Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use

• US 20060159625A1
• Filed: 07/22/2005
• Published: 07/20/2006
• Est. Priority Date: 05/10/2000
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Nektar Therapeutics Incorporated
• Inventors: Clark, Andrew, Narashimhan, Rangachari, Eldon, Michael A., Weers, Jeffry G., Tarara, Thomas E.
• Granted Patent: US 8,404,217 B2
• Time in Patent Office: Days
• US Class Current: 424/45
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• 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 9/1617 Organic compounds, e.g. phospholipids, fats

Abstract

Formulations are provided for pulmonary administration of an antifungal agent to a patient. Methods of using the formulations in the treatment of antifungal infections are also provided, including treatment of pulmonary aspergillosis with amphotericin B-containing formulations. Methods of manufacturing the formulations to achieve optimum properties are provided as well.

Claims

1. A pharmaceutical formulation for pulmonary administration, comprising a plurality of particulates having a mass median diameter less than 20 μ

m, wherein each particulate comprises;

(a) a lipid matrix; and

(b) at least one particle of an active agent in the lipid matrix, said active agent having an aqueous solubility of less than 1.0 mg/ml, wherein at least 90% of the active agent particles in the formulation have a geometric diameter less than 3 μ

m.

2. The pharmaceutical formulation of claim 1 wherein the plurality of particulates has a mass median diameter less than 10 μ

m.

3. The pharmaceutical formulation of claim 2, wherein the plurality of particulates has a mess median diameter less than 5 μ

m.

4. The pharmaceutical formulation of claim 1, wherein at least at least 95% of the active agent particles have a geometric diameter less than 3 μ

m.

5. The pharmaceutical formulation of claim 4, wherein at least 50% of the active agent particles have a geometric diameter between 0.5 μ

m and 3 μ

m.

6. The pharmaceutical formulation of claim 5, wherein at least 50% of the active agent particles have a geometric diameter between 1 μ

m and 3 μ

m.

7. The pharmaceutical formulation of claim 1, wherein the lipid matrix comprises a phospholipid.

8. The pharmaceutical formulation of claim 7, wherein the phospholipid has a gel to liquid phase transition temperature greater than about 40°

C.

9. The pharmaceutical formulation of claim 8, wherein the phospholipid has a gel to liquid phase transition temperature greater than about 60°

C.

10. The pharmaceutical formulation of claim 9, wherein the phospholipid has a gel to liquid phase transition temperature greater than about 80°

C.

11. The pharmaceutical formulation of claim 7, wherein the phospholipid is a phosphoglyceride.

12. The pharmaceutical formulation of claim 7, wherein the phospholipid is a saturated phospholipid.

13. The pharmaceutical formulation of claim 7, wherein the particulates further include a polyvalent cation effective to increase the gel-to-liquid transition temperature of the phospholipid.

14. The pharmaceutical formulation of claim 1, wherein the particulates further include a polyvalent cation.

15. The pharmaceutical formulation of claim 14, wherein the polyvalent cation is a divalent cation.

16. The pharmaceutical formulation of claim 15, wherein the divalent cation is Ca²⁺, Mg²⁺, or Zn²⁺.

17. The pharmaceutical formulation of claim 1, wherein the active agent is an antifungal agent.

18. The pharmaceutical formulation of claim 17, wherein the antifungal agent is a polyene.

19. The pharmaceutical formulation of claim 18, wherein the antifungal agent is selected from ambruticin, amphotericin B, hamycin, natamycin, nystatin, and pimaricin.

20. The pharmaceutical formulation of claim 19, wherein the antifungal agent is amphotericin B.

22. The pharmaceutical formulation of claim 1, further including particles of the active agent that are not incorporated in the particulates.

