Aerosolized fluoroquinolones and uses thereof

Abstract

Disclosed herein are formulations of fluoroquinolones suitable for aerosolization and use of such formulations for aerosol administration of fluoroquinolone antimicrobials for the treatment of pulmonary bacterial infections. In particular, inhaled levofloxacin specifically formulated and delivered for bacterial infections of the lungs is described. Methods include inhalation protocols and manufacturing procedures for production and use of the compositions described.

What is claimed is: 
     
         1 . A method of treating a bacterial lung infection in a subject with sinusitis in need thereof comprising administering to the subject with sinusitis a therapeutically effective amount of an aerosol of a solution comprising about 100 mM to about 625 mM of levofloxacin or ofloxacin and about 25 mM to about 400 mM of a divalent or trivalent cation, to treat the bacterial lung infection. 
     
     
         2 . The method of  claim 1 , wherein the solution has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg. 
     
     
         3 . The method of  claim 1 , wherein the divalent or trivalent cation is calcium, iron, or zinc. 
     
     
         4 . method of  claim 1 , wherein the divalent or trivalent cation is magnesium. 
     
     
         5 . The method of  claim 4 , wherein the magnesium is magnesium chloride. 
     
     
         6 . The method of  claim 5 , wherein the solution comprises about 100 mM to about 625 mM levofloxacin and about 25 mM to about 400 mM magnesium chloride; and wherein the solution has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg. 
     
     
         7 . The method of  claim 1 , wherein the solution comprises about 100 mM to about 625 mM levofloxacin and about 25 mM to about 400 mM of a divalent or trivalent cation selected from the group consisting of magnesium, calcium, iron, and zinc. 
     
     
         8 . The method of  claim 1 , wherein the lung infection is caused by a gram negative bacteria, a gram negative anaerobic bacteria, a gram positive bacteria, a gram positive anaerobic bacteria, or a combination of two or more thereof. 
     
     
         9 . The method of  claim 1 , wherein the lung infection is caused by one or more bacteria selected from the group consisting of  Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Pasteurella multocida, Pasteurella haemolytica, Helicobacter pylori, Campylobacter fetus, Campylobacter jejune, Campylobacter coli, Borrelia burgdorferi, Vibrio cholera, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Burkholderia cepacia, Francisella tularensis, Kingella , and  Moraxella.    
     
     
         10 . The method of  claim 1 , wherein the lung infection is caused by one or more bacteria selected from the group consisting of  Pseudomonas aeruginosa, Moraxella, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus , and  Haemophilus ducreyi.    
     
     
         11 . The method of  claim 1 , wherein the lung infection is caused by one or more bacteria selected from the group consisting of  Corynebacterium diphtherias, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus milleri; Streptococcus  (Group G);  Streptococcus  (Group C/F);  Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus  subsp.  hyicus, Staphylococcus haemolyticus, Staphylococcus hominis , and  Staphylococcus saccharolyticus.    
     
     
         12 . A method of treating sinusitis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an aerosol of a solution comprising about 100 mM to about 625 mM levofloxacin or ofloxacin and about 25 mM to about 400 mM of a divalent or trivalent cation to treat the sinusitis. 
     
     
         13 . The method of  claim 12 , wherein the solution has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg. 
     
     
         14 . The method of  claim 12 , wherein the divalent or trivalent cation is calcium, iron, or zinc. 
     
     
         15 . The method of  claim 12 , wherein the divalent or trivalent cation is magnesium. 
     
     
         16 . The method of  claim 15 , wherein the magnesium is magnesium chloride. 
     
     
         17 . The method of  claim 16 , wherein the solution comprises about 100 mM to about 625 mM levofloxacin and about 25 mM to about 400 mM magnesium chloride; and wherein the solution has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg. 
     
     
         18 . The method of  claim 12 , wherein the solution comprises about 100 mM to about 625 mM levofloxacin and about 25 mM to about 400 mM of a divalent or trivalent cation selected from the group consisting of magnesium, calcium, iron, and zinc. 
     
     
         19 . The method of  claim 12 , wherein the subject has a bacterial lung infection caused by a gram negative bacteria, a gram negative anaerobic bacteria, a gram positive bacteria, a gram positive anaerobic bacteria, or a combination of two or more thereof. 
     
     
         20 . The method of  claim 12 , wherein the subject has a bacterial lung infection caused by one or more bacteria selected from the group consisting of  Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Pasteurella multocida, Pasteurella haemolytica, Helicobacter pylori, Campylobacter fetus, Campylobacter jejune, Campylobacter coli, Borrelia burgdorferi, Vibrio cholera, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Burkholderia cepacia, Francisella tularensis, Kingella, and Moraxella.    
     
     
         21 . The method of  claim 12 , wherein the subject has a bacterial lung infection caused by one or more bacteria selected from the group consisting of  Pseudomonas aeruginosa, Moraxella, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus , and  Haemophilus ducreyi.    
     
     
         22 . The method of  claim 12 , wherein the subject has a bacterial lung infection caused by one or more bacteria selected from the group consisting of  Corynebacterium  diphtherias,  Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus  milleri;  Streptococcus  (Group G);  Streptococcus  (Group C/F);  Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus  subsp.  hyicus, Staphylococcus haemolyticus, Staphylococcus hominis , and  Staphylococcus saccharolyticus.