Sustained release of antiinfectives
View Patent ↗Provided are lipid antiinfective formulations substantially free of anionic lipids with a lipid to antiinfective ratio is about 1:1 to about 4:1, and a mean average diameter of less than about 1 μm. Also provided is a method of preparing a lipid antiinfective formulation comprising an infusion process. Also provided are lipid antiinfective formulations wherein the lipid to drug ratio is about 1:1 or less, about 0.75:1 or less, or about 0.50:1 or less prepared by an in line fusion process. The present invention also relates to a method of treating a patient with a pulmonary infection comprising administering to the patient a therapeutically effective amount of a lipid antiinfective formulation of the present invention. The present invention also relates to a method of treating a patient for cystic fibrosis comprising administering to the patient a therapeutically effective amount of a lipid antiinfective formulation of the present invention.
1. A liposomal aminoglycoside formulation comprising a liposome having a lipid bilayer and an aminoglycoside or a pharmaceutically acceptable salt thereof encapsulated therein, wherein the lipid bilayer comprises a neutral phospholipid and a sterol, the weight ratio of lipid to the aminoglycoside, or the pharmaceutically acceptable salt thereof in the formulation is 0.75:1 or less and the liposome has a mean diameter of about 0.1 μm to about 1.0 μm.
2. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is amikacin, gentamicin, tobramycin, streptomycin, netilmicin, kanamycin, or a pharmaceutically acceptable salt thereof.
3. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is amikacin, or a pharmaceutically acceptable salt thereof.
4. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is streptomycin, or a pharmaceutically acceptable salt thereof.
5. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is tobramycin, or a pharmaceutically acceptable salt thereof.
6. The liposomal aminoglycoside formulation of claim 1 , wherein the neutral phospholipid is a phosphatidylcholine.
7. The liposomal aminoglycoside formulation of claim 1 , wherein the neutral phospholipid is dipalmitoylphosphatidylcholine (DPPC).
8. The liposomal aminoglycoside formulation of claim 1 , wherein the sterol is cholesterol.
9. The liposomal aminoglycoside formulation of claim 1 , wherein the neutral phospholipid is DPPC, and the sterol is cholesterol.
10. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is amikacin or a pharmaceutically acceptable salt thereof, the neutral phospholipid is DPPC and the sterol is cholesterol.
11. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is an aminoglycoside sulfate.
12. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is amikacin sulfate.
13. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is tobramycin sulfate.
14. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is streptomycin sulfate.
15. The liposomal aminoglycoside formulation of claim 1 , wherein the liposome has a mean diameter of about 0.2 μm to about 1.0 μm.
16. The liposomal aminoglycoside formulation of claim 1 , wherein the liposome has a mean diameter of about 0.2 μm to about 0.5 μm.
17. A nebulized spray comprising the liposomal aminoglycoside formulation of claim 1 .
18. A nebulized spray comprising the liposomal aminoglycoside formulation of claim 3 .
19. A nebulized spray comprising the liposomal aminoglycoside formulation of claim 6 .
20. A nebulized spray comprising the liposomal aminoglycoside formulation of claim 7 .
21. A nebulized spray comprising the liposomal aminoglycoside formulation of claim 8 .
22. A nebulized spray comprising the liposomal aminoglycoside formulation of claim 9 .
23. A nebulized spray comprising the liposomal aminoglycoside formulation of claim 10 .
24. A method of treating a patient for a pulmonary infection comprising administering to the patient a therapeutically effective amount of the liposomal aminoglycoside formulation of claim 1 .
25. The method of claim 24 , wherein the pulmonary infection is a Pseudomonas , staphylococcal, streptococcal, Escherichia, Kiebsiella, Enterobacter, Serratia, Haemophilus, Yersinia, Burkholderia , or mycobacterial infection.
26. The method of claim 24 , wherein the pulmonary infection is a mycobacterial infection.
27. The method of claim 24 , wherein the pulmonary infection is a Pseudomonas infection.
28. The method of claim 24 , wherein the liposome has a mean diameter of about 0.2 μm to about 1.0 μm.
29. The method of claim 24 , wherein the liposome has a mean diameter of about 0.2 μm to about 0.5 μm.
30. The method of claim 24 , wherein the patient is a cystic fibrosis patient.
31. The method of claim 24 , wherein the aminoglycoside is amikacin or a pharmaceutically acceptable salt thereof.
32. The method of claim 25 , wherein the mycobacterial infection is Mycobacterium tuberculosis, Mycobacterium avium complex (MAC) ( Mycobacterium avium and Mycobacterium intracellulare ), Mycobacterium kansasii, Mycobacterium xenopi, Mycobacterium marinum, Mycobacterium ulcerans , or Mycobacterium fortuitum complex ( M. fortuitum and M. chelonae ).
33. The method of claim 27 , wherein the Pseudomonas infection is a Pseudomonas aeruginosa infection.
34. The method of claim 27 , wherein the Pseudomonas infection is a chronic Pseudomonas infection.
35. The method of claim 32 , wherein the mycobacterial infection is a Mycobacterium avium complex (MAC) ( Mycobacterium avium and Mycobacterium intracellulare ) infection.
36. The method of claim 34 , wherein the chronic Pseudomonas infection is a chronic Pseudomonas aeruginosa infection.
37. The method of claim 26 , wherein the aminoglycoside is amikacin sulfate.
38. The method of claim 27 , wherein the aminoglycoside is amikacin sulfate.
39. The method of claim 28 , wherein the aminoglycoside is amikacin sulfate.
40. The method of claim 29 , wherein the aminoglycoside is amikacin sulfate.
41. The method of claim 30 , wherein the aminoglycoside is amikacin sulfate.
42. The method of claim 31 , wherein the aminoglycoside is amikacin sulfate.
43. The method of claim 32 , wherein the aminoglycoside is amikacin sulfate.
44. The method of claim 33 , wherein the aminoglycoside is amikacin sulfate.
45. The method of claim 34 , wherein the aminoglycoside is amikacin sulfate.
46. The method of claim 35 , wherein the aminoglycoside is amikacin sulfate.
47. The method of claim 36 , wherein the aminoglycoside is amikacin sulfate.
48. The method of claim 26 , wherein the aminoglycoside is amikacin sulfate.
49. The method of claim 37 , wherein the neutral phospholipid is DPPC and the sterol is cholesterol.
50. The method of claim 38 , wherein the neutral phospholipid is DPPC and the sterol is cholesterol.
51. The method of claim 39 , wherein the neutral phospholipid is DPPC and the sterol is cholesterol.
52. The method of claim 40 , wherein the neutral phospholipid is DPPC and the sterol is cholesterol.
53. The method of claim 41 , wherein the neutral phospholipid is DPPC and the sterol is cholesterol.
54. The method of claim 42 , wherein the neutral phospholipid is DPPC and the sterol is cholesterol.
55. The method of claim 43 , wherein the neutral phospholipid is DPPC and the sterol is cholesterol.
56. The method of claim 44 , wherein the neutral phospholipid is DPPC and the sterol is cholesterol.
57. The method of claim 45 , wherein the neutral phospholipid is DPPC and the sterol is cholesterol.
58. The method of claim 46 , wherein the neutral phospholipid is DPPC and the sterol is cholesterol.
59. A nebulized spray comprising the liposomal aminoglycoside formulation of claim 11 .
60. A nebulized spray comprising the liposomal aminoglycoside formulation of claim 12 .