Stable polypeptide formulations

• US 20080124326A1
• Filed: 10/05/2007
• Published: 05/29/2008
• Est. Priority Date: 10/20/2006
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Bondarenko, Pavel, Rehder, Douglas, Matsumura, Masazumi, McAuley, Arnold, Chelius, Dirk
• Granted Patent: US 7,705,132 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 47/02 Inorganic compounds
• 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 9/19 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]

Abstract

The invention provides a formulation including a buffer having a pH less than 6.0, a divalent cation between about 5-200 mM, an excipient comprising a sugar or polyol and an effective amount of a therapeutic polypeptide. Also provided is a method of stabilizing a polypeptide. The method includes contacting a therapeutic polypeptide with a concentration of divalent cation between about 5-150 150 mM in a buffer having a pH less than 6.0 and an excipient comprising a sugar or polyol.

Claims

1. A formulation comprising a buffer having a pH from about 4.0 to less than 6.0, a divalent cation between about 5-150 mM, an excipient comprising a sugar or polyol and an effective amount of a therapeutic antibody having specific binding activity to human epidermal growth factor receptor (EGFR), wherein said therapeutic antibody retains at least about 80% stability for up to two months in solution.

2. The formulation of claim 1, wherein said divalent cation is selected from CaCl₂, ZnCl₂, MnCl₂ or MgCl₂.

3. The formulation of claim 2, wherein said divalent cation is CaCl₂.

4. The formulation of claim 1, wherein said divalent cation concentration is selected from about 25 mM, 50 mM, 75 mM, 100 mM or 125 mM.

5. The formulation of claim 3, wherein said CaCl₂ concentration is 75 mM.

6. The formulation of claim 1, wherein said pH comprises between 4.8-5.2

7. The formulation of claim 1, wherein said buffer is selected from acetic acid, glutamic acid or succinic acid, or a salt thereof.

8. The formulation of claim 1, wherein said buffer comprises a concentration of about 1-50 mM.

9. The formulation of claim 1, wherein said sugar or polyol is selected from glycerol, sucrose, trehalose or sorbitol.

10. The formulation of claim 9, wherein said glycerol, sucrose, trehalose or sorbitol comprises a concentration of about 1-20%.

11. The formulation of claim 9, wherein said glycerol comprises a concentration of between about 1-3%.

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

13. The formulation of claim 12, wherein said surfactant comprises a polysorbate.

14. The formulation of claim 12, wherein said surfactant comprises a concentration of about 0.001-0.10% (w/v).

15. The formulation of claim 1, further comprising a second excipient.

16. The formulation of claim 15, wherein said second excipient is selected from a buffer, stabilizer, tonicity agent, bulking agent, surfactant, cryoprotectant, lyoprotectant, anti-oxidant, metal ion, chelating agent and preservative.

17. The formulation of claim 1, wherein said therapeutic antibody having specific binding activity to human EGFR comprises an Asp or Asn residue susceptible to isomerization to isoaspartic acid.

18. The formulation of claim 1, wherein said therapeutic antibody having specific binding activity to human EGFR comprises a human antibody, a humanized antibody, a chimeric antibody, or a functional fragment thereof.

19. The formulation of claim 18, wherein said human antibody is panitumumab.

20. The formulation of claim 18, wherein said chimeric antibody is Erbitux™

(cetuximab).

21. The formulation of claim 18, wherein said human antibody is selected from IMC-11F8 or HUMAX-EGFR.

22. The formulation of claim 18, wherein said humanized antibody is selected from matuzumab (EMD-7200) or nimotuzumab (TheraCIM hR3).

23. The formulation of claim 18, wherein said functional fragment thereof comprises a Fd, Fv, Fab, F(ab′

), F(ab)₂, F(ab′

)₂, single chain Fv (scFv) or chimeric antibody.

24. The formulation of claim 1, wherein said therapeutic antibody comprises a concentration selected from between about 10-200 mg/ml.

25. A method of stabilizing a polypeptide, comprising contacting a therapeutic antibody having specific binding activity to human epidermal growth factor receptor (EGFR) with a concentration of divalent cation between about 5-150 150 mM in a buffer having a pH from about 4.0 to less than 6.0 and an excipient comprising a sugar or polyol, wherein said therapeutic antibody retains at least about 80% stability for up to two months in solution.

26. The method of claim 25, wherein said divalent cation is selected from CaCl₂, ZnCl₂, MnCl₂ or MgCl₂.

27. The method of claim 26, wherein said divalent cation is CaCl₂.

28. The method of claim 25, wherein said divalent cation concentration is selected from about 25 mM, 50 mM, 75 mM, 100 mM or 125 mM.

29. The method of claim 27, wherein said CaCl₂ concentration is 75 mM.

30. The method of claim 25, wherein said pH comprises between 4.8-5.2

31. The method of claim 25, wherein said buffer is selected from acetic acid, glutamic acid or succinic acid, or a salt thereof.

32. The method of claim 25, wherein said buffer comprises a concentration of about 1-50 mM.

33. The method of claim 25, wherein said sugar or polyol is selected from glycerol, sucrose, trehalose or sorbitol.

34. The method of claim 33, wherein said glycerol, sucrose, trehalose or sorbitol comprises a concentration of about 1-20%.

35. The method of claim 33, wherein said glycerol comprises a concentration of between about 1-3%.

36. The method of claim 25, further comprising a surfactant.

37. The method of claim 36, wherein said surfactant comprises a polysorbate.

38. The method of claim 36, wherein said surfactant comprises a concentration of about 0.001-0.10% (w/v).

39. The method of claim 25, further comprising a second excipient.

40. The method of claim 39, wherein said second excipient is selected from a buffer, stabilizer, tonicity agent, bulking agent, surfactant, cryoprotectant, lyoprotectant, anti-oxidant, metal ion, chelating agent and preservative.

41. The method of claim 25, wherein said therapeutic antibody having specific binding activity to human EGFR comprises an Asp or Asn residue susceptible to isomerization to isoaspartic acid.

42. The method of claim 25, wherein said therapeutic antibody having specific binding activity to human EGFR comprises a human antibody, a humanized antibody, a chimeric antibody, or a functional fragment thereof.

43. The method of claim 42, wherein said human antibody is panitumumab.

44. The method of claim 42, wherein said chimeric antibody is Erbitux™

(cetuximab).

45. The method of claim 42, wherein said human antibody is selected from IMC-11F8 or HUMAX-EGFR.

46. The method of claim 42, wherein said humanized antibody is selected from matuzumab (EMD-7200) or nimotuzumab (TheraCIM hR3).

47. The method of claim 42, wherein said functional fragment thereof comprises a Fd, Fv, Fab, F(ab′

), F(ab)₂, F(ab′

)₂, single chain Fv (scFv) or chimeric antibody.

48. The method of claim 25, wherein said therapeutic antibody comprises a concentration selected from between about 10-200 mg/ml.