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Details for Patent: 8,513,204

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Details for Patent: 8,513,204

Title:Compositions comprising amphotericin B, mehods and systems
Abstract: The present invention comprises compositions and formulations comprising amphotericin B, compositions and formulations comprising amphotericin B with one or more excipients, methods of making amphotericin B compositions and formulations, as well as systems for using amphotericin B compositions and formulations. Also provided are pharmaceutical compositions comprising the formulation, methods of administering the pharmaceutical compositions and methods of treating patients with the pharmaceutical compositions.
Inventor(s): Malcolmson; Richard (San Mateo, CA), Kugler; Alan (Montara, CA), Sweeney; Theresa D. (El Granada, CA), Washco; Keith (Fremont, CA), Miller; Danforth (San Carlos, CA)
Assignee: Novartis AG (Basel, CH)
Filing Date:Sep 20, 2006
Application Number:11/523,978
Claims:1. A pharmaceutical composition, comprising: an effective amount of amphotericin B wherein the pharmaceutical composition is made from particles comprising amphotericin B having a mass median diameter less than about 3 .mu.m; and wherein the amphotericin B has a crystallinity level of at least about 70%.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is made from particles comprising amphotericin B having a mass median diameter less than about 2 .mu.m.

3. The pharmaceutical composition of claim 1, wherein at least about 40 wt % of the particles have a geometric diameter ranging from about 1.1 .mu.m to about 1.9 .mu.m.

4. The pharmaceutical composition of claim 1, wherein the amphotericin B has a crystallinity level of at least about 80%.

5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises particulates.

6. The pharmaceutical composition of claim 1, and further including a pharmaceutically acceptable excipient, and wherein the composition comprises particles having a mass median aerodynamic diameter ranging from about 1 .mu.m to about 6 .mu.m.

7. The pharmaceutical composition of claim 6, wherein at least about 80% of the pharmaceutical composition comprises particulates comprising both amphotericin B and the pharmaceutically acceptable excipient.

8. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises particulates having a mass median aerodynamic diameter less than about 10 .mu.m.

9. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable excipient comprises at least one member selected from carbohydrate, lipid, amino acid, buffer, metal ion, salt, and mixtures thereof.

10. The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable excipient forms a matrix for the particles comprising amphotericin B.

11. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises hollow and/or porous particulates.

12. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises a powder.

13. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises particulates having a mass median aerodynamic diameter ranging from about 1 .mu.m to about 6 .mu.m, wherein the amphotericin B has a crystallinity level of at least about 70%, wherein at least about 80% of the pharmaceutical composition comprises particulates comprising amphotericin B in a matrix comprising a pharmaceutically acceptable excipient, and wherein the pharmaceutically acceptable excipient comprises at least one phospholipid.

14. A pharmaceutical composition, comprising: an effective amount of amphotericin B; and pharmaceutically acceptable excipient, wherein the pharmaceutical composition is made from particles comprising amphotericin B, wherein at least about 40% of the particles comprising amphotericin B have a geometric diameter ranging from about 1.1 .mu.m to about 1.9 .mu.m, and wherein the amphotericin B has a crystallinity level of at least about 70%.

15. The pharmaceutical composition of claim 14, wherein at least about 80% of the particles have a geometric diameter ranging from about 1.1 .mu.m to about 1.9 .mu.m.

16. The pharmaceutical composition of claim 15, wherein the amphotericin B has a crystallinity level of at least about 90%.

17. The pharmaceutical composition of claim 15, wherein the amphotericin B has a crystallinity level of at least about 80%.

18. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition comprises particulates having a mass median aerodynamic diameter less than about 10 .mu.m.

19. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition comprises particulates having a mass median aerodynamic diameter ranging from about 1 .mu.m to about 6 .mu.m.

20. The pharmaceutical composition of claim 14, wherein the pharmaceutically acceptable excipient comprises at least one member selected from carbohydrate, lipid, amino acid, buffer, and salt.

21. The pharmaceutical composition of claim 20, wherein the pharmaceutically acceptable excipient comprises phospholipid.

22. The pharmaceutical composition of claim 20, wherein the pharmaceutically acceptable excipient comprises metal ion.

23. The pharmaceutical composition of claim 14, wherein the pharmaceutically acceptable excipient comprises phospholipid and metal ion.

24. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition comprises hollow and/or porous particulates.

25. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition comprises a powder.

26. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition comprises a propellant.

27. The pharmaceutical composition of claim 26, wherein the propellant comprises at least one hydrofluoroalkane.

28. The pharmaceutical composition of claim 14 wherein the pharmaceutical composition comprises less than about 5 wt % degradants of amphotericin B, based on the weight of amphotericin B.

29. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition comprises particulates having a mass median aerodynamic diameter ranging from about 1 .mu.m to about 6 .mu.m, wherein at least about 80 wt % of the pharmaceutical composition comprises particulates comprising amphotericin B in a matrix comprising the pharmaceutically acceptable excipient, and wherein the pharmaceutically acceptable excipient comprises at least one phospholipid.

