Aerosol pirfenidone and pyridone analog compounds and uses thereof

Abstract

Disclosed herein are formulations of pirfenidone or pyridone analog compounds for aerosolization and use of such formulations for aerosol administration of pirfenidone or pyridone analog compounds for the prevention or treatment of various fibrotic and inflammatory diseases, including disease associated with the lung, heart, kidney, liver, eye and central nervous system. In some embodiments, pirfenidone or pyridone analog compound formulations and delivery options described herein allow for efficacious local delivery of pirfenidone or pyridone analog compound. Compositions include all formulations, kits, and device combinations described herein. Methods include inhalation procedures, indications and manufacturing processes for production and use of the compositions described.

1 . A composition for clinically efficacious treatment of idiopathic pulmonary fibrosis in an adult human comprising:
 delivering a therapeutically effective dose of pirfenidone or a pyridone analog compound to the lung of the adult human by inhalation of an aerosol formed by nebulization of an aqueous solution comprising water; pirfenidone, at a concentration from about 5.0 to about 19.0 mg/mL; a permeant ion concentration of between about 0.1% and about 5.0%, wherein the permeant ions are chloride ions, bromide ions, or a combination thereof; a citrate or phosphate buffer; and a taste masking agent at a concentration of between 0.1 and 2.0 mM, wherein a total daily dose of inhaled pirfenidone does not exceed 480 mg, and wherein the therapeutically effective dose treats idiopathic pulmonary fibrosis by reducing a decline in forced vital capacity (FVC) in the lung of the adult human.   
     
     
         2 . The composition of  claim 1 , wherein nebulization of the aqueous solution:
 (i) achieves lung deposition of at least 5% of the pirfenidone administered to the human;   (ii) creates:   a) a mass median aerodynamic diameter (MMAD) of droplet size of the aqueous solution emitted with the high efficiency liquid nebulizer of about 0.5 μm to about 5 μm; and/or   b) a volumetric mean diameter (VMD) of about 0.5 μm to about 5 μm;   (iii) creates a Geometric Standard Deviation (GSD) of emitted droplet size distribution of the aqueous solution of about 1.0 μm to about 3.4 μm;   (iv) creates a fine particle fraction (FPF=% of aerosol particles less than or equal to 5 microns) of droplets emitted from the liquid nebulizer of at least about 30%;   (v) creates an output rate of at least 0.1 mL/min; and/or   (vi) creates at least about 25% of the aqueous solution to the human.   
     
     
         3 . The composition of  claim 1 , wherein:
 the aerosol formed by the nebulization of the aqueous solution comprises between 0.1 mg and 250 mg of pirfenidone and the aerosol has a median diameter (MMAD) particle size from about 0.5 to about 5 micron.   
     
     
         4 . The composition of  claim 1 , wherein:
 the lung Cmax and/or AUC of pirfenidone of the aerosol obtained after a single administration of the aqueous solution to the human with a liquid nebulizer is about the same or greater than the lung Cmax and/or AUC of pirfenidone obtainable after administration of a single dose of orally administered pirfenidone to the human at a dose that is from about 80% to about 120% of the dose administered with the liquid nebulizer.   
     
     
         5 . The composition of  claim 1 , wherein the aqueous solution further comprises:
 one or more additional ingredients selected from co-solvents, taste masking agents, tonicity agents, sweeteners, surfactants, wetting agents, chelating agents, anti-oxidants, salts, and buffers and combinations thereof.   
     
     
         6 . The composition of  claim 1  further comprising a liquid nebulizer having an aerosol generator and a medicament chamber containing the aqueous solution. 
     
     
         7 . The composition  claim 6 , wherein the liquid nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer comprising a vibrating mesh or plate with multiple apertures, or a piston nebulizer. 
     
     
         8 . The composition of  claim 1  contained in a liquid nebulizer comprising an aerosol generator adapted to receive a liquid storage container containing a metered single or multidose volume, such that the received liquid storage container functions as the medicament container in the nebulizer, or a piston nebulizer. 
     
     
         9 . The composition of  claim 8 , wherein the liquid nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer comprising a vibrating mesh or plate with multiple apertures, or a piston nebulizer. 
     
     
         10 . The composition of  claim 1 , wherein the aerosol of the aqueous solution creates:
 a) a lung Cmax of pirfenidone obtained in the adult human lung upon administration of the therapeutically effective dose is at least equivalent to or greater than a lung Cmax achievable upon administration of 801 mg of an orally administered dosage of pirfenidone to the human; and/or   b) a blood AUC 0-24  of pirfenidone obtained in the adult human lung upon administration of the therapeutically effective dose is less than a blood AUC 0-24  achievable upon administration of 801 mg of an orally administered dosage of pirfenidone to the adult human lung.