Aerosol pirfenidone and pyridone analog compounds and uses thereof

Abstract

To provide a liquid for therapeutic inhalation delivery of a pyridone composition such as pirfenidone to a desired anatomical site for treating and / or preventing pathological conditions of various pulmonary, neurological, cardiovascular, and parenchymal organ diseases.SOLUTION: The present invention provides an aqueous solution for nebulized inhalation administration, the aqueous solution comprising water, pirfenidone or a pyridone analog compound at a concentration from about 0.1 mg / mL to about 60 mg / mL, and one or more co-solvents, wherein the osmolality of the aqueous solution is from about 50 mOsmol / kg to about 6000 mOsmol / kg.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] (Priority Claim) This application claims the benefit of U.S. Provisional Patent Application No. 61 / 438,203, filed on January 31, 2011, entitled "AEROSOL PIRFENIDONE AND PYRIDONE ANALOG COMPOUNDS AND USES THEREOF"; U.S. Provisional Patent Application No. 61 / 508,542, filed on July 15, 2011, entitled "AEROSOL PIRFENIDONE AND PYRIDONE ANALOG COMPOUNDS AND USES THEREOF"; U.S. Provisional Patent Application No. 61 / 559,670, filed on November 14, 2011, entitled "AEROSOL PIRFENIDONE AND PYRIDONE ANALOG COMPOUNDS AND USES THEREOF"; and U.S. Provisional Patent Application No. 61 / 584,119, filed on January 6, 2012, entitled "AEROSOL PIRFENIDONE AND PYRIDONE ANALOG COMPOUNDS AND USES THEREOF", all of which are hereby incorporated by reference in their entirety.

[0002] In several embodiments thereof, the present invention relates to liquid, dry powder, and metered formulations for the therapeutic inhalation delivery of pyridone compositions, such as pirfenidone, to a desired anatomical site for treating and / or preventing the conditions of various lung diseases, neurological diseases, cardiovascular diseases, and diseases of the parenchymal organs.

Background Art

[0003] Many undesirable lung diseases such as interstitial lung disease (ILD and its sub-classified diseases), chronic obstructive pulmonary disease (COPD and its sub-classified diseases), asthma, and signs of fibrosis in the kidneys, heart, and eyes begin due to external load. By way of non-limiting examples, these effectors may include infection, smoking, environmental exposure, radiation exposure, surgical procedures, and transplant rejection. However, it may also be attributed to other causes related to genetic nature and the action of aging. Compositions of compounds of pirfenidone or pyridone analogs suitable for inhaled delivery to the lungs and / or systemic compartments, and methods of using such compositions are described herein.

SUMMARY OF THE INVENTION

MEANS FOR SOLVING THE PROBLEM

[0004] According to certain embodiments of the present invention, there is provided a pharmaceutical composition of a compound of pirfenidone or a pyridone analog for delivery by oral, pulmonary, or intranasal inhalation, comprising a formulation for aerosol administration of the compound of pirfenidone or a pyridone analog for the prevention or treatment of various fibrotic and inflammatory diseases including diseases related to the lungs, heart, kidneys, liver, eyes, and central nervous system.

[0005] In one aspect, an aqueous solution for nebulized inhalation administration is described herein, the aqueous solution comprising water, a compound of pirfenidone or a pyridone analog at a concentration from about 10 mg / mL to about 50 mg / mL, and one or more co-solvents. In another aspect, an aqueous solution for nebulized inhalation administration is described herein, the aqueous solution comprising water, a compound of pirfenidone or a pyridone analog at a concentration from about 10 mg / mL to about 50 mg / mL, optionally one or more buffers for maintaining the pH between about pH 4.0 and about pH 8.0, and one or more co-solvents. In some embodiments, the pH of the aqueous solution is from about 4.0 to about 8.0. In some embodiments, the pH of the aqueous solution is from about 6.0 to about 8.0. In some embodiments, an aqueous solution for nebulized inhalation administration is described herein, the aqueous solution comprising water, a compound of pirfenidone or a pyridone analog at a concentration from about 0.1 mg / mL to about 60 mg / mL, and one or more co-solvents, and the osmotic pressure of the aqueous solution is from about 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the compound of pirfenidone or a pyridone analog is at a concentration from about 10 mg / mL to about 60 mg / mL. In some embodiments, the compound of pirfenidone or a pyridone analog is at a concentration from about 10 mg / mL to about 50 mg / mL. In some embodiments, the compound of pirfenidone or a pyridone analog is at a concentration from about 15 mg / mL to about 50 mg / mL. In some embodiments, the compound of pirfenidone or a pyridone analog is at a concentration from about 20 mg / mL to about 50 mg / mL. In some embodiments, the compound of pirfenidone or a pyridone analog is at a concentration from about 25 mg / mL to about 50 mg / mL. In some embodiments, the compound of pirfenidone or a pyridone analog is at a concentration from about 30 mg / mL to about 50 mg / mL. In some embodiments, the osmotic pressure of the aqueous solution is from about 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the osmotic pressure of the aqueous solution is from about 50 mOsmol / kg to about 5000 mOsmol / kg.In some embodiments, the osmotic pressure of the aqueous solution is from about 100 mOsmol / kg to about 5000 mOsmol / kg, from about 300 mOsmol / kg to about 5000 mOsmol / kg, from about 400 mOsmol / kg to about 5000 mOsmol / kg, from about 600 mOsmol / kg to about 5000 mOsmol / kg, from about 1000 mOsmol / kg to about 5000 mOsmol / kg, or from about 2000 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the total concentration of the co-solvent is from about 1% v / v to about 40% v / v. In some embodiments, the total concentration of the co-solvent is from about 1% v / v to about 30% v / v. In some embodiments, the total concentration of the co-solvent is from about 1% v / v to about 25% v / v. In some embodiments, one or more co-solvents are selected from ethanol, propylene glycol, and glycerol. In some embodiments, one or more co-solvents are selected from ethanol and propylene glycol. In some embodiments, the aqueous solution contains both ethanol and propylene glycol. In some embodiments, the aqueous solution further comprises one or more additional components selected from surfactants, taste making agents / sweeteners, and salts. In some embodiments, the taste making agent / sweetener is saccharin or a salt thereof. In some embodiments, the aqueous solution further comprises one or more additional components selected from surfactants and salts. In some embodiments, the surfactant is polysorbate 80 or cetylpyridinium bromide. In some embodiments, the salt is sodium chloride or magnesium chloride. In some embodiments, the surfactant is polysorbate 80 or cetylpyridinium bromide and the salt is sodium chloride or magnesium chloride. In some embodiments, the aqueous solution contains one or more buffers selected from citrate buffer and phosphate buffer. In some embodiments, the aqueous solution contains phosphate buffer. In some embodiments, the aqueous solution contains citrate buffer. In some embodiments, from about 0.5 mL to about 6 mL of the aqueous solution described herein is provided here.

[0006] In some embodiments, the aqueous solution further comprises one or more additional components selected from surfactants, buffers, and salts. In some embodiments, the surfactant is polysorbate 80 or cetylpyridinium bromide, the buffer is a citrate buffer or a phosphate buffer, and the salt is sodium chloride or magnesium chloride.

[0007] In some embodiments, the aqueous solution comprises water, a compound of pirlfenidone or a pyridone analog at a concentration from about 10 mg / mL to about 60 mg / mL, and one or more co-solvents, wherein the total concentration of the one or more co-solvents is from about 1% v / v to about 40% v / v, the one or more co-solvents are ethanol from about 1% v / v to about 25% v / v, propylene glycol from about 1% v / v to about 25% v / v, and glycerol from about 1% v / v to about 25% v / v, and the aqueous solution optionally comprises a phosphate buffer that maintains the pH of the solution from pH about 6.0 to pH about 8.0.

[0008] In some embodiments, the aqueous solution comprises water, a compound of pirlfenidone or a pyridone analog at a concentration from about 15 mg / mL to about 50 mg / mL, and one or more co-solvents, wherein the total amount of the one or more co-solvents is from about 1% v / v to about 30% v / v, the one or more co-solvents are selected from ethanol from about 1% v / v to about 10% v / v and propylene glycol from about 1% v / v to about 20% v / v, the aqueous solution optionally comprises a phosphate buffer that maintains the pH of the solution from pH about 6.0 to pH about 8.0, and wherein the osmotic pressure of the aqueous solution is from about 400 mOsmol / kg to about 6000 mOsmol / kg.

[0009] In some embodiments, the aqueous solution for nebulized inhalation administration described herein comprises water, a compound of pirfenidone or a pyridone analog at a concentration from about 10 mg / mL to about 50 mg / mL, optionally a phosphate buffer to maintain the pH of the solution from pH about 6.0 to pH about 8.0, ethanol from about 1% v / v to about 25% v / v, and one or more co-solvents selected from propylene glycol from about 1% v / v to about 25% v / v, wherein the total amount of the co-solvent is from 1% v / v to 25% v / v. In some embodiments, the aqueous solution for nebulized inhalation administration described herein comprises water, a compound of pirfenidone or a pyridone analog at a concentration from about 10 mg / mL to about 50 mg / mL, optionally a phosphate buffer to maintain the pH of the solution from pH about 6.0 to pH about 8.0, 8% v / v ethanol, and 16% v / v propylene glycol. In some embodiments, the aqueous solution for nebulized inhalation administration described herein consists essentially of water, a compound of pirfenidone or a pyridone analog at a concentration from about 10 mg / mL to about 50 mg / mL, optionally a phosphate buffer to maintain the pH of the solution from pH about 6.0 to pH about 8.0, ethanol from about 1% v / v to about 25% v / v, and one or more co-solvents selected from propylene glycol from about 1% v / v to about 25% v / v, wherein the total amount of the co-solvent is from 1% v / v to 25% v / v. In some embodiments, the aqueous solution for nebulized inhalation administration described herein consists essentially of water, a compound of pirfenidone or a pyridone analog at a concentration from about 10 mg / mL to about 50 mg / mL, optionally a phosphate buffer to maintain the pH of the solution from pH about 6.0 to pH about 8.0, 8% v / v ethanol, and 16% v / v propylene glycol. In some embodiments, from about 0.5 mL to about 6 mL of the aqueous solution described herein is described herein.

