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 amount of the lipid by weight is less than or equal to the amount of the aminoglycoside by weight, the lipid bilayer comprises a neutral phospholipid and a sterol, and the liposome has a mean diameter of 0.1 to 0.5 microns.
2. The liposomal aminoglycoside formulation of claim 1 , wherein the amount of the lipid is less than or equal to 75% of the amount of the aminoglycoside by weight.
3. The liposomal aminoglycoside formulation of claim 1 , wherein the amount of the lipid is less than or equal to 50% of the amount of the aminoglycoside by weight.
4. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is selected from the group consisting of amikacin, gentamicin, and tobramycin.
5. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is amikacin.
6. The liposomal aminoglycoside of claim 1 , wherein the aminoglycoside is gentamicin.
7. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is tobramycin.
8. The liposomal aminoglycoside of claim 1 , wherein the neutral phospholipid is dipalmitoylphosphatidylcholine (DPPC).
9. The liposomal aminoglycoside formulation of claim 1 , wherein the sterol is cholesterol.
10. The liposomal aminoglycoside formulation of claim 1 , wherein the neutral phospholipid is DPPC, and the sterol is cholesterol.
11. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is amikacin, the neutral phospholipid is DPPC and the sterol is cholesterol.
12. 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 .
13. The method of claim 12 , wherein the pulmonary infection is a Pseudomonas staphylococcal, streptococcal, Escherichia, Kiebsiella, Enterobacter, Serratia, Haemophilus, Yersinia, Burkholderia , or Mycobacterium infection.
14. A method of treating a patient for a pulmonary infection in a cystic fibrosis patient comprising administering to the patient a therapeutically effective amount of the liposomal aminoglycoside formulation of claim 1 .
15. The liposomal aminoglycoside formulation of claim 1 , which is substantially free of anionic lipids.
16. The liposomal aminoglycoside formulation of claim 1 , wherein the aminoglycoside is an aminoglycoside sulfate.
17. The liposomal aminoglycoside of claim 1 , wherein the aminoglycoside is amikacin sulfate.
18. The liposomal aminoglycoside of claim 1 , wherein the aminoglycoside is tobramycin sulfate.
19. The liposomal aminoglycoside of claim 1 , wherein the aminoglycoside is gentamicin sulfate.
20. The method of claim 13 , wherein the infection is a Pseudomonas infection.
21. The method of claim 20 , wherein the Pseudomonas infection is selected from the group consisting of a P. aeruginosa, P. paucimobilis, P. putida, P. fluorescens , and P. acidovorans infection.
22. The method of claim 21 , wherein the Pseudomonas infection is a P. aeruginosa infection.
23. The method of claim 13 , wherein the infection is a staphylococcal infection.
24. The method of claim 23 , wherein the staphylococcal infection is a Methicillin resistant Staphylococcus aureus (MRSA) infection.
25. The method of claim 13 , wherein the infection is a streptococcal infection.
26. The method of claim 25 , wherein the streptococcal infection is a Streptococcus pneumoniae infection.
27. The method of claim 13 , wherein the infection is an Escherichia infection.
28. The method of claim 27 , wherein the Escherichia infection is an Escherichia coli infection.
29. The method of claim 13 , wherein the infection is a Yersinia infection.
30. The method of claim 29 , wherein the Yersinia infection is a Yersinia pesos infection.
31. The method of claim 13 , wherein the infection is a Burkholderia infection.
32. The method of claim 31 , wherein the Burkholderia infection is selected from the group consisting of Burkholderia pseudomallel, B. cepacia, B. gladioli, B. multivorans , and B. Vietnamiensis.
33. The method of claim 13 , wherein the infection is a Mycobacterium infection.
34. The method of claim 33 , wherein the Mycobacterium infection is selected from the group consisting of Mycobacterium tuberculosis, M avium complex (MAC), M avium, M intracellulare, M kansasii, M xenopi, M marinum, M ulcerans, M fortuitum complex, M fortuitum , and M chelonei.
35. The liposomal aminoglycoside formulation of claim 2 , wherein the aminoglycoside is selected from the group consisting of amikacin, gentamicin, and tobramycin.
36. The liposomal aminoglycoside formulation of claim 2 , wherein the aminoglycoside is amikacin.
37. The liposomal aminoglycoside of claim 2 , wherein the aminoglycoside is gentamicin.
38. The liposomal aminoglycoside of claim 2 , wherein the aminoglycoside is tobramycin.
39. The liposomal aminoglycoside of claim 2 , wherein the aminoglycoside is an aminoglycoside sulfate.
40. The liposomal aminoglycoside of claim 2 , wherein the aminoglycoside is an amikacin sulfate.
41. The liposomal aminoglycoside of claim 2 , wherein the aminoglycoside is tobramycin sulfate.
42. The liposomal aminoglycoside of claim 2 , wherein the aminoglycoside is gentamicin sulfate.
43. The liposomal aminoglycoside of claim 2 , wherein the neutral phospholipid is a phosphatidylcholine.
44. The liposomal aminoglycoside of claim 2 , wherein the neutral phospholipid is DPPC.
45. The liposomal aminoglycoside of claim 2 , wherein the sterol is cholesterol.
46. The liposomal aminoglycoside of claim 2 , wherein the neutral phospholipid is DPPC and the sterol is cholesterol.
47. The liposomal aminoglycoside of claim 2 , wherein the aminoglycoside is amikacin and the neutral phospholipid is DPPC.
