Systems for treating pulmonary infections

Abstract

Provided herein are systems for treating a subject with a pulmonary infection, for example, a nontuberculous mycobacterial pulmonary infection, a Burkholderia pulmonary infection, a pulmonary infection associated with bronchiectasis, or a Pseudomonas pulmonary infection. The system includes a pharmaceutical formulation comprising a liposomal aminoglycoside dispersion, and the lipid component of the liposomes consist essentially of electrically neutral lipids. The system also includes a nebulizer which generates an aerosol of the pharmaceutical formulation at a rate greater than about 0.53 gram per minute. The aerosol is delivered to the subject via inhalation for the treatment of the pulmonary infection.

1 . A system for treating or providing prophylaxis against a pulmonary infection in a patient, comprising:
 (a) a pharmaceutical formulation comprising a liposomal complexed aminoglycoside, wherein the formulation is an aqueous dispersion, and the lipid component of the liposome consists of electrically neutral lipids, and   (b) a vibrating mesh nebulizer comprising a plurality of through holes each having a nozzle portion defined by the continuous portion of the through hole in the extension direction starting from the smallest diameter of the through hole towards the first side until it reaches a diameter 2 or 3 times of the smallest diameter of the hole and wherein the length of the nozzle portion is less than 25 μm, wherein the vibrating mesh nebulizer generates an aerosol of the pharmaceutical formulation at a rate of about 0.60 g per minute to about 0.80 g per minute, wherein the fine particle fraction (FPF) of the aerosol is greater than or equal to about 64%, as measured by the Andersen Cascade Impactor (ACI), or greater than or equal to about 51%, as measured by the Next Generation Impactor (NGI), and the percent associated aminoglycoside post-nebulization is from 60% to 70%, wherein the FPF refers to the fraction of the aerosol having a particle size less than 5 μm in diameter.   
     
     
         2 . (canceled) 
     
     
         3 . The system of  claim 1 , wherein the aminoglycoside is selected from AC4437, amikacin, apramycin, arbekacin, astromicin, bekanamycin, boholmycin, brulamycin, capreomycin, dibekacin, dactimicin, etimicin, framycetin, gentamicin, H107, hygromycin, hygromycin B, inosamycin, K-4619, KA-5685, isepamicin, kanamycin, neomycin, netilmicin, paromomycin, plazomicin, rhodestreptomycin, ribostamycin, sisomicin, sorbistin, sporaricin, spectinomycin, streptomycin, tobramycin, verdamicin, vertilmicin, a pharmaceutically acceptable salt thereof, or a combination thereof 
     
     
         4 . The system of  claim 1 , wherein the aminoglycoside is amikacin. 
     
     
         5 . The system of  claim 1 , wherein the aminoglycoside is amikacin sulfate. 
     
     
         6 . The system of  claim 1 , wherein the liposome comprises unilamellar vesicles, multilamellar vesicles, or a mixture thereof 
     
     
         7 . The system of  claim 1 , wherein the electrically neutral lipids comprise an electrically neutral phospholipid or an electrically neutral phospholipid and a sterol. 
     
     
         8 . The system of  claim 1 , wherein the electrically neutral lipids comprise a phosphatidylcholine and a sterol. 
     
     
         9 . The system of  claim 1 , wherein the electrically neutral lipids comprise dipalmitoylphosphatidylcholine (DPPC) and a sterol. 
     
     
         10 . The system of  claim 1 , wherein the electrically neutral lipids comprise DPPC and cholesterol. 
     
     
         11 . The system of  claim 1 , wherein the aminoglycoside is amikacin, the electrically neutral lipids consist of dipalmitoylphosphatidylcholine (DPPC) and cholesterol, and the liposome comprises unilamellar vesicles, multilamellar vesicles, or a mixture thereof. 
     
     
         12 .- 14 . (canceled) 
     
     
         15 . The system of  claim 1 , wherein the volume of pharmaceutical formulation is about 8 mL. 
     
     
         16 .- 29 . (canceled) 
     
     
         30 . A method for treating or providing prophylaxis against a pulmonary infection in a patient, the method comprising:
 aerosolizing, at a rate of about 0.60 g per minute to about 0.80 per minute, with a vibrating mesh nebulizer comprising a plurality of through holes each having a nozzle portion defined by the continuous portion of the through hole in the extension direction starting from the smallest diameter of the through hole towards the first side until it reaches a diameter 2 or 3 times of the smallest diameter of the hole and wherein the length of the nozzle portion is less than 25 μm, a pharmaceutical formulation comprising an aqueous dispersion of a liposomal complexed aminoglycoside, wherein the lipid component of the liposome consists of electrically neutral lipids, to form an aerosolized pharmaceutical formulation   administering the aerosolized pharmaceutical formulation to the lungs of the patient; wherein the aerosolized pharmaceutical formulation comprises a mixture of free aminoglycoside and liposomal complexed aminoglycoside, the fine particle fraction (FPF) of the aerosolized pharmaceutical formulation is greater than or equal to about 64%, as measured by the Andersen Cascade Impactor (ACI), or greater than or equal to about 51%, as measured by the Next Generation Impactor (NGI) and the percent liposomal complexed aminoglycoside of the aerosolized pharmaceutical formulation is from 60% to 70%.   
     
     
         31 .- 40 . (canceled) 
     
     
         41 . The method of  claim 30 , wherein the aerosolized pharmaceutical formulation is administered once per day in a single dosing session. 
     
     
         42 . The method of  claim 30 , wherein the aminoglycoside is amikacin. 
     
     
         43 . The method of  claim 42 , wherein the aminoglycoside is amikacin sulfate. 
     
     
         44 .- 98 . (canceled) 
     
     
         99 . The method of  claim 30 , wherein the pulmonary infection is a nontuberculous mycobacterial infection. 
     
     
         100 .- 107 . (canceled) 
     
     
         108 . The method of  claim 99 , wherein the nontuberculous mycobacterial infection is  Mycobacterium avium  complex ( M. avium  and  M. intracellulare ). 
     
     
         109 . The method of  claim 99 , wherein the nontuberculous mycobacterial infection is selected from from  M avium, M. avium  subsp.  hominissuis  (MAH),  M. abscessus, M chelonae, M bolletii, M kansasii, M. ulcerans, M avium, M avium  complex (MAC) ( M. avium  and  M. intracellulare ),  M. conspicuum, M kansasii, M peregrinum, M. immunogenum, M xenopi, M. marinum, M malmoense, M. marinum, M mucogenicum, M. nonchromogenicum, M. scrofulaceum, M simiae, M. smegmatis, M szulgai, M. terrae, M terrae  complex,  M haemophilum, M. genavense, M. asiaticum, M shimoidei, M. gordonae, M. nonchromogenicum, M. triplex, M. lentiflavum, M celatum, M. fortuitum, M. fortuitum  complex ( M. fortuitum  and  M chelonae ), or a combination thereof. 
     
     
         110 .- 112 . 
     
     
         113 . The method of  claim 108 , wherein the aminoglycoside is amikacin. 
     
     
         114 . The method of  claim 113 , wherein the aminoglycoside is amikacin sulfate. 
     
     
         115 .- 146 . (canceled)