Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use
View Patent ↗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.
1. A pharmaceutical formulation for pulmonary administration, comprising a plurality of particulates having a mass median diameter less than 20 μm, 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 μm.
2. The pharmaceutical formulation of claim 1 wherein the plurality of particulates has a mass median diameter less than 10 μm.
3. The pharmaceutical formulation of claim 2 , wherein the plurality of particulates has a mass median diameter less than 5 μm.
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 μm.
5. The pharmaceutical formulation of claim 4 , wherein at least 50% of the active agent particles have a geometric diameter between 0.5 μm and 3 μm.
6. The pharmaceutical formulation of claim 5 , wherein at least 50% of the active agent particles have a geometric diameter between 1 μm and 3 μm.
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 Ca 2+ , Mg 2+ , or Zn 2+ .
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.
21. The pharmaceutical formulation of claim 1 , further including particles of the active agent that are not incorporated in the particulates.