48. The liposomal aminoglycoside of claim 2 , wherein the aminoglycoside is amikacin and the sterol is cholesterol.
49. The liposomal aminoglycoside of claim 2 , wherein the aminoglycoside is amikacin, the neutral phospholipid is DPPC and the sterol is cholesterol.
50. The liposomal aminoglycoside of claim 2 , wherein the aminoglycoside is amikacin sulfate and the neutral phospholipid is DPPC.
51. The liposomal aminoglycoside of claim 2 , wherein the aminoglycoside is amikacin sulfate and the sterol is cholesterol.
52. The liposomal aminoglycoside of claim 2 , wherein the aminoglycoside is amikacin sulfate, the neutral phospholipid is DPPC and the sterol is cholesterol.
53. The liposomal aminoglycoside formulation of claim 3 , wherein the aminoglycoside is selected from the group consisting of amikacin, gentamicin, and tobramycin.
54. The liposomal aminoglycoside formulation of claim 3 , wherein the aminoglycoside is amikacin.
55. The liposomal aminoglycoside of claim 3 , wherein the aminoglycoside is gentamicin.
56. The liposomal aminoglycoside of claim 3 , wherein the aminoglycoside is tobramycin.
57. The liposomal aminoglycoside of claim 3 , wherein the aminoglycoside is an aminoglycoside sulfate.
58. The liposomal aminoglycoside of claim 3 , wherein the aminoglycoside is an amikacin sulfate.
59. The liposomal aminoglycoside of claim 3 , wherein the aminoglycoside is tobramycin sulfate.
60. The liposomal aminoglycoside of claim 3 , wherein the aminoglycoside is gentamicin sulfate.
61. The liposomal aminoglycoside of claim 3 , wherein the neutral phospholipid is a phosphatidylcholine.
62. The liposomal aminoglycoside of claim 3 , wherein the neutral phospholipid is DPPC.
63. The liposomal aminoglycoside of claim 3 , wherein the sterol is cholesterol.
64. The liposomal aminoglycoside of claim 3 , wherein the neutral phospholipid is DPPC and the sterol is cholesterol.
65. The liposomal aminoglycoside of claim 3 , wherein the aminoglycoside is amikacin and the neutral phospholipid is DPPC.
66. The liposomal aminoglycoside of claim 3 , wherein the aminoglycoside is amikacin and the sterol is cholesterol.
67. The liposomal aminoglycoside of claim 3 , wherein the aminoglycoside is amikacin, the neutral phospholipid is DPPC and the sterol is cholesterol.
68. The liposomal aminoglycoside of claim 3 , wherein the aminoglycoside is amikacin sulfate and the neutral phospholipid is DPPC.
69. The liposomal aminoglycoside of claim 3 , wherein the aminoglycoside is amikacin sulfate and the sterol is cholesterol.
70. The liposomal aminoglycoside of claim 3 , wherein the aminoglycoside is amikacin sulfate, the neutral phospholipid is DPPC and the sterol is cholesterol.
71. The liposomal aminoglycoside formulation of claim 1 , wherein the amount of the lipid is less than or equal to 91% of the amount of the aminoglycoside by weight.
72. The liposomal aminoglycoside formulation of claim 1 , wherein the amount of the lipid is less than or equal to 83% of the amount of the aminoglycoside by weight.
73. The liposomal aminoglycoside formulation of claim 1 , wherein the amount of the lipid is less than or equal to 60% of the amount of the aminoglycoside by weight.
74. The liposomal aminoglycoside of claim 1 , wherein the neutral phospholipid is a phosphatidylcholine.
75. The liposomal aminoglycoside of claim 1 , wherein the aminoglycoside is amikacin and the neutral phospholipid is DPPC.
76. The liposomal aminoglycoside of claim 1 , wherein the aminoglycoside is amikacin and the sterol is cholesterol.
77. The liposomal aminoglycoside of claim 1 , wherein the aminoglycoside is amikacin sulfate and the neutral phospholinid is DPPC.
78. The liposomal aminoglycoside of claim 1 , wherein the aminoglycoside is amikacin sulfate and the sterol is cholesterol.
79. The liposomal aminoglycoside of claim 1 , wherein the aminoglycoside is amikacin sulfate, the neutral phospholipid is DPPC and the sterol is cholesterol.