Interleukin-13 antagonist powders, spray-dried particles, and methods

• US 20050186146A1
• Filed: 02/14/2005
• Published: 08/25/2005
• Est. Priority Date: 02/12/2004
• Status: Abandoned Application

• Current Assignee: Novartis Pharma AG (Novartis Ag)
• Original Assignee: Nektar Therapeutics Incorporated
• Inventors: Patton, John S., Gong, David K., Hastedt, Jayne E.
• Application Number:
  US11/058,509
• Publication Number:
  US 20050186146A1
• Time in Patent Office: Days
• US Class Current: 424/46
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1688 resulting in pure drug agglomerate optionally containing up to 5% of excipient
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 33/12 Schistosomicides
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/7155 for interleukins [IL]
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• 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

A powder includes IL-13 antagonist, wherein the powder has a mass median aerodynamic diameter (MMAD) of less than about 10 μm. A composition includes a spray-dried particle including IL-13 antagonist. A method of administering IL-13 antagonist to the lungs of a subject includes: dispersing a dry powder composition involving IL-13 antagonist to form an aerosol; and delivering the aerosol to the lungs of the subject by inhalation of the aerosol by the subject, thereby ensuring delivery of the IL-13 antagonist to the lungs of the subject. A method of treating an IL-13-related condition includes: pulmonarily administering a therapeutically effective amount of a dry powder including IL-13 antagonist. A method of preparing IL-13 antagonist-containing powder involves: combining IL-13 antagonist, optional excipient, and solvent to form a mixture or solution; and spray drying the mixture or solution to obtain the powder.

Claims

1. A powder comprising IL-13 antagonist, wherein the powder has a mass median aerodynamic diameter (MMAD) of less than about 10 μ

m.

2. The powder of claim 1, wherein the IL-13 antagonist comprises at least one IL-13 binding member selected from IL-13Rα

1, IL-13Rα

2, antibody to IL-13, fragments thereof, homologs thereof, and conjugates thereof.

3. The powder of claim 1, wherein the IL-13 antagonist comprises at least one member selected from IL-13Rα

2 and IL-13Rα

2-IgG fusion protein.

4. The powder of claim 1, wherein the IL-13 antagonist is present in an amount ranging from about 2 wt % to 100 wt %, based on total weight of the powder.

5. The powder of claim 1, wherein the IL-13 antagonist is present in an amount ranging from about 5 wt % to about 60 wt %, based on total weight of the powder.

6. The powder of claim 1, wherein the MMAD ranges from about 0.5 μ

m to about 4 μ

m.

7. The powder of claim 1, wherein the powder has a fine particle fraction (FPF_<

3.3 μ

m) ranging from about 0.4 to about 0.95.

8. The powder of claim 1, wherein the powder has a fine particle fraction (FPF_<

4.7 μ

m) ranging from about 0.5 to about 0.7.

9. The powder of claim 1, further comprising a pharmaceutically acceptable excipient.

10. The powder of claim 9, wherein the pharmaceutically acceptable excipient comprises at least one member selected from carbohydrate, amino acid, peptide, and buffer.

11. The powder of claim 10, wherein the pharmaceutically acceptable excipient comprises carbohydrate.

12. The powder of claim 11, wherein the carbohydrate comprises at least one member selected from cellobiose, dextrans, dextrose, fructose, galactose, glucitol, glucose, lactitol, lactose, maltodextrans, maltose, mannitol, mannose, melezitose, myoinositol, pyranosyl, raffinose, sorbitol, sorbose, starches, sucrose, trehalose, and xylitol.