[0010] In some embodiments, a unit dosage suitable for use in a liquid nebulizer is described that comprises an aqueous solution of a compound of pirfenidone or a pyridone analog from about 0.5 mL to about 6 mL, and the concentration of the compound of pirfenidone or the pyridone analog in the aqueous solution is from about 0.1 mg / mL to about 60 mg / mL. In some embodiments, the aqueous solution further comprises one or more additional components selected from co-solvents, tonicity agents, sweeteners, surfactants, wetting agents, chelating agents, antioxidants, salts, and buffers, and the osmotic pressure of the aqueous solution is from about 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the aqueous solution further comprises one or more co-solvents selected from ethanol, propylene glycol, and glycerol, and one or both of a citrate buffer or a phosphate buffer. In some embodiments, the aqueous solution comprises a compound of pirfenidone or a pyridone analog dissolved in water at a concentration from about 15 mg / mL to about 50 mg / mL, optionally a phosphate buffer that maintains the pH of the solution from pH about 6.0 to pH about 8.0, and one or more co-solvents, wherein the total amount of the one or more co-solvents is from about 1% v / v to about 30% v / v, and the one or more co-solvents are selected from about 1% v / v to about 10% v / v ethanol, and from about 1% v / v to about 20% v / v propylene glycol, wherein the osmotic pressure of the aqueous solution is from about 400 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the aqueous solution is as described herein.

[0011] In some embodiments, a kit is described herein that comprises a unit dosage of an aqueous solution of a pirfenidone or a pyridone analog as described herein in a container suitable for use in a liquid nebulizer.

[0012] In some embodiments, water droplets of a compound of pirfenidone or a pyridone analog are provided herein, and the water droplets have a diameter of less than about 5.0 μm. In some embodiments, the water droplets are generated from a liquid nebulizer and an aqueous solution of a compound of pirfenidone or a pyridone analog. In some embodiments, the aqueous solution of a compound of pirfenidone or a pyridone analog is as described herein. In some embodiments, the aqueous solution has a concentration of a compound of pirfenidone or a pyridone analog from about 0.1 mg / mL to about 60 mg / mL and an osmotic pressure from about 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the water droplets are generated by spraying an aqueous solution of a compound of pirfenidone or a pyridone analog as described herein using a nebulizer. In some embodiments, the nebulizer is a liquid nebulizer. In some embodiments, the nebulizer is a high-efficiency liquid nebulizer.

[0013] In some embodiments, an aqueous aerosol comprising a plurality of water droplets of a compound of pirfenidone or a pyridone analog is provided herein. In some embodiments, an aqueous aerosol comprising a plurality of water droplets of a compound of pirfenidone or a pyridone analog is described herein, and the plurality of water droplets have a volumetric mean diameter (VMD) of less than about 5.0 μm, a mass median aerodynamic diameter (MMAD), and / or a mass median diameter (MMD). In some embodiments, the plurality of water droplets are generated from a liquid nebulizer and an aqueous solution of a compound of pirfenidone or a pyridone analog. In some embodiments, the aqueous solution has a concentration of a compound of pirfenidone or a pyridone analog from about 10 mg / mL to about 60 mg / mL and an osmotic pressure from about 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, at least 30% of the water droplets in the aerosol have a diameter of less than about 5 μm. In some embodiments, the aqueous aerosol is generated by spraying an aqueous solution of a compound of pirfenidone or a pyridone analog described herein using a nebulizer. In some embodiments, the nebulizer is a liquid nebulizer. In some embodiments, the nebulizer is a high-efficiency body fluid nebulizer.

[0014] In some embodiments, the nebulizer used in any of the methods described herein is a liquid nebulizer. In some embodiments, the nebulizer used in any of the methods described herein is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer including a vibrating mesh or plate with many holes, or a nebulizer including a vibration generator and an aqueous chamber. In some embodiments, the nebulizer used in any of the methods described herein is a nebulizer including a vibrating mesh or plate with many holes. In some embodiments, the liquid nebulizer: (i) achieves at least 7% lung deposition of the compound of pirfenidone or a pyridone analog administered to a mammal; (ii) provides a geometric standard deviation (GSD) of the particle size distribution of the released droplets of an aqueous solution from about 1.0 μm to about 2.5 μm; (iii) provides (a) an aerodynamic mass median diameter (MMAD) of the particle size of the droplets of an aqueous solution released using a highly efficient liquid nebulizer from about 1 μm to about 5 μm, (b) a volume median diameter (VMD) from about 1 μm to about 5 μm, and / or (c) a mass median diameter (MMD) from about 1 μm to about 5 μm; (iv) provides at least about 30% fine particle fraction (FPF = % ≤ 5 microns) of the droplets released from the liquid nebulizer; (v) provides an output rate of at least 0.1 mL / min, and / or (vi) delivers at least about 25% of the aqueous solution to a mammal.

[0015] In some embodiments, the liquid nebulizer is characterized as having at least two, at least three, at least four, at least five, or all six of (i), (ii), (iii), (iv), (v), (vi). In some embodiments, the aqueous solution achieves at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% pulmonary deposition of a compound of pirfenidone or a pyridone analog administered to a mammal. In some embodiments, the aqueous solution provides a geometric standard deviation (GSD) of the droplet size distribution of the aqueous solution released of from about 1.0 μm to about 2.5 μm, from about 1.2 μm to about 2.3 μm, from about 1.4 μm to about 2.1 μm, or from about 1.5 μm to about 2.0 μm. In some embodiments, the liquid nebulizer provides (iii) a) an aerodynamic mass median diameter (MMAD) of the droplet size of the aqueous solution released by a high-efficiency liquid nebulizer of less than about 5 μm or from about 1 μm to about 5 μm, b) a volume median diameter (VMD) of less than about 5 μm or from about 1 μm to about 5 μm, and / or c) a mass median diameter (MMD) of less than about 5 μm or from about 1 μm to about 5 μm. In some embodiments, the liquid nebulizer provides (iv) at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% fine particle fraction (FPF = %≤5 microns) of the droplets released from the liquid nebulizer.In some embodiments, the liquid nebulizer provides an output rate of at least 0.1 mL / min, at least 0.2 mL / min, at least 0.3 mL / min, at least 0.4 mL / min, at least 0.5 mL / min, at least 0.6 mL / min, at least 0.7 mL / min, at least 0.8 mL / min, at least 0.9 mL / min, at least 1.0 mL / min, or less than about 1.0 mL / min. In some embodiments, the liquid nebulizer provides at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 95% of an aqueous solution to a mammal. In some embodiments, the liquid nebulizer provides at least 5%, at least 6%, at least 7%, at least 8%, at least 10%, at least 12%, at least 16%, at least 20%, at least 24%, at least 28%, at least 32%, at least 36%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% of a respirable delivery dose (RDD).

[0016] In some embodiments, methods for treating mammalian lung diseases are described herein, the methods comprising administering to a mammal an aqueous solution comprising a compound of pirfenidone or a pyridone analog using a liquid nebulizer. In some embodiments, methods for treating mammalian lung diseases are described herein, the methods comprising administering to a mammal an aqueous solution comprising a compound of pirfenidone or a pyridone analog using a liquid nebulizer, wherein the aqueous solution comprises water, a compound of pirfenidone or a pyridone analog at a concentration from about 0.1 mg / mL to about 60 mg / mL, and one or more co-solvents, and the osmotic pressure of the aqueous solution is from about 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the aqueous solution comprises water, a compound of pirfenidone or a pyridone analog at a concentration from about 10 mg / mL to about 60 mg / mL, one or more co-solvents, wherein the total amount of the one or more co-solvents is from about 1% v / v to about 40% v / v, and the one or more co-solvents are selected from about 1% v / v to about 25% v / v ethanol, about 1% v / v to about 25% v / v propylene glycol, or about 1% v / v to about 25% v / v glycerol, and the aqueous solution optionally comprises a phosphate buffer that maintains the pH of the aqueous solution from pH about 6.0 to pH about 8.0. In some embodiments, the aqueous solution comprises water, a compound of pirfenidone or a pyridone analog at a concentration from about 15 mg / mL to about 50 mg / mL, one or more co-solvents, wherein the total amount of the one or more co-solvents is from about 1% v / v to about 30% v / v, and the one or more co-solvents are selected from about 1% v / v to about 10% v / v ethanol, or about 1% v / v to about 20% v / v propylene glycol, and the aqueous solution optionally comprises a phosphate buffer that maintains the pH of the aqueous solution from pH about 6.0 to pH about 8.0, wherein the osmotic pressure of the aqueous solution is from about 400 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer comprising a vibrating mesh or plate with many holes, or a nebulizer comprising a vibration generator and an aqueous chamber.In some embodiments, the liquid nebulizer achieves at least 7% lung deposition of a compound of pirfenidone or a pyridone analog administered to a mammal, provides a geometric standard deviation (GSD) of the released droplet size distribution of an aqueous solution from about 1.0 μm to about 2.5 μm, provides (iii) a) an aerodynamic mass median diameter (MMAD) of the droplet size of an aqueous solution released by a high-efficiency liquid nebulizer from about 1 μm to about 5 μm, b) a volume median diameter (VMD) from about 1 μm to about 5 μm, and / or c) a mass median diameter (MMD) from about 1 μm to about 5 μm, provides at least about 30% fine particle fraction (FPF = % ≤ 5 microns) of the droplets released from the liquid nebulizer, provides an output rate of at least 0.1 mL / min, and / or delivers at least about 25% of the aqueous solution to the mammal. In some embodiments, the mammal is a human. In some embodiments, the lung disease is pulmonary fibrosis and the mammal is a human. In some embodiments, the lung disease is idiopathic pulmonary fibrosis and the mammal is a human. In some embodiments, the liquid nebulizer delivers a compound of pirfenidone or a pyridone analog from about 0.1 mg to about 360 mg to the lungs of a mammal in less than about 20 minutes at a mass median diameter (MMAD) particle size from about 1 micron to about 5 microns.

