LIPID-BASED COMPOSITIONS OF ANTIINFECTIVES FOR TREATING PULMONARY INFECTIONS AND METHODS OF USE THEREOF
A system for treating or providing prophylaxes against a pulmonary infection is disclosed comprising: a) a pharmaceutical formulation comprising a mixture of free antiinfective and antiinfective encapsulated in a lipid-based composition, and b) an inhalation delivery device. A method for providing prophylaxis against a pulmonary infection in a patient and a method of reducing the loss of antiinfective encapsulated in a lipid-based composition upon nebulization comprising administering an aerosolized pharmaceutical formulation comprising a mixture of free antiinfective and antiinfective encapsulated in a lipid-based composition is also disclosed.
1 . A system for treating or providing prophylaxus against a pulmonary infection comprising:
a) a pharmaceutical formulation comprising a mixture of free antiinfective and antiinfective encapsulated in a lipid-based composition, wherein the amount of free antiinfective is sufficient to provide for immediate bactericidal activity, and the amount of encapsulated antiinfective is sufficient to provide sustained bactericidal activity and reduce the development of resistant strains of the infective agent, and
b) an inhalation delivery device.
2 . The system of claim 1 , wherein the antiinfective is selected from the group consisting of antibiotic agents, antiviral agents, and antifungal agents.
3 . The system of claim 1 , wherein the antiinfective is an antibiotic selected from the group consisting of cephalosporins, quinolones, fluoroquinolones, penicillins, beta lactamase inhibitors, carbepenems, monobactams, macrolides, lincosamincs, glycopeptides, rifampin, oxazolidonones, tetracyclines, aminoglycosides, streptogramins, and sulfonamides.
4 . The system of claim 1 , wherein the antiinfective is an aminoglycoside.
5 . The system of claim 1 , wherein the antiinfective is amikacin.
6 . The system of claim 1 , wherein the antiinfective is gentamicin.
7 . The system of claim 1 , wherein the antiinfective is tobramycin.
8 . The system of claim 1 , wherein the lipid-based composition is a liposome.
9 . The system of claim 8 , wherein the liposome comprises a mixture of unilamellar vesicles and multilamellar vesicles.
10 . The system of claim 8 , wherein the liposome comprises a phospholipid and a sterol.
11 . The system of claim 8 , wherein the liposome comprises a phosphatidylcholine and a sterol.
12 . The system of claim 8 , wherein the liposome comprises dipalmitoylphosphatidylcholine (DPPC) and a sterol.
13 . The system of claim 8 , wherein the liposome comprises dipalmitoylphosphatidylcholine (DPPC) and cholesterol.
14 . The system of claim 8 , wherein the antiinfective is an aminogylcoside and the liposome comprises DPPC and cholesterol.
15 . The system of claim 8 , wherein the antiinfective is amikacin, the liposome comprises DPPC and cholesterol, and the liposorne comprises a mixture of unilamellar vesicles and multilamellar vesicles.
16 . The system of claim 1 , wherein the ratio by weight of free antiinfective to antiinfective encapsulated in a lipid-based composition is between about 1:100 and about 100:1.
17 . The system of claim 1 , wherein the ratio by weight of free antiinfective to antiinfective encapsulated in a lipid-based composition is between about 1:10 and about 10:1.
18 . The system of claim 1 , wherein the ratio by weight of free antiinfective to antiinfective encapsulated in a lipid-based composition is between about 1:2 and about 2:1.
19 . A method for providing prophylaxis against a pulmonary infection in a patient comprising administering an aerosolized pharmaceutical formulation comprising the antiinfective to the lungs of the patient, wherein the pharmaceutical formulation comprises a mixture of free antiinfective and antiinfective encapsulated in a lipid-based composition, and wherein the amount of free antiinfective is sufficient to provide for bactericidal activity, and the amount of encapsulated antiinfective is sufficient to reduce the development of resistant strains of the infectious agent.
20 . The method of claim 19 , wherein the method first comprises determining the minimum inhibitory concentration (MIC) of the antiinfective for inhibiting pulmonary infections, and wherein the amount of free antiinfective is at least 2 times the MIC.
21 . The method of claim 20 , wherein the amount of free antiinfective is at least 4 times the MIC.
22 . The method of claim 20 , wherein the amount of free antiinfective is at least 10 times the MIC.
23 . The method of claim 20 , wherein the ratio of the area under a lung concentration/time curve to the MIC at 24 hours is greater than 25.
24 . The method of claim 20 , wherein the ratio of the area under a lung concentration/time curve to the MIC at 24 hours is greater than 100.
25 . The method of claim 20 , wherein the ratio of the area under a lung concentration/time curve to the MIC at 24 hours is greater than 250.
26 . The method of claim 19 , wherein the antiinfective is selected from the group consisting of antibiotic agents, antiviral agents, and antifungal agents.
27 . The method of claim 19 , wherein the antiinfective is an antibiotic selected from the group consisting of cephalosporins, quinolones, fluoroquinolones, penicillins, beta lactamase inhibitors, carbepenems, monobactams, macrolides, lincosamines, glycopeptides, rifampin, oxazolidonones, tetracyclines, aininoglycosides, streptogramins, and sulfonamides.
28 . The method of claim 19 , wherein the antiinfective is an aminoglycoside.
29 . The method of claim 19 , wherein the antiinfective is amikacin.
30 . The method of claim 19 , wherein the antiinfective is gentamicin.
31 . The method of claim 19 , wherein the antiinfective is tobramycin.
32 . The method of claim 19 , wherein the lipid-based composition is a liposome.
33 . The method of claim 32 , wherein the liposome comprises a mixture of unilamellar vesicles and multilamellar vesicles.
34 . The method of claim 32 , wherein the liposome comprises a phospholipid and a sterol.
35 . The method of claim 32 , wherein the liposorne comprises a phosphatidylcholine and a sterol.
36 . The method of claim 32 , wherein the liposome comprises dipalmitoylphosphatidylcholine (DPPC) and a sterol.
37 . The method of claim 32 , wherein the liposome comprises dipalmitoylphosphatidylcholine (DPPC) and cholesterol.
38 . The method of claim 32 , wherein the antiinfective is an aminogylcoside and the liposome comprises DPPC and cholesterol.
39 . The method of claim 32 , wherein the antiinfective is amikacin, the liposome comprises DPPC and cholesterol, and the liposome comprises a mixture of unilamellar vesicles and multilamellar vesicles.
40 . The method of claim 19 , wherein the ratio by weight of free antiinfective to antiinfective encapsulated in a lipid-based composition is between about 1:100 and about 100:1.
41 . The method of claim 19 , wherein the ratio by weight of free antiinfective to antiinfective encapsulated in a lipid-based composition is between about 1:10 and about 10:1.
42 . The method of claim 19 , wherein the ratio by weight of free antiinfective to antiinfective encapsulated in a lipid-based composition is between about 1:2 and about 2:1.
43 . The method of claim 19 , wherein the aerosolized pharmaceutical formulation is administered at least once a week.
44 . The method of claim 19 , wherein the pulmonary infection is selected from the group consisting of cystic fibrosis, chronic obstructive pulmonary disease (COPD), bronchiectasis, acterial pneumonia, acute bronchial exacerbations of chronic bronchitis (ABECB), Mycobacterium tuberculosis , infections caused by inhaled agents of bioterror, and opportunistic fungal infections.
45 . A method of reducing the loss of antiinfective encapsulated in a lipid-based composition upon nebulization comprising administering the antiinfective encapsulated in a lipid-based composition with free antiinfective.