13. The powder of claim 11, wherein the carbohydrate comprises at least one member selected from sucrose and mannitol.

14. The powder of claim 10, wherein the pharmaceutically acceptable excipient comprises amino acid.

15. The powder of claim 10, wherein the pharmaceutically acceptable excipient comprises peptide.

16. The powder of claim 15, wherein the peptide comprises at least one member selected from dileucine, leu-leu-gly, leu-leu-ala, leu-leu-val, leu-leu-leu, leu-leu-ile, leu-leu-met, leu-leu-pro, leu-leu-phe, leu-leu-trp, leu-leu-ser, leu-leu-thr, leu-leu-cys, leu-leu-tyr, leu-leu-asp, leu-leu-glu, leu-leu-lys, leu-leu-arg, leu-leu-his, leu-leu-nor, leu-gly-leu, leu-ala-leu, leu-val-leu, leu-ile-leu, leu-met-leu, leu-pro-leu, leu-phe-leu, leu-trp-leu, leu-ser-leu, leu-thr-leu, leu-cys-leu, leu-try-leu, leu-asp-leu, leu-glu-leu, leu-lys-leu, leu-arg-leu, leu-his-leu, and leu-nor-leu.

17. The powder of claim 16, wherein the peptide comprises at least one member selected from dileucine and trileucine.

18. The powder of claim 10, wherein the pharmaceutically acceptable excipient comprises buffer.

19. The powder of claim 18, wherein the buffer comprises at least one member selected from sodium citrate, phosphate, and citric acid.

20. The powder of claim 1, further comprising at least one additional member selected from immune modulating cytokine and cytokine antagonist.

21. The powder of claim 20, wherein the at least one additional member comprises IL-4 antagonist.

22. The powder of claim 1, wherein storage of the powder at 40°

C. and 75% relative humidity for one month results in an increase in soluble aggregation of less than 2.5%, as measured by size exclusion chromatography.

23. The powder of claim 1, wherein storage of the powder at 40°

C. and 75% relative humidity for one month results in an increase in covalent aggregation of less than 2.5%, as measured by SDS-PAGE.

24. A composition, comprising spray-dried particle comprising IL-13 antagonist.

25. The composition of claim 24, wherein the IL-13 antagonist comprises at least one IL-13 binding member selected from IL-13Rα

1, IL-13Rα

2, antibody to IL-13, fragments thereof, homologs thereof, and conjugates thereof.

26. The composition of claim 24, wherein the IL-13 antagonist comprises at least one member selected from IL-13Rα

2 and IL-13Rα

2-IgG fusion protein.

27. The composition of claim 24, wherein the IL-13 antagonist is present in an amount ranging from about 2 wt % to 100 wt %, based on total weight of the spray-dried particle.

28. The composition of claim 24, wherein the IL-13 antagonist is present in an amount ranging from about 5 wt % to about 60 wt %, based on total weight of the spray-dried particle.

29. The composition of claim 24, wherein the composition comprises a powder having a mass median aerodynamic diameter (MMAD) ranging from about 0.5 μ

m to about 5 μ

m.

30. The composition of claim 24, wherein the composition comprises a powder having a fine particle fraction (FPF_<

3.3 μ

m) ranging from about 0.4 to about 0.95.

31. The composition of claim 24, wherein the composition comprises a powder having a fine particle fraction (FPF_<

4.7 μ

m) ranging from about 0.5 to about 0.7.

32. The composition of claim 24, further comprising a pharmaceutically acceptable excipient.

33. The composition of claim 32, wherein the pharmaceutically acceptable excipient comprises at least one member selected from carbohydrate, amino acid, peptide, and buffer.

34. The composition of claim 33, wherein the pharmaceutically acceptable excipient comprises carbohydrate.

35. The composition of claim 34, wherein the carbohydrate comprises at least one member selected from cellobiose, dextrans, dextrose, fructose, galactose, glucitol, glucose, lactitol, lactose, maltodextrans, maltose, mannitol, mannose, melezitose, myoinositol, pyranosyl, raffinose, sorbitol, sorbose, starches, sucrose, trehalose, and xylitol.

36. The composition of claim 34, wherein the carbohydrate comprises at least one member selected from sucrose and mannitol.