[0017] In some embodiments, the pulmonary tissue Cmax (maximum plasma concentration) and / or AUC (area under the concentration curve) of a compound of pirfenidone or a pyridone analog obtained after a single administration of an aqueous solution to a mammal using a liquid nebulizer is approximately the same as, or greater than, the pulmonary tissue Cmax and / or AUC of a compound of pirfenidone or a pyridone analog obtained after a single oral administration of a compound of pirfenidone or a pyridone analog at a dose that is about 80% to about 120% of the dose administered using the liquid nebulizer, and / or the plasma Cmax and / or AUC of a compound of pirfenidone or a pyridone analog obtained after a single administration of an aqueous solution to a mammal using a liquid nebulizer is at least 10% of, or higher than, the plasma Cmax and / or AUC of a compound of pirfenidone or a pyridone analog obtained after a single oral administration of a compound of pirfenidone or a pyridone analog at a dose that is about 80% to about 120% of the dose administered using the liquid nebulizer. In some embodiments, the pulmonary tissue Cmax of a compound of pirfenidone or a pyridone analog obtained after a single administration of an aqueous solution to a mammal using a liquid nebulizer is higher than the pulmonary tissue Cmax of a compound of pirfenidone or a pyridone analog obtained after a single oral administration of a compound of pirfenidone or a pyridone analog at a dose that is about 80% to about 120% of the dose administered using the liquid nebulizer. In some embodiments, the pulmonary tissue AUC of a compound of pirfenidone or a pyridone analog obtained after a single administration of an aqueous solution to a mammal using a liquid nebulizer is greater than the pulmonary tissue ACU of a compound of pirfenidone or a pyridone analog obtained after a single oral administration of a compound of pirfenidone or a pyridone analog at a dose that is about 80% to about 120% of the dose administered using the liquid nebulizer.In some embodiments, the plasma Cmax of the compound of pifidone or a pyridone analog obtained after a single administration of an aqueous solution to a mammal using a liquid nebulizer is at least 10% of the plasma Cmax of the compound of pifidone or a pyridone analog obtained after a single oral administration of the compound of pifidone or a pyridone analog at a dose that is from about 80% to about 120% of the dose administered using the liquid nebulizer, or higher. In some embodiments, the plasma AUC of the compound of pifidone or a pyridone analog obtained after a single administration of an aqueous solution to a mammal using a liquid nebulizer is at least 10% of the plasma AUC of the compound of pifidone or a pyridone analog obtained after a single oral administration of the compound of pifidone or a pyridone analog at a dose that is from about 80% to about 120% of the dose administered using the liquid nebulizer, or greater.

[0018] In some embodiments, the liquid nebulizer delivers from about 0.1 mg to about 360 mg of the compound of pifidone or a pyridone analog to the lungs of a mammal in less than about 20 minutes at a mass median aerodynamic diameter (MMAD) particle size from about 1 micron to about 5 microns.

[0019] In some embodiments, administration using a liquid nebulizer does not include an initial dose titration period.

[0020] In some embodiments, methods are described herein for reducing the risk of gastrointestinal (GI) adverse events in the treatment of humans with compounds of pirfenidone or pyridone analogs, the method comprising administering to a human, using a liquid nebulizer, an atomized aqueous solution comprising a pirfenidone human or pyridone analog compound, wherein the aqueous solution comprises water, a compound of pirfenidone or pyridone analog at a concentration from about 0.1 mg / mL to about 60 mg / mL, and one or more co-solvents, and the osmotic pressure of the aqueous solution is from about 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the aqueous solution comprises water, a compound of pirfenidone or pyridone analog at a concentration from about 10 mg / mL to about 60 mg / mL, and one or more co-solvents, wherein the total amount of the one or more co-solvents is from about 1% v / v to about 40% v / v, and the one or more co-solvents are selected from about 1% v / v to about 25% v / v ethanol, about 1% v / v to about 25% v / v propylene glycol, or about 1% v / v to about 25% v / v glycerol, and the aqueous solution optionally comprises a phosphate buffer to maintain the pH of the aqueous solution from pH about 6.0 to pH about 8.0.

[0021] In some embodiments, the aqueous solution comprises water, a compound of pirfenidone or pyridone analog at a concentration from about 15 mg / mL to about 50 mg / mL, and one or more co-solvents, wherein the total amount of the one or more co-solvents is from about 1% v / v to about 30% v / v, and the one or more co-solvents are selected from about 1% v / v to about 10% v / v ethanol, or about 1% v / v to about 20% v / v propylene glycol, and the aqueous solution optionally comprises a phosphate buffer to maintain the pH of the aqueous solution from pH about 6.0 to pH about 8.0, wherein the osmotic pressure of the aqueous solution is from about 400 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog is administered for treating a human lung disease. In some embodiments, the lung disease is idiopathic pulmonary fibrosis.

[0022] In some embodiments, the liquid nebulizer delivers from about 0.1 mg to about 360 mg of a compound of pifenedone or a pyridone analog to the lung in less than about 20 minutes at a mass median aerodynamic diameter (MMAD) particle size of from about 1 micron to about 5 microns.

[0023] In some embodiments, administration using a liquid nebulizer does not include an initial dose titration period.

[0024] In some embodiments, from about 0.5 mL to about 6 mL of an aqueous solution is administered to a mammal by a liquid nebulizer, the aqueous solution having a concentration of a compound of pifenedone or a pyridone analog from about 0.1 mg / mL to about 60 mg / mL, the osmotic pressure of the aqueous solution being from about 50 mOsmol / kg to about 5000 mOsmol / kg, and the liquid nebulizer being a nebulizer comprising a vibrating mesh or plate with many holes.

[0025] In some embodiments, the liquid nebulizer delivers from about 0.1 mg to about 360 mg of a compound of pifenedone or a pyridone analog to the lung in less than about 20 minutes at a mass median aerodynamic diameter (MMAD) particle size of from about 1 micron to about 5 microns. In some embodiments, the aqueous solution has a pH of from about 4.0 to about 8.0 and an osmotic pressure of from about 400 mOsmol / kg to about 5000 mOsmol / kg.

[0026] In some embodiments, an inhalation system for administering a compound of pirfenidone or a pyridone analog to the human airway is described herein, the inhalation system comprising: (a) an aqueous solution of a compound of pirfenidone or a pyridone analog from about 0.5 mL to about 6 mL; and (b) a high-efficiency liquid nebulizer. In some embodiments, the aqueous solution is any of the aqueous solutions described herein. In some embodiments, the concentration of the compound of pirfenidone or a pyridone analog in the aqueous solution is from about 0.1 mg / mL to about 60 mg / mL, and the osmotic pressure of the aqueous solution is from about 400 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the aqueous solution comprises water, a compound of pirfenidone or a pyridone analog at a concentration from about 10 mg / mL to about 50 mg / mL, optionally a phosphate buffer to maintain the pH of the aqueous solution from pH about 6.0 to pH about 8.0, from about 1% to about 8% ethanol, and / or from about 2% to about 16% propylene glycol. In some embodiments, the aqueous solution is as described herein.

[0027] In one aspect, a method for achieving a lung tissue Cmax of a compound of pirfenidone or a pyridone analog that is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 1.5 times - 20 times, at least 1.5 times - 15 times, at least 1.5 times - 10 times, at least 1.5 times - 5 times, or at least 1.5 times - 3 times the Cmax of an orally administered amount of the compound of pirfenidone or a pyridone analog up to 801 mg is described herein, the method comprising the steps of atomizing an aqueous solution comprising the compound of pirfenidone or a pyridone analog and administering the atomized aqueous solution to a human. In some embodiments, a method for achieving a lung tissue Cmax of a compound of pirfenidone or a pyridone analog that is at least equal to or higher than the Cmax of an orally administered amount of the compound of pirfenidone or a pyridone analog up to 801 mg is described herein, the method comprising the steps of atomizing an aqueous solution comprising the compound of pirfenidone or a pyridone analog and administering the atomized aqueous solution to a human.

[0028] In one aspect, the AUC of an orally administered amount of a compound of pirfenidone or a pyridone analog up to 801 mg 0-24 is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 1.5 times - 20 times, at least 1.5 times - 15 times, at least 1.5 times - 10 times, at least 1.5 times - 5 times, or at least 1.5 times - 3 times that. The lung tissue AUC of a compound of pirfenidone or a pyridone analog 0-24A method for achieving the same is described herein, the method comprising the steps of atomizing an aqueous solution containing a compound of pirfenidone or a pyridone analog, and administering the atomized aqueous solution to a human. In some embodiments, the AUC of an orally administered amount of a compound of pirfenidone or a pyridone analog up to 801 mg 0-24 is at least equivalent to, or greater than, the lung tissue AUC of a compound of pirfenidone or a pyridone analog 0-24 A method for achieving the same is described herein, the method comprising the steps of atomizing an aqueous solution containing a compound of pirfenidone or a pyridone analog, and administering the atomized aqueous solution to a human.

[0029] In one aspect, a method of administering a compound of pirfenidone or a pyridone analog to a human is described herein, the method comprising the step of administering an atomized aqueous solution containing a compound of pirfenidone or a pyridone analog, wherein the lung tissue Cmax achieved using the atomized aqueous solution is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 1.5 - 20 times, at least 1.5 - 15 times, at least 1.5 - 10 times, at least 1.5 - 5 times, or at least 1.5 - 3 times the lung tissue Cmax achieved with an orally administered dose of a compound of pirfenidone or a pyridone analog, which is 80% to 120% of the dose of pirfenidone administered by inhalation.

[0030] In one aspect, a method of administering a compound of pirfenidone or a pyridone analog to a human is described herein, the method comprising the step of administering an atomized aqueous solution comprising pirfenidone or a pyridone analog, wherein the lung tissue Cmax achieved with the atomized aqueous solution is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 1.5 - 20 times, at least 1.5 - 15 times, at least 1.5 - 10 times, at least 1.5 - 5 times, or at least 1.5 - 3 times the lung tissue Cmax achieved with the dosage of the compound of pirfenidone or a pyridone analog administered orally, which is 80% to 120% of the dosage of the compound of pirfenidone or a pyridone analog in the atomized aqueous solution. In some embodiments, a method of administering a compound of pirfenidone or a pyridone analog to a human is described herein, the method comprising the step of administering an atomized aqueous solution comprising pirfenidone or a pyridone analog, wherein the lung tissue Cmax achieved with the atomized aqueous solution is at least equivalent to, or higher than, the lung tissue Cmax achieved with the dosage of the compound of pirfenidone or a pyridone analog administered orally, which is 80% to 120% of the dosage of the compound of pirfenidone or a pyridone analog in the atomized aqueous solution.

