Stable liquid interferon-beta formulations

• US 8,512,691 B2
• Filed: 10/18/2007
• Issued: 08/20/2013
• Est. Priority Date: 12/24/1996
• Status: Expired due to Fees

• Current Assignee: Biogen MA Inc. (Biogen, Inc.)
• Original Assignee: Biogen Idec MA Inc. (Biogen, Inc.)
• Inventors: DiBiase, Mary D., Chung, Wen-Li, Staples, Mark, Scharin, Eric
• Primary Examiner(s): Ford, Vanessa L.
• Assistant Examiner(s): Hissong, Bruce D
• Application Number:
  US11/975,379
• Publication Number:
  US 20080050338A1
• Time in Patent Office: 2,133 Days
• Field of Search: None
• US Class Current: 424/85.6
• 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 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• 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: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07K 14/565 IFN-beta

Abstract

Liquid interferon compositions having a pH between 4.0 and 7.2 are described. The compositions comprise interferon-beta and a stabilizing agent at between about 0.3% and 5% by weight which is an amino acid selected from the group consisting of acidic amino acids, arginine and glycine. If needed, salt is added to provide sufficient ionic strength. The liquid composition has not been previously lyophilized or previously cavitated. The liquid is preferably contained within a vessel having at least one surface in contact with the liquid that is coated with a material inert to adsorption of interferon-beta. A kit for parenteral administration of a liquid interferon formulation and a method for stabilizing liquid interferon compositions are also described.

Claims

1. A liquid formulation comprising:

(i) an interferon-beta, and (ii) between about 0.3% and 5% by weight of an amino acid selected from the group consisting of acidic amino acids, arginine and glycine, wherein the formulation does not comprise serum albumin and;

wherein the formulation has not been previously lyophilized.

2. The formulation of claim 1, wherein the formulation has a pH of between about 4.0 and 7.2.

3. The formulation of claim 1, wherein the formulation has a pH of between about 4.0 and 5.0.

4. The formulation of claim 1, wherein the formulation has a pH of between about 4.5 and 5.5.

5. The formulation of claim 1, wherein the formulation has a pH of between about 4.8 and 5.2.

6. The formulation of claim 1, wherein the arginine is arginine-HCl.

7. The formulation of claim 1, wherein the interferon-beta is present at between 6 MIU/ml and 50 MIU/ml.

8. The formulation of claim 1, wherein the formulation further comprises a solution of a weak acid comprising acetate and acetate salt.

9. The formulation of claim 8, wherein the acetate or acetate salt is present at 20 mM.

10. The formulation of claim 1, further comprising a surfactant.

11. The formulation of claim 10, wherein the surfactant is 0.1% (w/v) PLURONIC F-68.

12. The formulation of claim 1, wherein said liquid formulation has a dissolved oxygen level that is less than 30% of atmospheric equilibrium levels.

13. The formulation of claim 12, wherein said liquid formulation has a dissolved oxygen level that is less than or equal to 10% of atmospheric equilibrium levels.

14. A liquid formulation comprising:

(i) an interferon-beta present at between 6 MIU/ml and 50 MIU/ml and (ii) between about 0.3% and 5% by weight of arginine-HCl, wherein the formulation does not comprise serum albumin, wherein the formulation has not been previously lyophilized, wherein the formulation has a pH of between 4.8 and 5.2, wherein the formulation further comprises an acetate or acetate salt present at 20 mM and;

wherein the formulation further comprises a surfactant, and;

wherein the formulation has a dissolved oxygen level that is less than or equal to 10% of atmospheric equilibrium levels.

15. A packaged kit for parenteral administration of an interferon-beta, the kit containing a syringe pre-filled with a liquid formulation comprising the interferon-beta and an acidic amino acid stabilizing agent selected from the group consisting of acidic amino acids, arginine and glycine;

wherein the amino acid stabilizing agent is present at between 0.3% and 5% w/v;

wherein the liquid formulation has not been reconstituted from lyophilized interferon;

wherein the liquid formulation is not further lyophilized, wherein the liquid formulation does not comprise serum albumin, and wherein the syringe has a head space flushed with an inert gas.

16. The packaged kit of claim 15, wherein at least one surface of the syringe in contact with the liquid formulation is coated with a material inert to interferon.

17. The packaged kit of claim 15, wherein the formulation has not been cavitated.

18. The packaged kit of claim 15, wherein the formulation has a pH of between about 4.0 and 7.2.

19. The packaged kit of claim 15, wherein the formulation has a pH of between about 4.0 and 5.0.

20. The packaged kit of claim 15, wherein the formulation has a pH of between about 4.5 and 5.5.

21. The packaged kit of claim 15, wherein the formulation has a pH of between about 4.8 and 5.2.

22. The packaged kit of claim 15, wherein the arginine is arginine-HCl.

23. The packaged kit of claim 15, wherein the interferon-beta is present at between 6 MIU/ml and 50 MIU/ml.

24. The packaged kit of claim 15, wherein the formulation further comprises a solution of a weak acid comprising acetate and acetate salt.

25. The packaged kit of claim 24, wherein the acetate or acetate salt is present at 20 mM.

26. The packaged kit of claim 15, wherein the formulation further comprises a surfactant.

27. The packaged kit of claim 26, wherein the surfactant is 0.1% (w/v) PLURONIC F-68.

28. The packaged kit of claim 15, wherein said liquid formulation has a dissolved oxygen level that is less than 30% of atmospheric equilibrium levels.

29. The packaged kit of claim 28, wherein said liquid formulation has a dissolved oxygen level that is less than or equal to 10% of atmospheric equilibrium levels.