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 encapsulated therein, wherein the lipid bilayer comprises a neutral phospholipid and a sterol, the weight ratio of lipid to aminoglycoside in the formulation is 2:1 or less, and the liposome has a mean diameter of 0.1 microns to 0.5 microns.
2. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is selected from the group consisting of amikacin, gentamicin, and tobramycin.
3. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is amikacin.
4. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is gentamicin.
5. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is tobramycin.
6. The liposomal aminoglycoside formulation of claim 1 , wherein the neutral phospholipid is dipalmitoylphosphatidylcholine (DPPC).
7. The liposomal aminoglycoside formulation of claim 1 , wherein the sterol is cholesterol.
8. The liposomal aminoglycoside formulation of claim 1 , wherein the neutral phospholipid is DPPC, and the sterol is cholesterol.
9. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is amikacin, the neutral phospholipid is DPPC and the sterol is cholesterol.
10. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is an aminoglycoside sulfate.
11. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is amikacin sulfate.
12. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is tobramycin sulfate.
13. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is gentamicin sulfate.
14. 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 .
15. The method of claim 14 , wherein the pulmonary infection is a Pseudomonas , staphylococcal, streptococcal, Escherichia, Kiebsiella, Enterobacter, Serratia, Haemophilus, Yersinia, Burkholderia , or mycobacterial infection.
16. A method of treating a cystic fibrosis patient for a pulmonary infection comprising administering to the cystic fibrosis patient a therapeutically effective amount of the liposomal aminoglycoside formulation of claim 1 .
17. The method of claim 16 , wherein the pulmonary infection is a Pseudomonas , staphylococcal, streptococcal, Escherichia, Kiebsiella, Enterobacter, Serratia, Haemophilus, Yersinia, Burkholderia , or mycobacterial infection.
18. The method of claim 15 , wherein the pulmonary infection is a mycobacterial infection.
19. The method of claim 17 , wherein the pulmonary infection is a mycobacterial infection.
20. The method of claim 18 , 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 ).
21. The method of claim 19 , 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 ).
22. The method of claim 15 , wherein the pulmonary infection is a Pseudomonas infection.
23. The method of claim 16 , wherein the pulmonary infection is a chronic Pseudomonas infection.
24. The method of claim 17 , wherein the pulmonary infection is a Pseudomonas infection.
25. The method of claim 22 , wherein the Pseudomonas infection is a Pseudomonas aeruginosa infection.
26. The method of claim 22 , wherein the Pseudomonas infection is a Pseudomonas aeruginosa infection.
27. The method of claim 14 , wherein the weight ratio of lipid to aminoglycoside is 0.75:1 or less.
28. The method of claim 15 , wherein the weight ratio of lipid to aminoglycoside is 0.75:1 or less.
29. The method of claim 16 , wherein the weight ratio of lipid to aminoglycoside is 0.75:1 or less.
30. The method of claim 17 , wherein the weight ratio of lipid to aminoglycoside is 0.75:1 or less.
31. The method of claim 18 , wherein the weight ratio of lipid to aminoglycoside is 0.75:1 or less.
32. The method of claim 22 , wherein the weight ratio of lipid to aminoglycoside is 0.75:1 or less.
33. The method of claim 23 , wherein the weight ratio of lipid to aminoglycoside is 0.75:1 or less.
34. The method of claim 24 , wherein the weight ratio of lipid to aminoglycoside is 0.75:1 or less.
35. The method of claim 25 , wherein the weight ratio of lipid to aminoglycoside is 0.75:1 or less.
36. The method of claim 14 , wherein the weight ratio of lipid to aminoglycoside is about 2:1 to about 0.5:1.
37. The method of claim 15 , wherein the weight ratio of lipid to aminoglycoside is about 2:1 to about 0.5:1.
38. The method of claim 16 , wherein the weight ratio of lipid to aminoglycoside is about 2:1 to about 0.5:1.
39. The method of claim 17 , wherein the weight ratio of lipid to aminoglycoside is about 2:1 to about 0.5:1.
40. The method of claim 18 , wherein the weight ratio of lipid to aminoglycoside is about 2:1 to about 0.5:1.
41. The method of claim 22 , wherein the weight ratio of lipid to aminoglycoside is about 2:1 to about 0.5:1.
42. The method of claim 23 , wherein the weight ratio of lipid to aminoglycoside is about 2:1 to about 0.5:1.
43. The method of claim 24 , wherein the weight ratio of lipid to aminoglycoside is about 2:1 to about 0.5:1.
44. The method of claim 25 , wherein the weight ratio of lipid to aminoglycoside is about 2:1 to about 0.5:1.
45. The method of claim 14 , wherein the weight ratio of lipid to aminoglycoside is about 1:1 to about 0.5:1.
46. The method of claim 15 , wherein the weight ratio of lipid to aminoglycoside is about 1:1 to about 0.5:1.
47. The method of claim 16 , wherein the weight ratio of lipid to aminoglycoside is about 1:1 to about 0.5:1.
48. The method of claim 17 , wherein the weight ratio of lipid to aminoglycoside is about 1:1 to about 0.5:1.
49. The method of claim 18 , wherein the weight ratio of lipid to aminoglycoside is about 1:1 to about 0.5:1.
50. The method of claim 22 , wherein the weight ratio of lipid to aminoglycoside is about 1:1 to about 0.5:1.
51. The method of claim 23 , wherein the weight ratio of lipid to aminoglycoside is about 1:1 to about 0.5:1.
52. The method of claim 24 , wherein the weight ratio of lipid to aminoglycoside is about 1:1 to about 0.5:1.
53. The method of claim 25 , wherein the weight ratio of lipid to aminoglycoside is about 1:1 to about 0.5:1.
54. A nebulized spray comprising the liposomal aminoglycoside formulation of claim 1 .
55. A nebulized spray comprising the liposomal aminoglycoside formulation of claim 3 .
56. A nebulized spray comprising the liposomal aminoglycoside formulation of claim 6 .
57. A nebulized spray comprising the liposomal aminoglycoside formulation of claim 7 .
58. A nebulized spray comprising the liposomal aminoglycoside formulation of claim 8 .
59. A nebulized spray comprising the liposomal aminoglycoside formulation of claim 9 .