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.

What is claimed is: 
     
         1 . A method for the treatment of lung disease in a mammal comprising:
 administering a dose of pirfenidone or a pyridone analog compound by inhalation to the mammal in need thereof on a continuous dosing schedule.   
     
     
         2 . The method of  claim 1 , wherein:
 each inhaled dose of pirfenidone or a pyridone analog compound is administered with a nebulizer, a metered dose inhaler, or a dry powder inhaler.   
     
     
         3 . The method of  claim 2 , wherein each inhaled dose comprises an aqueous solution of pirfenidone or a pyridone analog compound. 
     
     
         4 . The method of  claim 3 , wherein each inhaled dose comprises from about 0.1 mL to about 6 mL of an aqueous solution of pirfenidone or a pyridone analog compound, wherein the concentration of pirfenidone or pyridone analog compound in the aqueous solution is from about 0.1 mg/mL and about 60 mg/mL and the osmolality of the of the aqueous solution is from about 50 mOsmol/kg to about 6000 mOsmol/kg. 
     
     
         5 . The method of  claim 4 , wherein the aqueous solution of each inhaled dose further comprises:
 one or more additional ingredients selected from co-solvents, tonicity agents, sweeteners, surfactants, wetting agents, chelating agents, anti-oxidants, salts, and buffers.   
     
     
         6 . The method of  claim 4 , wherein the aqueous solution of each inhaled dose further comprises:
 a citrate buffer or phosphate buffer, and one or more salts selected from the group consisting of sodium chloride, magnesium chloride, sodium bromide, magnesium bromide, calcium chloride and calcium bromide.   
     
     
         7 . The method of  claim 3 , wherein the aqueous solution of each inhaled dose comprises:
 water;   pirfenidone or pyridone analog compound at a concentration from about 0.1 mg/mL to about 20 mg/mL;   one or more salts, wherein the total amount of the one or more salts is from about 0.01% to about 2.0% by weight of the weight of aqueous solution;   and   optionally a phosphate buffer that maintains the pH of the solution from about pH 5.0 to about pH 8.0, or citrate buffer than maintains the pH of the solution from about 4.0 to about 7.0.   and   the osmolality of the of the aqueous solution is from about 50 mOsmol/kg to about 2000 mOsmol/kg.   
     
     
         8 . The method of  claim 3 , wherein each inhaled dose is administered with a liquid nebulizer. 
     
     
         9 . The method of  claim 8 , wherein the liquid nebulizer:
 (i) after administration of the inhaled dose, achieves lung deposition of at least 7% of the pirfenidone or pyridone analog compound administered to the mammal;   (ii) provides a Geometric Standard Deviation (GSD) of emitted droplet size distribution of the aqueous solution of about 1.0 μm to about 2.5 μm;   (iii) provides:
 a) a mass median aerodynamic diameter (MMAD) of droplet size of the aqueous solution emitted with the high efficiency liquid nebulizer of about 1 μm to about 5 μm; 
 b) a volumetric mean diameter (VMD) of about 1 μm to about 5 μm; and/or 
 c) a mass median diameter (MMD) of about 1 μm to about 5 μm; 
   (iv) provides a fine particle fraction (FPF=%≤5 μm) of droplets emitted from the liquid nebulizer of at least about 30%;   (v) provides an output rate of at least 0.1 mL/min; and/or   (vi) provides at least about 25% of the aqueous solution to the mammal.   
     
     
         10 . The method of  claim 9 , wherein:
 a) the lung tissue Cmax of pirfenidone or pyridone analog compound from each inhaled dose is at least equivalent to or greater than a lung tissue Cmax of up to 801 mg of an orally administered dosage of pirfenidone or pyridone analog compound;   and/or   b) the blood AUC 0-24  of pirfenidone or pyridone analog compound from each inhaled dose that is directly administered to the lungs of the mammal is less than or equivalent to the blood AUC 0-24  of up to 801 mg of an orally administered dosage of pirfenidone or pyridone analog compound.   
     
     
         11 . The method of  claim 9 , wherein:
 the blood AUC 0-24  of pirfenidone or pyridone analog compound from each inhaled dose is less than the blood AUC 0-24  of up to 801 mg of an orally administered dosage of pirfenidone or pyridone analog compound.   
     
