Liquid formulation of G-CSF conjugate

• US 8,546,328 B2
• Filed: 08/27/2008
• Issued: 10/01/2013
• Est. Priority Date: 08/27/2007
• Status: Active Grant

• Current Assignee: Ratiopharm GmbH (Teva Pharmaceutical Industries Limited)
• Original Assignee: Biogenerix Ag (Teva Pharmaceutical Industries Limited)
• Inventors: Hinderer, Walter, Scheckermann, Christian
• Primary Examiner(s): Kemmerer, Elizabeth C
• Assistant Examiner(s): Deberry, Regina M
• Application Number:
  US12/675,749
• Publication Number:
  US 20110053844A1
• Time in Patent Office: 1,861 Days
• Field of Search: None
• US Class Current: 514/7.6
• 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 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 Antianaemics

Abstract

The present invention relates to a liquid pharmaceutical composition comprising a granulocyte colony stimulating factor polypeptide conjugated with a polymer, the composition having a pH value in the range of 4.5 to 5.5. The composition further comprises a surfactant and optionally one or more other pharmaceutically acceptable excipients. Further, the composition of the invention is free from tartaric acid or salts thereof and from succinic acid and salts thereof as buffering agents and does not contain amino acids as stabilizer. The composition has a good storage stability and is especially useful for the prophylaxis and treatment of disorders and medical indications where granulocyte colony stimulating factor preparations are considered as useful remedies.

Claims

1. An aqueous preparation comprising a polymer-G-CSF conjugate, wherein the preparation has a pH in the range of 4.5 to 5.5 and further comprises a surfactant, wherein the polymer and G-CSF are linked via a glycosyl linker, and wherein the preparation is free from sulfate ions.

2. Aqueous preparation according to claim 1, wherein the polymer is polyalkylene glycol.

3. Aqueous preparation according to claim 1, wherein the glycosyl linkage is via O-glycosylation.

4. Aqueous preparation according to claim 3, wherein the O-glycosylation is at a threonine residue of the G-CSF protein.

5. Aqueous preparation according to claim 4, wherein the threonine residue is Thr 134 based on the amino acid sequence of methionyl-G-CSF protein or Thr 133 based on the amino acid sequence of naturally occurring human G-CSF.

6. Aqueous preparation according to claim 1, wherein the glycosyl linker comprises a mono-, di- or oligosaccharide.

7. Aqueous preparation according to claim 1, wherein the glycosyl linker comprises sialic acid and N-acetylgalactosamine.

8. Aqueous preparation according to claim 1, wherein the surfactant is present in a concentration of 0.0001% (w/v)- 0.05% (w/v).

9. Aqueous preparation according to claim 1, wherein the surfactant is a polyoxy ethylene sorbitan alkyl ester.

10. Aqueous preparation according to claim 9, wherein the polyoxy ethylene sorbitan alkyl ester is Polysorbate 20 or Polysorbate 80.

11. Aqueous preparation according to claim 1, wherein the pH is in the range of 4.7 to 5.3.

12. Aqueous preparation according to claim 1, wherein the pH is in the range of 4.9 to 5.1.

13. Aqueous preparation according to claim 1, further comprising a physiologically acceptable buffering agent.

14. Aqueous preparation according to claim 13, wherein the buffering agent comprises acetic acid or a salt thereof.

15. Aqueous preparation according to claim 13, wherein the buffering agent is present in a concentration of 2-50 mmol/1.

16. Aqueous preparation according to claim 1, further comprising a tonicity modifying agent selected from sorbitol and mannitol.

17. Aqueous preparation according to claim 1, wherein the tonicity modifying agent is present in a concentration of 1-10%.

18. Aqueous preparation according to claim 1, wherein the preparation is free from stabilising agents selected from amino acids, polymeric stabilising agents and proteinaceous stabilising agents.

19. Aqueous preparation according to claim 1, wherein the preparation is free from preservatives.

20. Aqueous preparation according to claim 1, wherein the pH is adjusted using NaOH.

21. Aqueous preparation according to claim 1, wherein the preparation contains sodium ions.

22. Aqueous preparation according to claim 1, wherein the preparation contains a polymer-G-CSF conjugate as active agent, Polysorbate 20 and/or Polysorbate 80 as surfactant, sorbitol and/or mannitol as tonicity modifier, acetate as buffer and sodium, and no other excipients.

23. Aqueous preparation according to claim 1, wherein the polymer-G-CSF conjugate is present in a concentration of 1-20 mg/ml.

24. Aqueous preparation according to claim 1, wherein the polymer-G-CSF conjugate is present in a concentration of 8-12 mg/ml.

25. Aqueous dilution preparation derived from the aqueous preparation according to claim 1, wherein the aqueous preparation is diluted 1:

2 to 1;

8.

26. Pharmaceutical container containing an aqueous preparation according to claim 1.

27. Pharmaceutical container according to claim 26, wherein the container is a syringe, vial, infusion bottle, ampoule or carpoule.

28. Pharmaceutical container according to claim 26, wherein the container is a syringe equipped with a needle protection system.

29. Pharmaceutical container according to claim 26, wherein the container is a carpoule within an injection pen.

30. Process for preparing an aqueous preparation according to claim 1, wherein the polymer-G-CSF conjugate as the active agent is formulated in an aqueous preparation having a pH in the range of 4.5 to 5.5 and comprising a surfactant and further pharmaceutical excipients.