[0031] In some embodiments, a method of administering a compound of pirfenidone or a pyridone analog to a human is described herein, the method comprising the step of administering an atomized aqueous solution comprising pirfenidone or a pyridone analog, wherein the plasma AUC 0-24 achieved with the atomized aqueous solution is 80% to 120% of the dosage of the compound of pirfenidone or a pyridone analog in the atomized aqueous solution, and is the plasma AUC achieved with the dosage of the compound of pirfenidone or a pyridone analog administered orally.0-24 is at least 10% or greater than that.

[0032] In one aspect, a method of administering a compound of pirfenidone or a pyridone analog to a human is described herein, the method comprising the step of administering an atomized aqueous solution comprising pirfenidone or a pyridone analog, and the lung tissue AUC achieved with the atomized aqueous solution 0-24 is from 80% to 120% of the dose of the compound of pirfenidone or a pyridone analog in the atomized aqueous solution of the compound of pirfenidone or a pyridone analog, the lung tissue AUC achieved with the orally administered dose of the compound of pirfenidone or a pyridone analog 0-24 is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least 1.5 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 1.5 - 20 times, at least 1.5 - 15 times, at least 1.5 - 10 times, at least 1.5 - 5 times, or at least 1.5 - 3 times. In some embodiments, a method of administering a compound of pirfenidone or a pyridone analog to a human is described herein, the method comprising the step of administering an atomized aqueous solution comprising pirfenidone or a pyridone analog, and the lung tissue AUC achieved with the atomized aqueous solution 0-24 is from 80% to 120% of the dose of the compound of pirfenidone or a pyridone analog in the atomized aqueous solution of the compound of pirfenidone or a pyridone analog, the lung tissue AUC achieved with the orally administered dose of the compound of pirfenidone or a pyridone analog 0-24 is at least 1.5 times.

[0033] In one aspect, provided herein is a method of improving the pharmacokinetic profile obtained in humans after a single oral administration of pirfenidone or a pyridone analog. In some embodiments, the pirfenidone or pyridone analog is administered to a human for treating a lung disease. In some embodiments, the lung disease is pulmonary fibrosis. In some embodiments, the lung disease is idiopathic pulmonary fibrosis. In some embodiments, the single oral dose comprises a compound of pirfenidone or a pyridone analog up to about 801 mg. In some embodiments, the method of improving the pharmacokinetic profile comprises administering the pirfenidone or pyridone analog by inhalation. In some embodiments, the pharmacokinetic profile comprises the pharmacokinetic profile of lung tissue. In some embodiments, the pharmacokinetic profile comprises the pharmacokinetic profile of lung tissue and / or the pharmacokinetic profile of plasma. In some embodiments, the pirfenidone or pyridone analog is administered as an aqueous solution using a liquid nebulizer. In some embodiments, the aqueous solution of the pirfenidone or pyridone analog is as described herein. In some embodiments, the method of improving the pharmacokinetic profile further comprises comparing the pharmacokinetic parameters after inhaled administration with the same parameters obtained after oral administration. In some embodiments, the improvement in the pharmacokinetic profile is substantially the same as that depicted in FIG. 1. In some embodiments, the initial improvement in the pharmacokinetic profile is substantially the same as that depicted in FIG. 1, but the half-life in the lung is longer, providing a longer residence time in the lung.

[0034] In some embodiments, pharmaceutical compositions for pulmonary delivery are described herein that include a solution of pirfenidone or a pyridone analog having a concentration greater than about 34 mcg / mL, an osmotic pressure greater than about 100 mOsmol / kg, and a pH greater than about 4.0. In some embodiments, the concentration of pirfenidone or the pyridone analog is greater than about 1.72 mg / mL. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 86 mg / mL. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic ion concentration from about 30 mM to about 300 mM. In some embodiments, the osmotic ion is chloride or bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH from about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic pressure from about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic pressure from about 50 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the composition includes a flavoring agent. In some embodiments, the flavoring agent is selected from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucralose, ascorbate, and citrate. In some embodiments, the composition includes a mucolytic agent suitable for pulmonary delivery. In some embodiments, the composition includes a second anti-fibrotic agent suitable for pulmonary delivery. In some embodiments, the composition includes a second anti-inflammatory agent suitable for pulmonary delivery.

[0035] In some embodiments, pharmaceutical compositions for pulmonary delivery are described herein that include a solution of pirfenidone or a pyridone analog and a flavoring agent, where the solution has an osmotic pressure greater than about 100 mOsmol / kg and a pH greater than about 4.0. In some embodiments, the concentration of pirfenidone or the pyridone analog is greater than about 34 mcg / mL. In some embodiments, the concentration of pirfenidone or the pyridone analog is greater than about 1.72 mg / mL. In some embodiments, the concentration of pirfenidone or the pyridone analog is greater than about 86 mg / mL. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic ionic concentration from about 30 mM to about 300 mM. In some embodiments, the osmotic ions are chloride or bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH from about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic pressure from about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic pressure from about 50 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the composition includes a flavoring agent. In some embodiments, the flavoring agent is selected from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucralose, ascorbate, and citrate. In some embodiments, the composition includes a mucolytic agent suitable for pulmonary delivery. In some embodiments, the composition includes a second anti-fibrotic agent suitable for pulmonary delivery. In some embodiments, the composition includes a second anti-inflammatory agent suitable for pulmonary delivery.

[0036] In some embodiments, a sterile, disposable container is described herein that contains a solution of pirfenidone or a pyridone analog in an amount from about 0.1 mL to about 20 mL, having a concentration greater than about 34 mcg / mL, an osmotic pressure greater than about 100 mOsmol / kg, and a pH greater than about 4.0. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 1.72 mg / mL. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 86 mg / mL. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic ion concentration from about 30 mM to about 300 mM. In some embodiments, the osmotic ion is chloride or bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH from about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic pressure from about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic pressure from about 50 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the container further comprises a flavoring agent. In some embodiments, the flavoring agent is selected from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucralose, ascorbate, and citrate. In some embodiments, the container further comprises a mucolytic agent suitable for pulmonary delivery. In some embodiments, the container further comprises a second anti-fibrotic agent suitable for pulmonary delivery. In some embodiments, the container further comprises a second anti-inflammatory agent suitable for pulmonary delivery.

[0037] In one aspect, a method for treating a lung disease is described herein, which includes the step of inhaling an aerosol of a pirfenidone or pyridone analog solution having a concentration greater than about 34 mcg / mL, an osmotic pressure greater than about 100 mOsmol / kg, and a pH greater than about 4.0. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 1.72 mg / mL. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 86 mg / mL. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic ionic concentration from about 30 mM to about 300 mM. In some embodiments, the osmotic ions are chloride or bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH from about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic pressure from about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic pressure from about 50 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has a flavoring agent. In some embodiments, the flavoring agent is selected from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucralose, ascorbate, and citrate. In some embodiments, the method further includes the step of administering a mucolytic agent suitable for pulmonary delivery. In some embodiments, the method further includes the step of administering a second anti-fibrotic agent suitable for pulmonary delivery. In some embodiments, the method further includes the step of administering a second anti-inflammatory agent suitable for pulmonary delivery. In some embodiments, the lung disease is an interstitial lung disease. In some embodiments, the interstitial lung disease is idiopathic pulmonary fibrosis. In some embodiments, the interstitial lung disease is radiation-induced pulmonary fibrosis. In some embodiments, the lung disease is chronic obstructive pulmonary disease. In some embodiments, the lung disease is chronic bronchitis. In some embodiments, the lung disease is asthma. In some embodiments, the aerosol contains particles having an average aerodynamic diameter from about 1 micron to about 5 microns.In some embodiments, the aerosol has a volume median diameter average particle size of from about 1 micron to about 5 microns and a geometric standard deviation of particle size less than or equal to 3 microns. In some embodiments, the step of inhalation delivers a dose of at least 6.8 mcg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation delivers a dose of at least 340 mcg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation delivers a dose of at least 740 mcg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation delivers a dose of at least 1.7 mg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation delivers a dose of at least 93 mg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation delivers a dose of at least 463 mg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation is performed in less than about 20 minutes. In some embodiments, the step of inhalation is performed in less than about 10 minutes. In some embodiments, the step of inhalation is performed in less than about 7.5 minutes. In some embodiments, the step of inhalation is performed in less than about 5 minutes. In some embodiments, the step of inhalation is performed in less than about 2.5 minutes. In some embodiments, the step of inhalation is performed in less than about 1.5 minutes. In some embodiments, the step of inhalation is performed in less than about 30 seconds. In some embodiments, the step of inhalation is performed within less than about 5 breaths. In some embodiments, the step of inhalation is performed within less than about 3 breaths.

[0038] In one aspect, a method of administering an antifibrotic agent to a patient's lung is described herein, the method comprising introducing into a nebulizer a pirfenidone or pyridone analog solution having a concentration greater than about 34 mcg / mL, an osmotic pressure greater than about 100 mOsmol / kg, and a pH greater than about 4.0. In another aspect, a method of administering an anti-inflammatory agent to a patient's lung is described herein, the method comprising introducing into a nebulizer a pirfenidone or pyridone analog concentration having a concentration greater than about 34 mcg / mL, an osmotic pressure greater than about 100 mOsmol / kg, and a pH greater than about 4.0. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 1.72 mg / mL. In some embodiments, the pirfenidone or pyridone analog solution is greater than about 86 mg / mL. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic ionic concentration from about 30 mM to about 300 mM. In some embodiments, the osmotic ions are chloride or bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH from about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic pressure from about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic pressure from about 50 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has a flavoring agent. In some embodiments, the flavoring agent is selected from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucralose, ascorbate, and citrate. In some embodiments, the method further comprises administering a mucolytic agent suitable for pulmonary delivery. In some embodiments, the mucolytic agent is inhaled separately from the pirfenidone or pyridone analog solution. In some embodiments, the method further comprises administering a second antifibrotic agent suitable for pulmonary delivery. In some embodiments, the method further comprises administering a second anti-inflammatory agent suitable for pulmonary delivery.