37. The composition of claim 33, wherein the pharmaceutically acceptable excipient comprises amino acid.

38. The composition of claim 33, wherein the pharmaceutically acceptable excipient comprises peptide.

39. The composition of claim 38, wherein the peptide comprises at least one member selected from dileucine, leu-leu-gly, leu-leu-ala, leu-leu-val, leu-leu-leu, leu-leu-ile, leu-leu-met, leu-leu-pro, leu-leu-phe, leu-leu-trp, leu-leu-ser, leu-leu-thr, leu-leu-cys, leu-leu-tyr, leu-leu-asp, leu-leu-glu, leu-leu-lys, leu-leu-arg, leu-leu-his, leu-leu-nor, leu-gly-leu, leu-ala-leu, leu-val-leu, leu-ile-leu, leu-met-leu, leu-pro-leu, leu-phe-leu, leu-trp-leu, leu-ser-leu, leu-thr-leu, leu-cys-leu, leu-try-leu, leu-asp-leu, leu-glu-leu, leu-lys-leu, leu-arg-leu, leu-his-leu, and leu-nor-leu.

40. The composition of claim 39, wherein the peptide comprises at least one member selected from dileucine and trileucine.

41. The composition of claim 33, wherein the pharmaceutically acceptable excipient comprises buffer.

42. The composition of claim 41, wherein the buffer comprises at least one member selected from sodium citrate, phosphate, and citric acid.

43. The composition of claim 24, further comprising at least one additional member selected from immune modulating cytokine and cytokine antagonist.

44. The composition of claim 43, wherein the at least one additional member comprises IL-4 antagonist.

45. The composition of claim 24, wherein storage of the powder at 40°

C. and 75% relative humidity for one month results in an increase in soluble aggregation of less than 2.5%, as measured by size exclusion chromatography.

46. The composition of claim 24, wherein storage of the powder at 40°

C. and 75% relative humidity for one month results in an increase in covalent aggregation of less than 2.5%, as measured by SDS-PAGE.

47. A method of administering IL-13 antagonist to the lungs of a subject, comprising:

dispersing a dry powder composition comprising IL-13 antagonist to form an aerosol, wherein the dry powder composition has a mass median aerodynamic diameter (MMAD) of less than about 10 μ

m; and

delivering the aerosol to the lungs of the subject by inhalation of the aerosol by the subject, thereby ensuring delivery of the IL-13 antagonist to the lungs of the subject.

48. The method of claim 47, wherein the composition comprises a therapeutically effective amount of the IL-13 antagonist.

49. The method of claim 47, wherein the composition comprises IL-13 antagonist in an amount ranging from about 0.1 mg to about 30 mg.

50. The method of claim 47, wherein the method is repeated so that a therapeutically effective amount of the IL-13 antagonist is delivered to the lungs of the subject.

51. The method of claim 47, wherein the IL-13 antagonist comprises at least one IL-13 binding member selected from IL-13Rα

1, IL-13Rα

2, antibody to IL-13, fragments thereof, homologs thereof, and conjugates thereof.

52. The method of claim 47, wherein the IL-13 antagonist comprises at least one member selected from IL-13Rα

2 and IL-13Rα

2-IgG fusion protein.

53. The method of claim 47, wherein the composition comprises spray-dried powder.

54. The method of claim 47, wherein the composition is delivered via a dry powder inhaler.

55. The method of claim 47, wherein the composition is delivered via a metered-dose inhaler.

56. A method of treating an IL-13-related condition, comprising:

pulmonarily administering a therapeutically effective amount of a dry powder comprising IL-13 antagonist, wherein the dry powder a mass median aerodynamic diameter (MMAD) of less than about 10 μ

m.

57. The method of claim 56, wherein the IL-related condition comprises at least one condition selected from inflammation, asthma, allergies, fibrosis, graft rejection, granuloma, sclerosis, progressive systemic sclerosis, and schistosomiasis.

58. The method of claim 56, wherein the at least one condition comprises idiopathic pulmonary fibrosis, chronic graft rejection, bleomycin-induced pulmonary fibrosis, radiation-induced pulmonary fibrosis, pulmonary granuloma, progressive systemic sclerosis, schistosomiasis, and hepatic fibrosis.

59. The method of claim 56, wherein the therapeutically effective amount ranges from about 0.05 mg/kg to about 5 mg/kg.

60. A method of preparing IL-13 antagonist-containing powder, comprising:

combining IL-13 antagonist, optional excipient, and solvent to form a mixture or solution; and

spray drying the mixture or solution to obtain the powder.

61. The method of claim 60, wherein the powder is dry.

62. The method of claim 60, wherein the powder is suitable for pulmonary administration.