23. A method for treating a patient suffering from a fungal infection of the lung, comprising administering to the patient a therapeutically effective amount of a pharmaceutical formulation comprising a plurality of particulates having a mass median diameter less than 20 μ

m, wherein each particulate comprises (a) a lipid matrix, and (b) at least one particle of an antifungal agent in the lipid matrix, said active agent having an aqueous solubility of less than 1.0 mg/ml, wherein at least 90% of the active agent particles in the formulation have a geometric diameter less than 3 μ

m, and further wherein the pharmaceutical formulation is administered via inhalation.

24. The method of claim 23, wherein the fungal infection is aspergillosis and the antifungal agent is amphotericin B.

25. A method for administering an active agent to the lungs of a patient, comprising activating a dry powder inhaler to emit a dose of a pharmaceutical formulation that comprises a plurality of particulates having a mass median aerodynamic diameter of less than 5 μ

m and a bulk density of less than 0.5 g/cm³, each particulate comprising a lipid matrix and at least one particle of the active agent in the lipid matrix, wherein the dose is inhaled by the patient and inhalation of the dose by the patient provides a T_max within 15 minutes of inhalation.

26. The method of claim 25, wherein the active agent has an aqueous solubility of less than 1.0 mg/ml.

27. The method of claim 25, wherein the active agent is an antifungal agent.

28. The method of claim 27, wherein the antifungal agent is a polyene.

29. The method of claim 28, wherein the antifungal agent is selected from ambruticin, amphotericin B, hamycin, natamycin, nystatin, and pimaricin.

30. The method of claim 29, wherein the antifungal agent is amphotericin B.

31. The method of claim 25, wherein substantially no active agent is detectable in the patient'"'"'s serum subsequent to administration of the formulation.

32. The method of claim 25, wherein substantially no active agent is detectable in the patient'"'"'s organs subsequent to administration of the formulation.

33. The method of claim 30, wherein substantially no amphotericin B is detectable in the patient'"'"'s serum subsequent to administration of the formulation.

34. The method of claim 30, wherein substantially no amphotericin B is detectable in the patient'"'"'s organs subsequent to administration of the formulation.

35. A method for treating a patient suffering from a fungal infection of the lung, comprising administering an aerosolized formulation of an antifungal agent to the patient in an amount sufficient to maintain a target lung concentration of the antifungal agent that is at least twice the minimum inhibitory concentration of the antifungal agent, for at least one week.

36. The method of claim 35, wherein the minimum inhibitory concentration is the minimum inhibitory concentration in the epithelial lining of the lung.

37. The method of claim 35, wherein the minimum inhibitory concentration is the minimum inhibitory concentration in the solid tissue of the lung.

38. The method of claim 35, wherein the fungal infection is aspergillosis and the antifungal agent is amphotericin B.

39. The method of claim 35, wherein the target lung concentration is maintained for at least three weeks.

40. The method of claim 35, wherein the target lung concentration is maintained for at least three months.

41. The method of claim 38, wherein the target lung concentration is maintained for at least three weeks.

42. The method of claim 38, wherein the target lung concentration is maintained for at least three months.

43. The method of claim 38, wherein the target antifungal lung concentration is at least 9 μ

g/g.

44. The method of claim 43, wherein the target antifungal lung concentration is in the range of 9 μ

g/g to 15 μ

g/g.

45. A method for manufacturing a particulate amphotericin B formulation for pulmonary administration, the method comprising:

(a) mixing a phospholipid, amphotericin B particles each having an initial geometric diameter, and a solvent, to form a suspension;

(b) homogenizing the suspension to form solvent-containing particulates in which the geometric diameter of the amphotericin B particles is less than or equal to the initial geometric diameter; and

(c) spray-drying the particulates at a temperature effective to remove the solvent from the microparticles and thereby provide dry formulation particulates of the phospholipid and amphotericin B.

46. The method of claim 45, wherein steps (b) and (c) do not substantially change the morphology of the amphotericin B particles in step (a).

47. The method of claim 45, wherein the amphotericin B particles in step (a) and the amphotericin B in the formulation particulates provided in step (c) are crystalline.