Methods of reducing aggregation of IL-1ra

• US 20070098684A9
• Filed: 04/01/2005
• Published: 05/03/2007
• Est. Priority Date: 04/02/2004
• Status: Active Grant

• Current Assignee: Swedish Orphan Biovitrum AB (publ)
• Original Assignee: Swedish Orphan Biovitrum AB (publ)
• Inventors: Kerwin, Bruce, Raibekas, Andrei
• Granted Patent: US 10,765,747 B2
• Time in Patent Office: Days
• US Class Current: 424/85.2
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/7012 Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid gluconic acid A61K31/191; ascorbic acid A61K31/375
• CPC Class Codes: A61K 33/42 Phosphorus; Compounds thereof
• CPC Class Codes: A61K 38/20 Interleukins [IL]
• CPC Class Codes: A61K 47/02 Inorganic compounds
• 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 9/0019 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 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 13/12 of the kidneys
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07K 14/54 Interleukins [IL]
• CPC Class Codes: C07K 14/545 IL-1
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Methods of reducing aggregation of an aggregating IL-1ra comprising incubating IL-1ra with at least one accessory molecule are provided. Kits comprising IL-1ra and at least one accessory molecule are also provided. Pharmaceutical compositions comprising IL-1ra and at least one accessory molecule are also provided.

Claims

1. A method of reducing aggregation of an aggregating interleukin-1 receptor antagonist (IL-1ra) comprising incubating IL-1ra with at least one accessory molecule at a concentration sufficient to reduce aggregation of the IL-1ra or reduce the rate of aggregation of the IL-1ra, wherein at least one of the at least one accessory molecule is selected from a sugar and a multiple-charge anion.

2. The method of claim 1, wherein at least one accessory molecule is a multiple-charge anion.

3. The method of claim 2, wherein said multiple-charge anion is 1 to 20 mM pyrophosphate.

4. The method of claim 2, wherein said multiple-charge anion is 1 to 20 mM citrate.

5. The method of claim 1, wherein at least one accessory molecule is a sugar.

6. The method of claim 5, wherein said sugar is glycerol, sorbitol, or sucrose.

7. The method of claim 5, wherein said sugar is at a concentration of from 1 to 3 percent.

8. The method of claim 1, wherein at least one accessory molecule is selected from a lysine-reactive accessory molecule and an arginine-reactive accessory molecule.

9. The method of claim 1, wherein at least one accessory molecule is selected from 6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoic acid (NBD-X), methyl acetyl phosphate (MAP), and citraconic anhydride.

10. A method of preparing an interleukin-1 receptor antagonist (IL-1 ra) drug formulation comprising incubating an aggregating IL-1ra with at least one accessory molecule at a concentration sufficient to reduce aggregation of the IL-1ra or reduce the rate of aggregation of the IL-1ra, wherein at least one of the at least one accessory molecule is selected from a sugar and a multiple-charge anion, wherein aggregation is reduced.

11. The method of claim 10, wherein at least one accessory molecule is a multiple-charge anion.

12. The method of claim 11, wherein said multiple-charge anion is 1 to 20 mM pyrophosphate.

13. The method of claim 11, wherein said multiple-charge anion is 1 to 20 mM citrate.

14. The method of claim 10, wherein at least one accessory molecule is a sugar.

15. The method of claim 14, wherein said sugar is glycerol, sorbitol, or sucrose.

16. The method of claim 14, wherein said sugar is at a concentration of from 1 to 3 percent.

17. The method of claim 10, wherein at least one accessory molecule is selected from a lysine-reactive accessory molecule and an arginine-reactive accessory molecule.

18. The method of claim 10, wherein at least one accessory molecule is selected from 6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoic acid (NBD-X), methyl acetyl phosphate (MAP), and citraconic anhydride.

19. A method of treating a patient comprising administering to the patient a composition comprising (i) a therapeutically effective amount of an aggregating interleukin-1 receptor antagonist (IL-1ra) and (ii) at least one accessory molecule at a concentration sufficient to reduce aggregation of the IL-1ra or reduce the rate of aggregation of the IL-1ra, wherein at least one of the at least one accessory molecule is selected from a sugar and a multiple-charge anion.

