Pulmonary delivery of alpha-1 proteinase inhibitor

Abstract

The present invention relates to a system that includes a pharmaceutical composition of a purified, stable, active alpha-1 proteinase inhibitor (API) in a form of a ready to use sterile solution and an inhalation nebulizer, and to methods of use thereof for treating pulmonary diseases.

1 . A system for the treatment of pulmonary, comprising:
 a) a pharmaceutical composition comprising a purified, stable, active alpha-1 proteinase inhibitor (API) in a ready to use sterile solution, wherein the stable alpha-1 proteinase inhibitor is at least 90% pure; and b) an inhalation nebulizer comprising:
 i) an aerosol generator comprising: a liquid storage container comprising the liquid pharmaceutical composition; a diaphragm having a first side and an opposite second side, the diaphragm having a plurality of openings extending therethrough from the first side to the second side, where the first side is connected to the liquid storage container such that the liquid filled into the liquid storage container comes into contact with the first side of the diaphragm; and a vibration generator capable of vibrating the diaphragm so that the liquid filled into the liquid storage container is atomized on the second side of the diaphragm through the openings of the diaphragm; 
 ii) a mixing chamber into which the aerosol generator expels said aerosol, the mixing chamber in contact with the second side of the diaphragm; 
 iii) an inhalation valve that is open to allow an inflow of ambient air into the mixing chamber during an inhalation phase and is closed to prevent escape of said aerosol from the mixing chamber during an exhalation phase; and 
 iv) an exhalation valve that is open to allow the discharge of the respiratory air of a patient into the surroundings during the exhalation phase and is closed to prevent the inflow of ambient air during the inhalation phase; 
   wherein the pharmaceutical composition is nebulized by the inhalation nebulizer to form an aerosol composition and wherein at least 90% of the pure API is in its active form.   
     
     
         2 . The system according to  claim 1 , wherein the purified, stable alpha-1 proteinase inhibitor is purified from an unpurified mixture of proteins by a process comprising elution from a plurality of ion exchange resins. 
     
     
         3 . The system according to  claim 2 , wherein the purified, stable alpha-1 proteinase inhibitor is purified from an unpurified mixture of proteins by a process comprising elution from at least two anion exchange resins and at least one cation exchange resin. 
     
     
         4 . The system according to  claim 1 , wherein the pH of the pharmaceutical composition is in the range of 6.5-7.5 and the concentration of the purified, stable alpha-1 proteinase inhibitor is less than 10% w/v. 
     
     
         5 . The system according to  claim 4 , wherein the concentration of the purified, stable alpha-1 proteinase inhibitor is between about 1% to about 5%. 
     
     
         6 . The system according to  claim 5 , wherein the concentration of the purified, stable alpha-1 proteinase inhibitor is about 2% and the purified, stable alpha-1 proteinase inhibitor is at least 95% to 99% pure. 
     
     
         7 . The system according to  claim 1 , wherein the mass median diameter of the aerosol droplets produced by the inhalation nebulizer is less than 5 μm. 
     
     
         8 . The system according to  claim 7 , wherein the geometric standard deviation (GSD) is lower than 2.0. 
     
     
         9 . The system according to  claim 1 , wherein at least 60% of API is dissolved in aerosol droplets of a size that is less than 5 μm. 
     
     
         10 . The system according to  claim 1  wherein the diseases are selected from the group consisting of emphysema; chronic obstructive pulmonary disorder (COPD); bronchiectasis; tuberculosis; cystic fibrosis; interstitial pulmonary fibrosis; interstitial pulmonary sarcoidosis; and pulmonary diseases secondary to HIV. 
     
     
         11 . A system for the treatment of pulmonary diseases selected from the group consisting of emphysema; chronic obstructive pulmonary disorder (COPD); bronchiectasis; tuberculosis; cystic fibrosis; interstitial pulmonary fibrosis; interstitial pulmonary sarcoidosis;
 and pulmonary diseases secondary to HIV, comprising:   a) a pharmaceutical composition comprising a purified, stable, active alpha-1 proteinase inhibitor (API) in a ready to use sterile solution, wherein the stable alpha-1 proteinase inhibitor is at least 90% pure; and b) an inhalation nebulizer comprising:
 i) an aerosol generator comprising: a liquid storage container comprising the liquid pharmaceutical composition; a diaphragm having a first side and an opposite second side, the diaphragm having a plurality of openings extending therethrough from the first side to the second side, where the first side is connected to the liquid storage container such that the liquid filled into the liquid storage container comes into contact with the first side of the diaphragm; and a vibration generator capable of vibrating the diaphragm so that the liquid filled into the liquid storage container is atomized on the second side of the diaphragm through the openings of the diaphragm; 
 ii) a mixing chamber into which the aerosol generator expels said aerosol, the mixing chamber in contact with the second side of the diaphragm; 
 iii) an inhalation valve that is open to allow an inflow of ambient air into the mixing chamber during an inhalation phase and is closed to prevent escape of said aerosol from the mixing chamber during an exhalation phase; and 
 iv) an exhalation valve that is open to allow the discharge of the respiratory air of a patient into the surroundings during the exhalation phase and is closed to prevent the inflow of ambient air during the inhalation phase;
 wherein the pharmaceutical composition is nebulized by the inhalation nebulizer to form an aerosol composition, at least 90% of the pure API is in its active form, the mass median diameter of the aerosol droplets produced by the inhalation nebulizer is less than 5 μm, and the geometric standard deviation (GSD) is lower than 2.0. 
 
   
     
     
         12 . A method for treating pulmonary diseases which comprises administering to a subject in need thereof a therapeutically effective amount of the aerosol composition comprising alpha-1 proteinase inhibitor by the system of  claim 1 . 
     
     
         13 . The method according to  claim 12 , wherein the inhibitor is administered for treating a pulmonary disease at a phase of acute exacerbation. 
     
     
         14 . The method according to  claim 12 , wherein the pulmonary disease is inherited emphysema or cystic fibrosis. 
     
     
         15 . The method according to  claim 12 , wherein at least 50% to 70% of the API is delivered to the subject by the system and the API is absorbed by lung tissues of the subject. 
     
     
         16 . The method according to  claim 12 , wherein the subject is a human subject. 
     
     
         17 . A method for treating pulmonary diseases which comprises administering to a subject in need thereof a therapeutically effective amount of the aerosol composition comprising alpha-1 proteinase inhibitor by the system of  claim 11 .