Pulmonary delivery of polyene antifungal agents
View Patent ↗The present invention provides spray-dried polyene compositions for oral inhalation to the lung. The polyene antifungal compositions demonstrate superior aerosol properties, do not exhibit appreciable degradation of the polyene upon spray-drying, and are useful in the treatment and prophylaxis of both pulmonary and systemic fungal infections.
1. A dry powder for delivery by inhalation to the lungs, the dry powder produced by a method comprising:
i) dissolving a polyene antifungal compound in an acidified solvent to form an acidic polyene-containing solution, and
ii) spray drying said polyene-containing solution to form an inhaleable dry powder containing no more than about 10% polyene degradation products and characterized by an emitted dose greater than 60%.
2. A dry powder produced by a method comprising:
i) suspending a polyene antifungal compound in an aqueous solvent to form a suspension,
ii) wet milling the suspension from (i) to form a wet-milled suspension, and
iii) spray drying the wet milled suspension to produce an inhaleable dry powder containing no more than about 10% polyene degradation products and characterized by an emitted dose greater than about 60%.
3. A spray-dried powder composition suitable for oral inhalation to the lung comprising a therapeutically effective amount of a polyene antifungal compound, wherein the composition comprises no more than about 10% polyene degradation products and is characterized by an emitted dose greater than about 60%.
4. The powder composition of claim 3 , containing no more than about 5% polyene degradation products.
5. The powder composition of claim 3 , wherein the powder comprises particles having an MMAD of less than about 5 microns.
6. The powder composition of claim 5 , wherein the powder comprises particles having an MMAD of less than about 3.5 microns.
7. The powder composition of claim 3 , which is non-proteinaceous.
8. The powder composition of claim 3 , wherein said polyene is nystatin or amphotericin B.
9. The powder composition of claim 3 , wherein said polyene is non-encapsulated.
10. The powder composition of claim 9 , wherein said polyene is non-liposome and non-polymer encapsulated.
11. The powder composition of claim 3 substantially comprising neat polyene.
12. The powder composition of claim 3 , further comprising a pharmaceutically acceptable excipient.
13. The powder composition of claim 12 , wherein said excipient is selected from the group consisting of buffers, leucine, and trileucine.
14. The powder composition of claim 12 , comprising at least about 30% by weight polyene.
15. The powder composition of claim 14 , comprising at least about 50% by weight polyene.
16. The powder composition of claim 3 , having a water content greater than about 4% by weight.
17. The powder composition of claim 16 , having a water content ranging from about greater than 4% by weight to about 10% by weight.
18. A spray-dried powder composition suitable for oral inhalation to the lung comprising a therapeutically effective amount of a polyene antifungal compound and a leucyl-containing excipient comprising from 1 to 3 amino acid residues.
19. An aerosolized, spray-dried powder composition suitable for oral inhalation to the lung comprising a therapeutically effective amount of a polyene antifungal compound, wherein the composition comprises no more than about 10% polyene degradation products and is characterized by an emitted dose greater than about 60%.
20. A method for treating or preventing fungal infection in a subject in need thereof, said method comprising administering to said subject by oral inhalation a therapeutically effective amount of a spray dried powder composition of claim 3 in aerosolized form.