20. The method of claim 19, wherein at least one accessory molecule is a multiple-charge anion.

21. The method of claim 20, wherein said multiple-charge anion is 1 to 20 mM pyrophosphate.

22. The method of claim 20, wherein said multiple-charge anion is 1 to 20 mM citrate.

23. The method of claim 19, wherein at least one accessory molecule is a sugar.

24. The method of claim 23, wherein said sugar is glycerol, sorbitol, or sucrose.

25. The method of claim 23, wherein said sugar is at a concentration of from 1 to 3 percent.

26. The method of claim 19, wherein at least one accessory molecule is selected from a lysine-reactive accessory molecule and an arginine-reactive accessory molecule.

27. The method of claim 19, wherein at least one accessory molecule is selected from 6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoic acid (NBD-X), methyl acetyl phosphate (MAP), and citraconic anhydride.

28. A method of treating a patient having rheumatoid arthritis comprising administering to the patient a composition comprising (i) a therapeutically effective amount of an aggregating interleukin-1 receptor antagonist (IL-1ra) and (ii) at least one accessory molecule at a concentration sufficient to reduce aggregation of the IL-1ra or reduce the rate of aggregation of the IL-1ra, wherein at least one of the at least one accessory molecule is selected from a sugar and a multiple-charge anion.

29. The method of claim 28, wherein at least one accessory molecule is a multiple-charge anion.

30. The method of claim 29, wherein said multiple-charge anion is 1 to 20 mM pyrophosphate.

31. The method of claim 29, wherein said multiple-charge anion is 1 to 20 mM citrate.

32. The method of claim 28, wherein at least one accessory molecule is a sugar.

33. The method of claim 32, wherein said sugar is glycerol, sorbitol, or sucrose.

34. The method of claim 32, wherein said sugar is at a concentration of from 1 to 3 percent.

35. The method of claim 28, wherein at least one accessory molecule is selected from a lysine-reactive accessory molecule and an arginine-reactive accessory molecule.

36. The method of claim 28, wherein at least one accessory molecule is selected from 6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoic acid (NBD-X), methyl acetyl phosphate (MAP), and citraconic anhydride.

37. A method of treating a patient having osteoarthritis comprising administering to the patient a composition comprising (i) a therapeutically effective amount of an aggregating interleukin-1 receptor antagonist (IL-1ra) and (ii) at least one accessory molecule at a concentration sufficient to reduce aggregation of the IL-1ra or reduce the rate of aggregation of the IL-1ra, wherein at least one of the at least one accessory molecule is selected from a sugar and a multiple-charge anion.

38. The method of claim 37, wherein at least one accessory molecule is a multiple-charge anion.

39. The method of claim 38, wherein said multiple-charge anion is 1 to 20 mM pyrophosphate.

40. The method of claim 38, wherein said multiple-charge anion is 1 to 20 mM citrate.

41. The method of claim 37, wherein at least one accessory molecule is a sugar.

42. The method of claim 41, wherein said sugar is glycerol, sorbitol, or sucrose.

43. The method of claim 41 wherein said sugar is at a concentration of from 1 to 3 percent.

44. The method of claim 37, wherein at least one accessory molecule is selected from a lysine-reactive accessory molecule and an arginine-reactive accessory molecule.

45. The method of claim 37, wherein at least one accessory molecule is selected from 6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoic acid (NBD-X), methyl acetyl phosphate (MAP), and citraconic anhydride.

46. A pharmaceutical composition comprising an aggregating interleukin-1 receptor antagonist (IL-1ra) and at least one accessory molecule at a concentration sufficient to reduce aggregation of the IL-1ra or reduce the rate of aggregation of the IL-1ra, wherein at least one of the at least one accessory molecule is selected from a sugar and a multiple-charge anion, and wherein aggregation is reduced.

47. The pharmaceutical composition of claim 46, wherein at least one accessory molecule is a multiple-charge anion.

48. The pharmaceutical composition of claim 47, wherein said multiple-charge anion is −

1 to 20 mM pyrophosphate.

49. The pharmaceutical composition of claim 47, wherein said multiple-charge anion is 1 to 20 mM citrate.

50. The pharmaceutical composition of claim 46, wherein at least one accessory molecule is a sugar.

51. The pharmaceutical composition of claim 50, wherein said sugar is glycerol, sorbitol, or sucrose.

52. The pharmaceutical composition of claim 50, wherein said sugar is at a concentration of from 1 to 3 percent.

53. The pharmaceutical composition of claim 46, wherein at least one accessory molecule is selected from a lysine-reactive accessory molecule and an arginine-reactive accessory molecule.

54. The pharmaceutical composition of claim 46, wherein at least one accessory molecule is selected from 6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoic acid (NBD-X), methyl acetyl phosphate (MAP), and citraconic anhydride.