a calculated amounts of surfactant, antioxidant and isotonicity agent to the buffered solution and then adding the interferon (IFN).

28. A container hermetically sealed in conditions sterile and appropriate for storage prior to use, comprising the liquid pharmaceutical formulation according to claim 1.

29. The container of claim 28, wherein said container is a pre-filled syringe for mono-dose administration.

30. The container of claim 28, wherein said container is a vial.

31. The container of claim 28, wherein said container is a cartridge for an auto-injector.

32. The container of claim 28, wherein said container is for mono-dose or multi-dose administration.

33. A kit for multi-dose administration of a pharmaceutical composition, wherein the kit comprises a first container filled with a pharmaceutical composition according to claim 1 and a second cartridge filled of a solution of a bacteriostatic agent.