Liposomal ciprofloxacin formulations with activity against non-tuberculous mycobacteria

Abstract

Methods of treatment of NTM lung infections using formulations of liposomal ciprofloxacin. Specific liposome formulations and delivery of such for treatment of respiratory tract infections and other medical conditions, and devices and formulations used in connection with such are described.

1 .- 21 . (canceled) 
     
     
         22 . A method of treating an antibiotic resistant infection in a patient, comprising:
 aerosolizing a formulation comprising free ciprofloxacin and ciprofloxacin encapsulated in liposomes; and   inhaling the aerosol into the patient's lungs whereby 90% or more of the liposomes maintain structural integrity after being aerosolized and after contacting lung tissue provide a ciprofloxacin release rate of 0.5% to 10% per hour,   wherein the antibiotic resistant infection comprises microorganisms in a biofilm in the lung of the patient and the formulation releases drug over a period of time and at a rate effective in treating a biofilm infection;   wherein the formulation comprises a cryopreservative and a surfactant and the liposomes have an average particle size of about 75 nm to about 120 nm and are unilamellar.   
     
     
         23 . The method of treatment of  claim 22 , wherein the infection is an infection of microorganisms selected from the group consisting of mycobacteria,  P. aeruginosa  and  F. tularensis.    
     
     
         24 . The method of  claim 22 , wherein:
 the liposomes are comprised of cholesterol and hydrogenated soy phosphatidyl-choline (HSPC)—a semi-synthetic fully hydrogenated derivative of nature soy lecithin at a ratio of about 30 to 70 (plus or minus 10%); and   wherein the formulation further comprising an excipient suitable for pulmonary delivery comprised of sodium acetate and an isotonic buffer; and   further wherein 90% or more of the liposomes maintain integrity when aerosolized.   
     
     
         25 . The method of  claim 22 , wherein:
 95% or more of the liposomes maintain integrity when aerosolized and after contacting lung tissue provide a ciprofloxacin release rate of 1% to 8% per hour; and   the liposomes comprise cholesterol and hydrogenated soy phosphatidyl-choline (HSPC) at a ratio of 29.4 to 70.6, and are unilamellar and wherein 98% or more of the liposomes maintain integrity when aerosolized, and provide a ciprofloxacin release rate of 2% to 6% per hour.   
     
     
         26 . The method of  claim 22 , wherein:
 the formulation is further comprised of 0.1 to 0.3% polysorbate 20, and 200 to 400 mg/mL sucrose;   the aerosolizing and inhaling are repeated once each day over a period of seven days or more; and   the formulation comprises 50 mg to 500 mg of ciprofloxacin.   
     
     
         27 . The method of  claim 22 , wherein:
 the aerosolizing and inhaling are repeated once each day to provide a daily dose over a period of seven days to fifty-six days; and   each daily dose comprises 75 mg to 300 mg of ciprofloxacin.   
     
     
         28 . A method of treatment, comprising:
 aerosolizing a formulation to create aerosolized particles having an aerodynamic diameter in a range of from 1 micron to 12 microns;   wherein the aerosolized formulation comprises:   a liquid carrier comprising ciprofloxacin at a concentration of 20 mg/mL to 80 mg/mL of ciprofloxacin in solution,   liposome unencapsulated ciprofloxacin in solution;   and ciprofloxacin as nanocrystals encapsulated inside the liposomes;   inhaling the aerosol into the patient's lungs whereby 90% or more of the liposomes maintain structural integrity after being aerosolized and after contacting lung tissue provide a ciprofloxacin release rate of 0.5% to 10% per hour,   whereby an antibiotic resistant infection comprises microorganisms in a biofilm in the lung of the patient, and the liposomes release drug over a period of time and at a rate effective in treating the biofilm infection;   wherein the formulation comprises a cryopreservative and a surfactant and have an average particle size of about 75 nm to about 120 nm and are unilamellar.   
     
     
         29 . The method of treatment of  claim 28 , wherein the infection is an infection of microorganisms selected from the group consisting of mycobacteria,  P. aeruginosa  and  F. tularensis.    
     
     
         30 . The method of  claim 28 , wherein:
 the liposomes are comprised of cholesterol and hydrogenated soy phosphatidyl-choline (HSPC)—a semi-synthetic fully hydrogenated derivative of nature soy lecithin at a ratio of about 30 to 70 (plus or minus 10%); and
 wherein the formulation further comprising an excipient suitable for pulmonary delivery comprised of sodium acetate and an isotonic buffer; and 
 further wherein 90% or more of the liposomes maintain integrity when aerosolized. 
   
     
     
         31 . The method of  claim 28 , wherein:
 95% or more of the liposomes maintain integrity when aerosolized and after contacting lung tissue provide a ciprofloxacin release rate of 1% to 8% per hour; and   the liposomes are unilamellar, and comprise cholesterol and hydrogenated soy phosphatidyl-choline (HSPC) at a ratio of such that 98% or more of the liposomes maintain integrity when aerosolized, and provide a ciprofloxacin release rate of 2% to 6% per hour.   
     
     
         32 . The method of  claim 28 , wherein:
 the formulation is further comprised of 0.1 to 0.3% polysorbate 20, and 200 to 400 mg/mL sucrose;   the aerosolizing and inhaling are repeated once each day to provide a daily dose over a period of seven days or more; and   each daily dose comprises 50 mg to 500 mg of ciprofloxacin.   
     
     
         33 . The method of  claim 28 , wherein:
 the aerosolizing and inhaling are repeated once each day over a period of seven days to fifty-six days; and   each daily dose comprises 75 mg to 300 mg of ciprofloxacin.   
     
     
         34 . The method of  claim 28 , wherein,
 the aerosolized particles have an aerodynamic diameter of two microns to eight microns,   the liposomes have a diameter of less than 1 micron,   and nanocrystals in the liposome have a dimension of 100 nanometers; and   wherein the ciprofloxacin is present in the solution at a concentration of 40 mg/mL to 60 mg/mL; and   further wherein the liposomes are unilamellar and maintain structural integrity at a level of 90% or more after aerosolizing.   
     
     
         35 . The aerosolized formulation of  claim 28 ,
 wherein the liposomes are characterized such that 95% or more of the liposomes maintain structural integrity and continue to encapsulate nanocrystals of ciprofloxacin in the aerosolized formulation.   
     
     
         36 . The aeorosolized formulation of  claim 28 , wherein the liposomes are characterized such that 98% or more of the liposomes maintain structural integrity and continue to encapsulate nanocrystals of ciprofloxacin in the aerosolized formulation.