Inhalable aztreonam for treatment and prevention of pulmonary bacterial infections

Abstract

A method and a composition for treatment of pulmonary bacterial infections caused by gram-negative bacteria suitable for treatment of infection caused by Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Pseudomonas aeruginosa, Haemophilus influenzae, Proteus mirabilis, Enterobacter species, Serratia marcescens as well as those caused by Burkholderia cepacia, Stenotrophomonas maltophilia, Alcaligenes xylosoxidans , and multidrug resistant Pseudomonas aeruginosa , using a concentrated formulation of aztreonam, or a pharmaceutically acceptable salt thereof, delivered as an aerosol or dry powder formulation.

1 . A method of treating pulmonary infections caused by gram-negative bacteria, said method comprising delivering an aerosol of an inhalable aztreonam formulation to the lung endobronchial space of airways of a patient in need thereof, wherein said inhalable aztreonam formulation does not comprise an arginine salt of aztreonam. 
     
     
         2 . The method of  claim 1  wherein said inhalable aztreonam formulation comprises from about 1 to about 250 mg of aztreonam or a pharmaceutically acceptable salt thereof per one dose. 
     
     
         3 . The method of  claim 1  wherein said aerosol comprises from about 1 to about 250 mg of aztreonam or a pharmaceutically acceptable salt thereof dissolved in about 1 to about 5 ml of a saline solution containing from about 0.1 to about 0.9% of sodium chloride or an equivalent thereof. 
     
     
         4 . The method of  claim 3  wherein said aerosol is nebulized into particles, at least 70% of which have sizes between about 1 and about 5 μm. 
     
     
         5 . The method of  claim 4  wherein the inhalable aztreonam formulation is delivered one to twelve times a day, provided that a total dose of aztreonam or a pharmaceutically acceptable salt thereof is not higher than 750 mg a day. 
     
     
         6 . The method of  claim 5  wherein the aerosol is delivered by a nebulizer. 
     
     
         7 . The method of  claim 6  wherein the nebulizer is an atomizing nebulizer or a jet, ultrasonic, electronic or vibrating porous plate nebulizer, wherein said nebulizer is able to or is modified to be able to nebulize volume from about 1 to about 5 ml of the inhalable aztreonam formulation to particle, the sizes of which range from about 1 to about 5 1 μm. 
     
     
         8 . The method of  claim 7  administering the inhalable aztreonam formulation comprising from about 10 to about 200 mg of the aztreonam or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The method of  claim 8  comprising administering the inhalable aztreonam formulation comprising from about 50 to about 100 mg of aztreonam or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The method of  claim 9  wherein the aerosol has pH from about 4.5 and about 7.5 and the saline solution contains from about 0.1 to about 0.45% of sodium chloride. 
     
     
         11 . The method of  claim 10  wherein said aerosol has pH from about 4.5 to about 5.5. 
     
     
         12 . The method of  claim 3  comprising administering the aerosol comprising from about 10 to about 100 mg of the aztreonam or a pharmaceutically acceptable salt thereof once, twice, three or four times a day. 
     
     
         13 . A method of treating infections caused by the gram-negative bacteria in patients with cystic fibrosis or bronchiectasis, or in patients on ventilators with pneumonia, comprising delivering an aerosol of an inhalable aztreonam formulation to the lung endobronchial space of airways of a patient in need thereof, wherein the inhalable aztreonam formulation comprises from about 1 to about 250 mg of aztreonam or a pharmaceutically acceptable salt thereof per one dose, wherein said pharmaceutically acceptable salt is selected from the group consisting of acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bytyrate, camphorate, camphorsulfonate, citrate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, lysinate, maleate, methanesulfonate, nicotinate, 2-napthalene-sulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. 
     
     
         14 . An inhalable pharmaceutically acceptable composition comprising from about 1 to about 250 mg per one dose of aztreonam or a pharmaceutically acceptable salt thereof, said composition suitable for treatment of pulmonary bacterial infections caused by gram-negative bacteria  Burkholderia cepacia, Stenotrophomonas maltophilia, Alcaligenes xylosoxidans  or multidrug resistant  Pseudomonas aeruginosa , wherein said aztreonam or the pharmaceutically acceptable salt thereof is prepared as an aerosolable saline solution. 
     
     
         15 . The composition of  claim 14  comprising from about 1 to about 250 mg or aztreonam base or the pharmaceutically acceptable salt thereof per one dose administered once, two, three or four times a day with a proviso that when the composition is administered more than three times a day, the total dose of the aztreonam or the pharmaceutically acceptable salt thereof does not exceed 750 mg a day. 
     
     
         16 . The composition of  claim 15  wherein said pharmaceutically acceptable salt is selected from the group consisting of acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bytyrate, camphorate, camphorsulfonate, citrate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, lysinate, maleate, methanesulfonate, nicotinate, 2-napthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. 
     
     
         17 . The composition of  claim 16  wherein said aztreonam or the pharmaceutically acceptable salt thereof is dissolved in from about 1 to about 5 ml of the aerosolable solution comprising at least 0.09% of sodium chloride or equivalent amount of bromine, iodine or bicarbonate salt. 
     
     
         18 . The composition of  claim 17  wherein said aerosolable saline solution comprises from about 0.1 to about 0.45% of sodium chloride and has a pH from about pH 4.5 to about pH 7.5. 
     
     
         19 . The composition of  claim 18  wherein said pH is from about pH 4.5 to about pH 5.5. 
     
     
         20 . The composition of  claim 19  nebulized into an aerosol having a particle size with a mass medium average diameter from about 1 to about 5μ. 
     
     
         21 . An aerosol composition comprising from about 1 to about 250 mg of aztreonam or a pharmaceutically acceptable salt thereof selected from the group consisting of acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bytyrate, camphorate, camphorsulfonate, citrate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, lysinate, maleate, methanesulfonate, nicotinate, 2-napthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate, said aztreonam or the salt dissolved in from about 1 to about 5 ml of a solution containing from about 0.1 to about 0.9% sodium chloride. 
     
     
         22 . A method of treating pulmonary infections caused by gram-negative bacteria comprising delivering an aerosol of an inhalable aztreonam formulation to the lung endobronchial space of airways of a patient in need thereof, wherein the inhalable aztreonam formulation comprises from about 1 to about 250 mg of aztreonam or a pharmaceutically acceptable salt thereof per one dose, and the pharmaceutically acceptable salt thereof is selected from the group consisting of acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bytyrate, camphorate, camphorsulfonate, citrate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, lysinate, maleate, methanesulfonate, nicotinate, 2-napthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. 
     
     
         23 . The method of  claim 22 , wherein the pharmaceutically acceptable salt is lysinate. 
     
     
         24 . The method of  claim 22  wherein said gram-negative bacteria is  Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Pseudomonas aeruginosa, Haemophilus influenzae, Proteus mirabilis, Serratia marcescens, Burkholderia cepacia, Stenotrophomonas maltophilia, Alcaligenes xylosoxidans  or multidrug resistant  Pseudomonas aeruginosa.