[0039] In one aspect, a method for treating an extrapulmonary disease target is described herein that includes inhaling an aerosol of a pirfenidone or pyridone analog solution having a concentration greater than about 34 mcg / mL, an osmotic pressure greater than about 100 mOsmol / kg, and a pH greater than about 4.0 to absorb the delivered pirfenidone or pyridone analog into the pulmonary vasculature and expose a downstream disease target to the delivered pirfenidone or pyridone analog. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 1.72 mg / mL. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 86 mg / mL. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic ionic concentration from about 30 mM to about 300 mM. In some embodiments, the osmotic ion is chloride or bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH from about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic pressure from about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic pressure from about 50 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has a flavoring agent. In some embodiments, the flavoring agent is selected from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucralose, ascorbate, and citrate. In some embodiments, the method further includes administering a mucolytic agent suitable for pulmonary delivery. In some embodiments, the mucolytic agent is inhaled separately from the pirfenidone or pyridone analog solution. In some embodiments, the method further includes administering a second anti-fibrotic agent suitable for pulmonary delivery. In some embodiments, the method further includes administering a second anti-inflammatory agent suitable for pulmonary delivery. In some embodiments, the extrapulmonary disease target is the heart. In some embodiments, the extrapulmonary disease target is the kidney. In some embodiments, the extrapulmonary disease target is the liver.

[0040] In any of the methods described herein for delivering a compound of pirfenidone or a pyridone analog to the lung using an aerosol or nebulizer, the aerosol comprises particles having an average aerodynamic diameter of from about 1 micron to about 5 microns. In some embodiments, the aerosol has an average particle size of a volume median diameter of from about 1 micron to about 5 microns and a geometric standard deviation of particle size less than or equal to 3 microns. In some embodiments, the step of inhalation delivers a dose of at least 6.8 mcg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation delivers a dose of at least 340 mcg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation delivers a dose of at least 740 mcg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation delivers a dose of at least 17 mg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation delivers a dose of at least 93 mg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation delivers a dose of at least 463 mg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation is performed in less than about 20 minutes. In some embodiments, the step of inhalation is performed in less than about 10 minutes. In some embodiments, the step of inhalation is performed in less than about 7.5 minutes. In some embodiments, the step of inhalation is performed in less than about 5 minutes. In some embodiments, the step of inhalation is performed in less than about 2.5 minutes. In some embodiments, the step of inhalation is performed in less than about 1.5 minutes. In some embodiments, the step of inhalation is performed in less than about 30 seconds. In some embodiments, the step of inhalation is performed within less than about 5 breaths. In some embodiments, the step of inhalation is performed within less than about 3 breaths.

[0041] In one aspect, provided herein is a method of treating a neurological disorder comprising intranasal inhalation of an aerosol of a pirfenidone or pyridone analog solution having a concentration greater than about 34 mcg / mL, an osmotic pressure greater than about 100 mOsmol / kg, and a pH greater than about 4.0. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 1.72 mg / mL. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 86 mg / mL. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic ionic concentration from about 30 mM to about 300 mM. In some embodiments, the osmotic ions are chloride or bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH from about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic pressure from about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic pressure from about 50 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the aerosol further comprises a flavoring agent. In some embodiments, the flavoring agent is selected from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucralose, ascorbate, and citrate. In some embodiments, the method further comprises administering a mucolytic agent suitable for intranasal delivery. In some embodiments, the method further comprises administering a second anti-fibrotic agent suitable for intranasal delivery. In some embodiments, the method further comprises administering a second anti-inflammatory agent suitable for intranasal delivery. In some embodiments, the neurological disorder is multiple sclerosis. In some embodiments, the aerosol comprises particles having an average aerodynamic diameter from about 1 micron to about 20 microns. In some embodiments, the aerosol has an average particle size of volume median diameter from about 1 micron to about 20 microns and a geometric standard deviation of particle size less than or equal to 3 microns. In some embodiments, the step of inhaling delivers a dose of at least 6.8 mcg of pirfenidone or pyridone analog.In some embodiments, the step of inhalation delivers a dosage of at least 340 mcg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation delivers a dosage of at least 740 mcg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation delivers a dosage of at least 1.7 mg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation delivers a dosage of at least 93 mg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation delivers a dosage of at least 463 mg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation is performed in less than about 20 minutes. In some embodiments, the step of inhalation is performed in less than about 10 minutes. In some embodiments, the step of inhalation is performed in less than about 7.5 minutes. In some embodiments, the step of inhalation is performed in less than about 5 minutes. In some embodiments, the step of inhalation is performed in less than about 2.5 minutes. In some embodiments, the step of inhalation is performed in less than about 1.5 minutes. In some embodiments, the step of inhalation is performed in less than about 30 seconds. In some embodiments, the step of inhalation is performed within less than about 5 breaths. In some embodiments, the step of inhalation is performed within less than about 3 breaths.

[0042] In some embodiments, methods for administering an anti-demylination agent to a patient's nasal cavity are described herein, the method comprising introducing into a nebulizer a pirfenidone or pyridone analog solution having a concentration greater than about 34 mcg / mL, an osmotic pressure greater than about 100 mOsmol / kg, and a pH greater than about 4.0. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 1.72 mg / mL. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 86 mg / mL. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic ionic concentration from about 30 mM to about 300 mM. In some embodiments, the osmotic ions are chloride or bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH from about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic pressure from about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmotic pressure from about 50 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the solution further comprises a flavoring agent. In some embodiments, the flavoring agent is selected from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucralose, ascorbate, and citrate. In some embodiments, the method further comprises administering a mucolytic agent suitable for intranasal delivery. In some embodiments, the mucolytic agent is inhaled separately from the pirfenidone or pyridone analog solution. In some embodiments, the method further comprises administering a second agent suitable for intranasal delivery.

[0043] In any of the methods described herein that include introducing a pirfenidone or pyridone analog solution into a nebulizer, the method includes opening a sterile disposable container containing from about 0.5 mL to about 10 mL of the pirfenidone or pyridone analog solution for introduction into the nebulizer.

[0044] In any of the methods described herein that include a nebulizer, the aerosol comprises particles having an average aerodynamic diameter of from about 1 micron to about 5 microns. In some embodiments, the aerosol has an average particle size of a volume median diameter of from about 1 micron to about 5 microns and a geometric standard deviation of particle size that is less than or equal to 3 microns. In some embodiments, the aerosol comprises particles having an average aerodynamic diameter of from about 1 micron to about 20 microns. In some embodiments, the aerosol has an average particle size of a volume median diameter of from about 1 micron to about 20 microns and a geometric standard deviation of particle size that is less than or equal to 3 microns. In some embodiments, the step of inhaling delivers a dose of at least 6.8 mcg of pirfenidone or a pyridone analog. In some embodiments, the step of inhaling delivers a dose of at least 340 mcg of pirfenidone or a pyridone analog. In some embodiments, the step of inhaling delivers a dose of at least 740 mcg of pirfenidone or a pyridone analog. In some embodiments, the step of inhaling delivers a dose of at least 1.7 mg of pirfenidone or a pyridone analog. In some embodiments, the step of inhaling delivers a dose of at least 93 mg of pirfenidone or a pyridone analog. In some embodiments, the step of inhaling delivers a dose of at least 463 mg of pirfenidone or a pyridone analog. In some embodiments, the step of inhaling is performed in less than about 20 minutes. In some embodiments, the step of inhaling is performed in less than about 10 minutes. In some embodiments, the step of inhaling is performed in less than about 7.5 minutes. In some embodiments, the step of inhaling is performed in less than about 5 minutes. In some embodiments, the step of inhaling is performed in less than about 2.5 minutes. In some embodiments, the step of inhaling is performed in less than about 1.5 minutes. In some embodiments, the step of inhaling is performed in less than about 30 seconds. In some embodiments, the step of inhaling is performed within less than about 5 breaths. In some embodiments, the step of inhaling is performed within less than about 3 breaths. In some embodiments, the step is performed in one breath.

[0045] In one aspect, there is provided herein a kit comprising a pharmaceutical composition comprising a solution of pirfenidone or a pyridone analog in a sterile container, wherein the solution of pirfenidone or a pyridone analog has a concentration greater than about 34 mcg / mL, an osmotic pressure greater than about 100 mOsmol / kg, and a pH greater than about 4.0, and a nebulizer suitable for aerosolizing the solution of pirfenidone or a pyridone analog for delivery from the central airway to the lower airway through oral inhalation. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 1.72 mg / mL. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 86 mg / mL. In some embodiments, the solution of pirfenidone or a pyridone analog has an osmotic ionic concentration from about 30 mM to about 300 mM. In some embodiments, the osmotic ions are chloride or bromide. In some embodiments, the solution of pirfenidone or a pyridone analog has a pH from about 4.0 to about 8.0. In some embodiments, the solution of pirfenidone or a pyridone analog has an osmotic pressure from about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the solution of pirfenidone or a pyridone analog has an osmotic pressure from about 50 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the solution further comprises a flavoring agent. In some embodiments, the flavoring agent is selected from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucralose, ascorbate, and citrate. In some embodiments, the kit further comprises a mucolytic agent suitable for lung delivery. In some embodiments, the kit further comprises a second anti-fibrotic agent suitable for lung delivery. In some embodiments, the kit further comprises a second anti-inflammatory agent suitable for lung delivery.

[0046] In another aspect, provided herein is a kit comprising a pharmaceutical composition comprising a solution of pirfenidone or a pyridone analog in a sterile container, wherein the solution of pirfenidone or a pyridone analog has a concentration greater than about 34 mcg / mL, an osmotic pressure greater than about 100 mOsmol / kg, and a pH greater than about 4.0, and a nebulizer suitable for aerosolizing the solution of pirfenidone or a pyridone analog for delivery to the nasal cavity through nasal inhalation.