     
         12 . The method of  claim 9 , wherein:
 wherein each inhaled dose is less than ½ of the up to 801 mg of an orally administered dosage of pirfenidone or pyridone analog compound.   
     
     
         13 . The method of  claim 1 , wherein the pirfenidone or a pyridone analog compound is administered at least once a week. 
     
     
         14 . The method of  claim 1 , wherein the pirfenidone or a pyridone analog compound is administered on a continuous daily dosing schedule. 
     
     
         15 . The method of  claim 1 , wherein the pirfenidone or a pyridone analog compound is administered once a day, twice a day, or three times a day. 
     
     
         16 . The method of  claim 1 , wherein the lung disease is idiopathic pulmonary fibrosis, lung cancer or pulmonary hypertension. 
     
     
         17 . The method of  claim 1 , wherein the lung disease is lung cancer and the treatment comprises inhibiting, reducing or slowing the growth of lung tumor stroma. 
     
     
         18 . The method of  claim 16 , wherein the method further comprises administration of one or more additional therapeutic agents to the mammal. 
     
     
         19 . A method for the treatment of lung disease in a mammal comprising:
 administering a dose of pirfenidone or a pyridone analog compound by inhalation to the mammal in need thereof, wherein the blood AUC 0-24  of pirfenidone or pyridone analog compound from the inhaled dose is less than the blood AUC 0-24  of up to 801 mg of an orally administered dosage of pirfenidone or pyridone analog compound.   
     
     
         20 . The method of  claim 19 , wherein the inhaled dose of pirfenidone or pyridone analog compound is administered with a nebulizer, a metered dose inhaler, or a dry powder inhaler. 
     
     
         21 . The method of  claim 19 , wherein the inhaled dose comprises an aqueous solution of pirfenidone or a pyridone analog compound and the dose is administered with a liquid nebulizer. 
     
     
         22 . The method of  claim 21 , wherein each inhaled dose that is directly administered to the lungs of the mammal comprises from about 0.1 mL to about 6 mL of an aqueous solution of pirfenidone or a pyridone analog compound, wherein the concentration of pirfenidone or pyridone analog compound in the aqueous solution is from about 0.1 mg/mL and about 60 mg/mL and the osmolality of the of the aqueous solution is from about 50 mOsmol/kg to about 6000 mOsmol/kg. 
     
     
         23 . The method of  claim 22 , wherein the aqueous solution of each inhaled dose further comprises:
 one or more additional ingredients selected from co-solvents, tonicity agents, sweeteners, surfactants, wetting agents, chelating agents, anti-oxidants, salts, and buffers.   
     
     
         24 . The method of  claim 22 , wherein the aqueous solution of each inhaled dose further comprises:
 a citrate buffer or phosphate buffer, and one or more salts selected from the group consisting of sodium chloride, magnesium chloride, sodium bromide, magnesium bromide, calcium chloride and calcium bromide.   
     
     
         25 . The method of  claim 22 , wherein the aqueous solution of each inhaled dose comprises:
 water;   pirfenidone or pyridone analog compound at a concentration from about 0.1 mg/mL to about 20 mg/mL;   one or more salts, wherein the total amount of the one or more salts is from about 0.01% to about 2.0% by weight of the weight of aqueous solution;   and   optionally a phosphate buffer that maintains the pH of the solution from about pH 5.0 to about pH 8.0, or citrate buffer than maintains the pH of the solution from about 4.0 to about 7.0.   
     
     
         26 . The method of  claim 19 , wherein the inhaled dose of pirfenidone or a pyridone analog compound is administered on a continuous dosing schedule. 
     
     
         27 . The method of  claim 19 , wherein the lung disease is idiopathic pulmonary fibrosis, lung cancer or pulmonary hypertension. 
     
     
         28 . The method of  claim 19 , wherein the lung disease is lung cancer and the treatment comprises inhibiting, reducing or slowing the growth of lung tumor stroma. 
     
     
         29 . The method of  claim 27 , wherein the method further comprises administration of one or more additional therapeutic agents to the mammal.