30. A powder, comprising: amphotericin B having a crystallinity level of at least about 70%, and wherein the powder comprises particles having a mass median aerodynamic diameter of less than about 10 .mu.m.

31. The pharmaceutical composition of claim 30, wherein the amphotericin B has a crystallinity level ranging from about 70% to about 99%.

32. The pharmaceutical composition of claim 31, wherein the powder comprises particles having a mass median aerodynamic diameter ranging from about 1 .mu.m to about 6 .mu.m.

33. The pharmaceutical composition of claim 32, wherein the powder comprises less than about 5 wt % of degradants of amphotericin B, based on weight of amphotericin B.

34. The pharmaceutical composition of claim 33, wherein the powder is made from particles comprising amphotericin B having a mass median diameter of less than about 3 .mu.m.

35. The pharmaceutical composition of claim 33, wherein the powder is made from particles comprising amphotericin B, and wherein at least about 80 wt % of the particles comprising amphotericin B have a geometric diameter of less than about 3 .mu.m.

36. The pharmaceutical composition of claim 33, further comprising a pharmaceutically acceptable excipient.

37. The pharmaceutical composition of claim 36, wherein at least about 80 wt % of the pharmaceutical composition comprises particulates comprising both amphotericin B and the pharmaceutically acceptable excipient.

38. The pharmaceutical composition of claim 36, wherein the pharmaceutically acceptable excipient comprises at least one member selected from carbohydrate, lipid, amino acid, buffer, and salt.

39. The pharmaceutical composition of claim 36, wherein the pharmaceutically acceptable excipient comprises phospholipid or metal ion or both.

40. The pharmaceutical composition of claim 30, wherein the powder comprises hollow and/or porous particles.

41. The pharmaceutical composition of claim 30, wherein the powder comprises particulates comprising amphotericin B in a matrix comprising a pharmaceutically acceptable excipient.

42. A pharmaceutical composition, comprising: an effective amount of amphotericin B and a pharmaceutically acceptable excipient, wherein the composition comprises particulates having a mass median aerodynamic diameter ranging from about 1 .mu.m to about 6 .mu.m, wherein the amphotericin B has a crystallinity level of at least about 70%, and wherein an amphotericin B lung-residence half-life is at least about 10 hr in lung epithelial lining fluid, as measured by bronchoalveolar lavage, or at least about 1 week in lung tissue, as measured by lung tissue homogenization.

43. The pharmaceutical composition of claim 42 wherein the amphotericin B has a crystallinity level of at least about 80%, wherein at least about 60 wt % of the pharmaceutical composition comprises particulates comprising amphotericin B in a matrix comprising the pharmaceutically acceptable excipient, and wherein the pharmaceutically acceptable excipient comprises at least one phospholipid.

44. A pharmaceutical composition, comprising: an effective amount of an antifungal agent and a pharmaceutically acceptable excipient, wherein the antifungal agent comprises an amphotericin compound, wherein the antifungal agent comprises particulates having a mass median aerodynamic diameter ranging from about 1 .mu.m to about 6 .mu.m, wherein the antifungal agent has a crystallinity level of at least about 70%, wherein at least about 80 wt % of the pharmaceutical composition comprises particulates comprising the antifungal agent in a matrix comprising the pharmaceutically acceptable excipient, and wherein the pharmaceutically acceptable excipient comprises at least one phospholipid; and wherein an antifungal agent lung-residence half-life is at least about 10 hr in epithelial lining fluid, as measured by bronchoalveolar lavage, or at least about 1 week in lung tissue, as measured by lung tissue homogenization.

45. A method of treating a fungal infection, the method comprising: administering a loading dose of a composition comprising an effective amount of amphotericin B and a pharmaceutically acceptable excipient, wherein the amphotericin B has a crystallinity level of at least about 70%; and administering a periodic maintenance dose of said composition comprising amphotericin B.

46. The method of claim 45 wherein the composition is administered as an aerosolized powder.

47. The method of claim 45 wherein the composition is administered as an aerosolized liquid.

48. The method of claim 45 wherein the composition comprises particulates having a mass median aerodynamic diameter ranging from about 1 .mu.m to about 6 .mu.m, wherein at least about 80 wt % of the pharmaceutical composition comprises particulates comprising amphotericin B in a matrix comprising the pharmaceutically acceptable excipient, and wherein the pharmaceutically acceptable excipient comprises at least one phospholipid.

49. The method of claim 48 wherein administration of the composition results in a maximum plasma amphotericin B concentration of less than about 50% of a maximum plasma amphotericin B concentration of a formulation which is less than about 40% crystalline, compared on a dose per dose basis.

50. The method of claim 48 wherein administration of the composition, when administered in a single inhaled dose of no more than about 0.11 mg/kg, results in a maximal plasma amphotericin B concentration of less than about 500 mg/mL measured anytime post dose.

51. The method of claim 45 wherein a fine particle fraction of less than about 3.3 .mu.m is above about 40% of an initial amount amphotericin B.

52. The method of claim 45 wherein a fine particle fraction of less than about 3.3 .mu.m is above about 40% of a total amount of composition.
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