[0047] In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 1.72 mg / mL. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 86 mg / mL. In some embodiments, the solution of pirfenidone or a pyridone analog has an osmotic ionic concentration from about 30 mM to about 300 mM. In some embodiments, the osmotic ion is chloride or bromide. In some embodiments, the solution of pirfenidone or a pyridone analog has a pH from about 4.0 to about 8.0. In some embodiments, the solution of pirfenidone or a pyridone analog has an osmotic pressure from about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the solution of pirfenidone or a pyridone analog has an osmotic pressure from about 50 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the solution further comprises a flavoring agent. In some embodiments, the flavoring agent is selected from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucralose, ascorbate, and citrate. In some embodiments, the kit further comprises a mucolytic agent suitable for nasal delivery. In some embodiments, the kit further comprises a second anti-fibrotic agent suitable for nasal delivery. In some embodiments, the kit further comprises a second anti-inflammatory agent suitable for nasal delivery.

[0048] In one aspect, a method for treating a lung disease is described herein, the method comprising administering pirfenidone or a pyridone analog from the central airways to the lower airways of a subject having or suspected of having an interstitial lung disease via oral inhalation of an aerosol comprising pirfenidone or a pyridone analog, the disease being selected from interstitial lung diseases including idiopathic pulmonary fibrosis and fibrosis induced by radiotherapy, chronic obstructive pulmonary disease, and asthma. In some embodiments, the subject is confirmed to have an interstitial lung disease. In some embodiments, the subject is confirmed to have idiopathic pulmonary fibrosis. In some embodiments, the subject is confirmed to have fibrosis induced by radiotherapy. In some embodiments, the subject is confirmed to have chronic obstructive pulmonary disease. In some embodiments, the subject is confirmed to have chronic bronchitis. In some embodiments, the subject is confirmed to have asthma. In some embodiments, the subject is a mechanically ventilated subject.

[0049] A method for treating an extrapulmonary disease comprises administering pirfenidone or a pyridone analog from the central airways to the lower airways of a subject having or suspected of having a disease associated with extrapulmonary fibrosis, inflammation and / or toxicity via oral inhalation of an aerosol comprising pirfenidone or a pyridone analog for pulmonary vascular uptake and delivery to the extrapulmonary diseased tissue, the disease being selected from cardiac fibrosis, renal fibrosis, hepatic fibrosis, renal toxicity, and cardiac toxicity. In some embodiments, the subject is confirmed to have cardiac fibrosis. In some embodiments, the subject is confirmed to have renal fibrosis. In some embodiments, the subject is confirmed to have hepatic fibrosis. In some embodiments, the subject is confirmed to have renal toxicity. In some embodiments, the subject is confirmed to have cardiac toxicity. In some embodiments, the subject is a mechanically ventilated subject.

[0050] In one aspect, for nasal vascular absorption and delivery to the central nervous system, a method for treating a neurological disorder is described herein that includes administering pirfenidone or a pyridone analog to the nasal cavity of a subject having or suspected of having a neurological disorder via intranasal inhalation of an aerosol containing pirfenidone or a pyridone analog, where the disorder is multiple sclerosis. In some embodiments, the subject is confirmed to have multiple sclerosis. In some embodiments, the subject is a subject wearing a ventilator.

[0051] In one aspect, a pharmaceutical composition for pulmonary delivery is described herein that includes a dry powder containing pirfenidone or a pyridone analog having a dosage content greater than about 1%. In some embodiments, the pirfenidone or pyridone analog dose content is greater than about 6.8 mcg. In some embodiments, the pirfenidone or pyridone analog content is greater than about 340 mcg. In some embodiments, the pirfenidone or pyridone analog content is greater than about 17 mg. In some embodiments, the pirfenidone or pyridone analog content is greater than about 463 mg. In some embodiments, the powder further includes a blend. In some embodiments, the blend is selected from the group consisting of lactose.

[0052] In one aspect, a pharmaceutical composition for pulmonary delivery is described herein that includes a dry powder containing pirfenidone or a pyridone analog having a dosage content greater than about 1%. In yet another aspect, a sterile disposable container is described herein that includes a dry powder from about 0.5 mg to about 100 mg containing pirfenidone or a pyridone analog having a dosage content greater than about 1%. In a further aspect, a method of treating a lung disease is described that includes inhalation of a dry powder aerosol containing a pirfenidone or pyridone dosage content greater than about 1%. In some embodiments, the pirfenidone or pyridone analog dosage content is greater than about 6.8 mcg. In some embodiments, the pirfenidone or pyridone analog content is greater than about 340 mcg. In some embodiments, the pirfenidone or pyridone analog content is greater than about 17 mg. In some embodiments, the pirfenidone or pyridone analog content is greater than about 463 mg. In some embodiments, the dry powder further includes a blend. In some embodiments, the blend is lactose. In some embodiments, the lung disease is an interstitial lung disease. In some embodiments, the interstitial lung disease is idiopathic pulmonary fibrosis. In some embodiments, the interstitial lung disease is radiation-induced pulmonary fibrosis. In some embodiments, the lung disease is chronic obstructive pulmonary disease. In some embodiments, the lung disease is chronic bronchitis. In some embodiments, the lung disease is asthma. In some embodiments, the aerosol includes particles having an average aerodynamic diameter from about 1 micron to about 5 microns. In some embodiments, the aerosol has a volume median diameter average particle size from about 1 micron to about 5 microns and a geometric standard deviation of particle size less than or equal to 3 microns. In some embodiments, the step of inhalation delivers a dosage of at least 6.8 mcg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation delivers a dosage of at least 340 mcg of pirfenidone or a pyridone analog. In some embodiments, the step of inhalation delivers a dosage of at least 740 mcg of pirfenidone or a pyridone analog.In some embodiments, the inhaling step delivers a dosage of at least 1.7 mg of pirfenidone or a pyridone analog. In some embodiments, the inhaling step delivers a dosage of at least 93 mg of pirfenidone or a pyridone analog. In some embodiments, the inhaling step delivers a dosage of at least 463 mg of pirfenidone or a pyridone analog. In some embodiments, the inhaling step is performed within less than about 5 breaths. In some embodiments, the inhaling step is performed within less than about 3 breaths. In some embodiments, the inhaling step is performed within less than about 2 breaths. In some embodiments, the step is performed in 1 breath.

[0053] In one aspect, provided herein is a method of administering an anti-fibrotic agent to a subject's lungs, comprising introducing a dry powder formulation of pirfenidone or a pyridone analog having a dosage content greater than about 1% into a dry powder inhaler. In another aspect, provided herein is a method of administering an anti-inflammatory agent to a subject's lungs, comprising introducing a dry powder formulation of pirfenidone or a pyridone analog having a dosage content greater than about 1% into a dry powder inhaler. In yet another aspect, provided herein is a method for treating an extra-pulmonary disease target, comprising inhalation of a dry powder aerosol comprising a pirfenidone or pyridone dosage content greater than about 1%. In some embodiments, the extra-pulmonary disease target is the heart. In some embodiments, the extra-pulmonary disease target is the kidney. In some embodiments, the extra-pulmonary disease target is the liver. In yet another aspect, provided herein is a method for treating a neurological disease, comprising intranasal inhalation of a dry powder aerosol comprising a pirfenidone or pyridone dosage content greater than about 1%. In some embodiments, the neurological disease is multiple sclerosis. In yet another aspect, provided herein is a method of administering an anti-demyelinating agent to a subject's nasal cavity, comprising introducing a dry powder formulation of pirfenidone or a pyridone analog having a dosage content greater than about 1% into a dry powder inhaler. In some embodiments, the pirfenidone or pyridone analog dosage content is greater than about 6.8 mcg. In some embodiments, the pirfenidone or pyridone analog content is greater than about 340 mcg. In some embodiments, the pirfenidone or pyridone analog content is greater than about 17 mg. In some embodiments, the pirfenidone or pyridone analog content is greater than about 463 mg. In some embodiments, the dry powder comprises a blend. In some embodiments, the blend is lactose. In some embodiments, the aerosol comprises particles having an average aerodynamic diameter of from about 1 micron to about 5 microns. In some embodiments, the aerosol has a volume median diameter of from about 1 micron to about 5 microns and a geometric standard deviation of particle size less than or equal to 3 microns.In some embodiments, the aerosol comprises particles having an average aerodynamic diameter of from about 1 micron to about 20 microns. In some embodiments, the aerosol has an average particle size of volume median diameter of from about 1 micron to about 20 microns and a geometric standard deviation of particle size that is less than or equal to 3 microns. In some embodiments, the step of inhaling delivers a dose of at least 6.8 mcg of pirfenidone or a pyridone analog. In some embodiments, the step of inhaling delivers a dose of at least 340 mcg of pirfenidone or a pyridone analog. In some embodiments, the step of inhaling delivers a dose of at least 740 mcg of pirfenidone or a pyridone analog. In some embodiments, the step of inhaling delivers a dose of at least 1.7 mg of pirfenidone or a pyridone analog. In some embodiments, the step of inhaling delivers a dose of at least 17 mg of pirfenidone or a pyridone analog. In some embodiments, the step of inhaling delivers a dose of at least 93 mg of pirfenidone or a pyridone analog. In some embodiments, the step of inhaling delivers a dose of at least 463 mg of pirfenidone or a pyridone analog. In some embodiments, the step of inhaling is performed within less than about 5 breaths. In some embodiments, the step of inhaling is performed within less than about 3 breaths. In some embodiments, the step of inhaling is performed within less than about 2 breaths. In some embodiments, the step is performed during 1 breath. In some embodiments, the method further comprises the step of opening a disposable dry powder container containing a dry powder formulation of from about 0.5 mg to about 10 mg of pirfenidone or a pyridone analog for introduction into a dry powder inhaler.

[0054] In one aspect, a pharmaceutical composition comprising a dry powder pifidone or pyridone analog formulation in a container, wherein the pifidone or pyridone analog dosage content is greater than about 1%, and a dry powder inhaler suitable for aerosolizing the dry powder formulation of pifidone or pyridone analog for delivery from the central airway to the lower airway via oral inhalation are described herein. In another aspect, a pharmaceutical composition comprising a dry powder pifidone or pyridone analog formulation in a container, wherein the pifidone or pyridone analog dosage content is greater than about 1%, and a dry powder inhaler suitable for aerosolizing the dry powder formulation of pifidone or pyridone analog for delivery to the nasal cavity via nasal inhalation are described herein. In some embodiments, the pifidone or pyridone analog dosage content is greater than about 6.8 mcg. In some embodiments, the pifidone or pyridone analog content is greater than about 340 mcg. In some embodiments, the pifidone or pyridone analog content is greater than about 17 mg. In some embodiments, the pifidone or pyridone analog content is greater than about 463 mg. In some embodiments, the dry powder further comprises a blend. In some embodiments, the blend is lactose.

[0055] In one aspect, a method for treating a lung disease is described herein, the method comprising administering pirfenidone or a pyridone analog from the central airways to the lower airways of a subject having or suspected of having an interstitial lung disease via oral inhalation of an aerosol comprising pirfenidone or a pyridone analog, the disease being selected from interstitial lung diseases including idiopathic pulmonary fibrosis and fibrosis induced by radiotherapy, chronic obstructive pulmonary disease, and asthma. In some embodiments, the subject is confirmed to have an interstitial lung disease. In some embodiments, the subject is confirmed to have idiopathic pulmonary fibrosis. In some embodiments, the subject is confirmed to have lung fibrosis induced by radiotherapy. In some embodiments, the subject is confirmed to have chronic obstructive pulmonary disease. In some embodiments, the subject is confirmed to have chronic bronchitis. In some embodiments, the subject is confirmed to have asthma. In some embodiments, the subject is a subject wearing a ventilator.

[0056] In one aspect, for pulmonary vascular uptake and delivery to extrapulmonary diseased tissue, a method for treating an extrapulmonary disease is described herein comprising administering pirfenidone or a pyridone analog from the central airways to the lower airways of a subject having or suspected of having a disease associated with extrapulmonary fibrosis, inflammation and / or toxicity via oral inhalation of an aerosol comprising pirfenidone or a pyridone analog, the disease being selected from cardiac fibrosis, renal fibrosis, hepatic fibrosis, renal toxicity, and cardiac toxicity.

[0057] In some embodiments, the subject is confirmed to have cardiac fibrosis. In some embodiments, the subject is confirmed to have renal fibrosis. In some embodiments, the subject is confirmed to have hepatic fibrosis. In some embodiments, the subject is confirmed to have renal toxicity. In some embodiments, the subject is confirmed to have cardiac toxicity. In some embodiments, the subject is a subject wearing a ventilator.

[0058] In one aspect, for nasal vascular absorption and delivery to the central nervous system, there is provided herein a method for treating a neurological disorder, comprising administering pirfenidone or a pyridone analog to the nasal cavity of a subject having or suspected of having a neurological disorder via intranasal inhalation of an aerosol comprising pirfenidone or a pyridone analog, wherein the disorder is multiple sclerosis. In some embodiments, the subject is confirmed to have multiple sclerosis. In some embodiments, the subject is a subject wearing a ventilator.

[0059] In one aspect, a method of administering pirfenidone or a pyridone analog to treat a patient with idiopathic pulmonary fibrosis (IPF) is described herein, wherein the patient avoids liver function abnormalities indicated by a grade 2 or higher abnormality of one or more biomarkers of liver function after oral administration of pirfenidone or a pyridone analog, and the method comprises administering pirfenidone or a pyridone analog to the patient at a dose of less than 300 mg per day. In some embodiments, "Grade 2 liver function abnormalities" include an elevation of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), or γ-glutamyl transferase (GGT) that is greater than 2.5 times and less than or equal to 5 times the upper limit of normal (ULN). Grade 2 liver function abnormalities also include an elevation of bilirubin levels that is greater than 1.5 times and less than or equal to 3 times the ULN. In some embodiments, pirfenidone or a pyridone analog is delivered to the patient by oral inhalation or intranasal inhalation. In some embodiments, the one or more biomarkers of liver function are selected from the group consisting of alanine transaminase, aspartate transaminase, bilirubin, and alkaline phosphatase. In some embodiments, the method further comprises measuring one or more biomarkers of liver function. In some embodiments, the blood Cmax after administration of pirfenidone or a pyridone analog is less than 10 mcg / mL. In some embodiments, the blood Cmax after administration of pirfenidone or a pyridone analog is greater than 10 mcg / mL.

[0060] In one aspect, a method of administering pirfenidone or a pyridone analog to a patient with idiopathic pulmonary fibrosis (IPF) is described herein, the patient avoids the occurrence of photosensitivity reactions observed after oral administration, and the method includes the step of administering pirfenidone or a pyridone analog to the patient at a dose of less than 360 mg per day. In some embodiments, pirfenidone or a pyridone analog is delivered to the patient by oral inhalation or intranasal inhalation. In some embodiments, the incidence of adverse events of photosensitivity reactions is less than about 12%. In some embodiments, the blood Cmax after administration of pirfenidone or a pyridone analog is less than 10 mcg / mL. In some embodiments, the blood Cmax after administration of pirfenidone or a pyridone analog is greater than 10 mcg / mL.

[0061] In one aspect, a method of administering pirfenidone or a pyridone analog to a patient with idiopathic pulmonary fibrosis (IPF) is described herein, the patient avoids the occurrence of phototoxicity after oral administration, and the method includes the step of administering pirfenidone or a pyridone analog to the patient at a dose of less than 360 mg per day. In some embodiments, pirfenidone or a pyridone analog is delivered to the patient by oral inhalation or intranasal inhalation. In some embodiments, the incidence of adverse events of photosensitivity reactions is less than about 12%. In some embodiments, the blood Cmax after administration of pirfenidone or a pyridone analog is less than 10 mcg / mL. In some embodiments, the blood Cmax after administration of pirfenidone or a pyridone analog is greater than 10 mcg / mL.

[0062] In one aspect, methods of administering pirfenidone or a pyridone analog for treating patients with idiopathic pulmonary fibrosis (IPF) by directly delivering pirfenidone or a pyridone analog to the lungs by oral inhalation or intranasal inhalation are described herein, and the patients avoid the occurrence of gastrointestinal adverse events after oral administration. In some embodiments, the gastrointestinal adverse events observed after oral administration of pirfenidone or a pyridone analog include, but are not limited to, any one or more of gastrointestinal disorders, nausea, diarrhea, gastroesophageal reflux disease (GERD), and vomiting. In some embodiments, less than 360 mg of pirfenidone or a pyridone analog per day is delivered to the patient by inhalation. In some embodiments, less than 1000 mg, less than 900 mg, less than 600 mg, or less than 300 mg of pirfenidone or a pyridone analog per day is delivered to the patient by inhalation. In some embodiments, less than 300 mg of pirfenidone or a pyridone analog per day is delivered to the patient by inhalation for each administration. In some embodiments, pirfenidone or a pyridone analog is delivered to the patient by inhalation once a day, twice a day, three times a day, or four times a day.

[0063] In some embodiments, up to about 360 mg of pirfenidone or a pyridone analog is delivered to the patient by inhalation for each administration. In some embodiments, about 1 mg to about 360 mg, about 10 mg to about 360 mg, about 20 mg to about 360 mg, about 30 mg to about 360 mg, about 40 mg to about 360 mg, about 50 mg to about 360 mg, about 60 mg to about 70 mg, about 80 mg to about 360 mg, about 90 mg to about 360 mg, about 100 mg to about 360 mg, about 120 mg to about 360 mg, about 140 mg to about 360 mg, about 160 mg to about 360 mg, about 180 mg to about 360 mg, or about 200 mg to about 360 mg of pirfenidone or a pyridone analog is delivered to the patient by inhalation for each administration. In some embodiments, pirfenidone or a pyridone analog is delivered to the patient by inhalation once a day, twice a day, three times a day, or four times a day.

[0064] In one aspect, a pharmaceutical composition is provided herein that comprises a therapeutically effective amount of an inhaled agent, where the agent is pirfenidone or a pyridone analog, the agent is particles having an aerodynamic mass median diameter of less than 5 microns or a volume median diameter of less than 10 microns, and the composition delivers, upon inhalation, a compound of pirfenidone or a pyridone analog in an amount greater than 1 mcg per gram of adult lung tissue per single dose to the lung.

[0065] In one aspect, there is described herein a pharmaceutical composition for aerosol delivery to the lungs, comprising a solution of a pirfenidone or a pyridone analog containing a divalent cation. In some embodiments, the divalent cation is selected from the group consisting of calcium, iron, magnesium, and beryllium. In some embodiments, the ratio of pirfenidone or pyridone analog to the divalent cation is within a molar concentration range of 1: about 0.1 to 10, in unit increments of about 0.01. For example, 1: about 10, 1: about 9, 1: about 8, 1: about 7, 1: about 6, 1: about 5, 1: about 4, 1: about 3, 1: about 2, 1: about 1.5, 1: about 1, 1: about 0.75, 1: about 0.5, 1: about 0.25, 1: about 0.1. In some embodiments, the pharmaceutical active ingredient is pirfenidone or a pyridone analog, and the concentration is between 0.1 mg / mL and 50 mg / mL, in unit increments of about 0.01 mg / mL of the composition. For example, about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, and about 60 mg / mL. In some embodiments, the pharmaceutical active ingredient is not a salt of pirfenidone or a pyridone analog. In some embodiments, the composition is a stable water-soluble formulation. In some embodiments, the osmotic pressure is greater than about 50 mOsmol / kg, in unit increments of about 1 mOsmol / kg.For example, greater than 50 mOsmol / kg, about 100 mOsmol / kg, about 150 mOsmol / kg, about 200 mOsmol / kg, about 250 mOsmol / kg, about 300 mOsmol / kg, about 350 mOsmol / kg, about 400 mOsmol / kg, about 450 mOsmol / kg, about 500 mOsmol / kg, about 550 mOsmol / kg, about 600 mOsmol / kg, about 650 mOsmol / kg, about 700 mOsmol / kg, about 750 mOsmol / kg, about 800 mOsmol / kg, about 850 mOsmol / kg, about 900 mOsmol / kg, about 950 mOsmol / kg, about 1000 mOsmol / kg, greater than about 1500 mOsmol / kg, greater than about 2000 mOsmol / kg, greater than about 2500 mOsmol / kg, greater than about 3000 mOsmol / kg, about 3500 mOsmol / kg, about 4000 mOsmol / kg, greater than about 4500 mOsmol / kg, about 5000 mOsmol / kg, about 5500 mOsmol / kg, about 6000 mOsmol / kg, or greater than about 6000 mOsmol / kg. In some embodiments, the pH is greater than about 3.0 with an increase of about 0.1 pH units. For example, about 3 pH, about 3.5 pH, about 4 pH, about 4.5 pH, about 5 pH, about 5.5 pH, about 6 pH, about 6.5 pH, about 7 pH, about 7.5 pH, about 8 pH, about 8.5 pH, about 9 pH, about 9.5 pH, about 10 pH, about 10.5 pH, and about 11 pH. In some embodiments, the pH is balanced by including an organic buffer selected from the group consisting of citric acid, citrate, malic acid, malate, pyridine, formic acid, formate, piperazine, succinic acid, succinate, histidine, maleic acid, bis-tris, pyrophosphoric acid, phosphoric acid, phosphate, PIPES, ACES, MES, cacodylic acid, carbonic acid, carbonate, ADA (N-(2-acetamido)-2-imino diacetic acid). In some embodiments, the pirlfenidone or pyridone analog solution contains an osmotic ion concentration. In some embodiments, the osmotic ion is selected from the group consisting of bromine, chloride, and lithium. In some embodiments, the osmotic ion concentration is from about 30 mM to about 300 mM in increments of about 0.1 mM.For example, it is about 30 mM, about 40 mM, about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, about 100 mM, about 150 mM, about 200 mM, about 250 mM, and about 300 mM. In some embodiments, the composition further comprises a flavoring agent. In some embodiments, the flavoring agent is selected from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucralose, ascorbate, polyvalent cations, and citrate. In some embodiments, the concentration of the flavoring agent is from 0.01 mM to about 50 mM in increments of about 0.01 mM. For example, it is about 0.01 mM, about 0.05 mM, about 0.1 mM, about 0.2 mM, about 0.3 mM, about 0.4 mM, about 0.5 mM, about 0.6 mM, about 0.7 mM, about 0.8 mM, about 0.9 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, and about 50 mM.

[0066] In some embodiments, the formulations described herein are filled into a primary package. In some embodiments, the primary package material is obtained from the group consisting of glass or plastic, and the plastic material may be selected from the group consisting of low density polyethylene (LDPE), high density polypropylene (HDPP), or high density polyethylene (HDPE). In some embodiments, the primary package consists of a vial, a syringe, or an ampule. In some embodiments, the composition is protected from light.

[0067] In some embodiments, the compositions described herein are formulated under hypoxic conditions or will result in hypoxic conditions. In some embodiments, oxygen is reduced by injecting a formulation diluent prior to addition of the active ingredient of the pharmaceutical. The injection gas may be selected from the group consisting of carbon dioxide, argon, or nitrogen. In some embodiments, oxygen is reduced by injecting a formulation diluent after addition of the active ingredient of the pharmaceutical. The injection gas may be selected from the group consisting of carbon dioxide, argon, or nitrogen.

[0068] In some embodiments, oxygen exposure is reduced by replacing the gas surrounding the headspace formed above the formulation container with an inert gas. The inert gas may be selected from the group consisting of argon or nitrogen.

[0069] In some embodiments, oxygen exposure is reduced by replacing the gas surrounding the headspace formed above the upper periphery of the primary package container with an inert gas. The inert gas may be selected from the group consisting of argon or nitrogen.

[0070] In some embodiments, oxygen exposure is reduced by inserting the primary package into a gas-impermeable secondary package container.

[0071] In some embodiments, oxygen exposure is reduced by replacing the gas surrounding the headspace formed above the secondary package with an inert gas. The inert gas may be selected from the group consisting of argon or nitrogen.

[0072] In some embodiments, the aerosol for delivery to the mammalian lung described herein comprises fine particulate fragments between 10% and 100% in 1% unit increments. For example, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. In some embodiments, the dosage of the fine particles is between about 0.1 mg and about 360 mg of pirfenidone or a pyridone analog in 0.1 mg increments. For example, about 0.1 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, or about 360 mg.

[0073] In some embodiments, the composition further comprises a mucolytic agent suitable for pulmonary delivery. In some embodiments, the composition further comprises a second anti-fibrotic agent suitable for pulmonary delivery. In some embodiments, the composition further comprises a second anti-inflammatory agent suitable for pulmonary delivery.

[0074] These and other aspects of the invention will become apparent upon reference to the following detailed description. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent literature cited herein are hereby incorporated by reference as if each were individually incorporated. Aspects of the invention may be modified as necessary to utilize concepts from various patents, applications, and publications to provide further embodiments of the invention.

Brief Description of the Drawings

[0075]

Figure 1

DETAILED DESCRIPTION OF THE INVENTION

[0076] Many undesirable lung diseases, such as interstitial lung disease (ILD and its sub-classified diseases), chronic obstructive pulmonary disease (COPD and its sub-classified diseases), asthma, and signs of fibrosis in the lungs, kidneys, heart, and eyes, begin with external stress. By way of non-limiting examples, these effectors may include infection, smoking, environmental exposure, radiation exposure, surgical procedures, and transplant rejection. However, they may also be attributed to other causes related to genetic nature and the effects of aging.

[0077] In the epithelium, scarring plays a valuable role in healing after injury. However, epithelial tissue may gradually leave scars after chronic and / or repeated injury, which may result in abnormal function. In the case of idiopathic pulmonary fibrosis (IPF and other sub-classifications of ILD), if a significant proportion of the lungs are damaged, there is a risk of respiratory failure. In any case, progressive scarring may result from a series of recurrent injuries to different regions of the organ or from the inability to stop the recovery process after the injury has healed. In such cases, the scarring process is uncontrolled and not alleviated. Depending on the form of fibrosis, the scarring may remain localized to a limited area but affect a more diffuse and extensive area, potentially resulting in direct or related organ failure.

[0078] In neurological diseases, inflammatory destruction of myelin (demyelination) is considered the first event in diseases such as multiple sclerosis. Demyelination causes scarring and sclerosis (sclerosis) of the nerve tissue in the spinal cord, brain, and optic nerve. Demyelination slows down the conduction of nerve impulses, resulting in weakness, numbness, pain, and vision loss.

[0079] In epithelial injury, epithelial cells cause the release of multiple fibrosis-promoting mediators, including potent fibroblast growth factor transforming growth factor beta (TGF-beta), tumor necrosis factor (TNF), endothelin, cytokines, metalloproteinases, and the coagulation mediator tissue factor. Importantly, the epithelial cells that caused the release become vulnerable to apoptosis and, perhaps combined with the inability to restore the epithelial cell layer, represent the most fundamental abnormality in fibrotic diseases. In the case of demyelination, abnormal TNF expression or activity is thought to be a root cause of other neurological diseases such as multiple sclerosis and rheumatoid diseases.

[0080] In diseases such as pulmonary fibrosis, renal fibrosis, cardiac fibrosis, and ocular fibrosis, multiple sclerosis and rheumatoid diseases, physiological responses characterized by the control of pro-inflammatory and pro-fibrotic factors using pyridone analogs such as pirfenidone can also be beneficial in attenuating and / or reversing fibrosis and demyelination. Therapeutic strategies that utilize the effects of pyridone analogs and / or pirfenidone as described above in these and other indications are discussed in depth herein.

[0081] TNF alpha is expressed in the airways of asthma and may play an important role in amplifying asthmatic inflammation through the activation of NF-kappaB, AP-1 and other transcription factors. Activation of the IgE receptor causes the release of TNF alpha from human lung tissue and upregulates the TNF mRNA levels in eosinophils. TNF-alpha causes a transient excessive reaction of the bronchi, perhaps through a reaction mediated by the expression of muscarinic receptors.

[0082] TNF-alpha is also thought to play a central role in the pathophysiology of COPD. It is produced by alveolar macrophages, neutrophils, T cells, mast cells, and epithelial cells after exposure to various pollutants, including cigarette smoke. TNF-alpha has been shown to induce pathological features associated with COPD, such as infiltration of inflammatory cells into the lungs, pulmonary fibrosis, and emphysema, in animal models. Interestingly, the levels of TNF-alpha in sputum are significantly increased during exacerbations of COPD.

[0083] The mechanism of action of pyridone analogs, such as pirfenidone, is thought to be anti-inflammatory and anti-fibrotic. Pirfenidone inhibits the synthesis and release of pro-inflammatory cytokines and reduces the accumulation of inflammatory cells in response to various stimuli. Pirfenidone also moderates fibroblast proliferation, production of proteins and cytokines associated with fibrosis, and increased biosynthesis and accumulation of extracellular matrix in response to cytokine growth factors such as TGF-beta and platelet-derived growth factor (PDGF).

[0084] In in vitro cell-based assays, pirfenidone inhibited fibroblast proliferation, suppressed the release of PDGF, tumor necrosis factor alpha (TNF-alpha), and TGF-beta1 stimulated by lipopolysaccharides (LPS), and inhibited collagen synthesis. Depending on the assay conditions, these in vitro activities were evident at pirfenidone concentrations from approximately 30 microM to approximately 10 mM (from approximately 5.5 mcg / mL to approximately 1.85 mg / mL). If the oral Cmax of pirfenidone in IPF patients ranges from approximately 42 microM in the fed state to approximately 84 microM in the fasting state (or approximately 7.9 mcg / mL to approximately 15.7 mcg / mL, respectively), these same activities may be promoted in vivo, although within a narrow range of observed efficacy.

[0085] Oral administration of pirfenidone to LPS-challenged mice resulted in a dose-dependent decrease in mortality, a decrease in the blood levels of the pro-inflammatory cytokines TNF alpha, interleukin (IL-12), and interferon-gamma, and an increase in the blood level of the anti-inflammatory cytokine, IL-10. Treatment with pirfenidone prevented LPS-related hemorrhagic necrosis and apoptosis in the liver and suppressed the increase in TGF beta.

[0086] In vitro studies suggest that pirfenidone may also suppress fibrosis through selective inhibition of p38 mitogen-activated protein kinase (MAPK). These observations were related to a decrease in collagen synthesis induced by TGF beta. A parallel observation that stopping p38 may restore corticosteroid sensitivity in COPD is also promising in this and other disease populations. Unfortunately, compounds that inhibit p38 MAPK have also been found to be toxic and have been withdrawn from the clinical setting. These compounds have each been used for oral administration.

[0087] In models of bleomycin-induced pulmonary fibrosis in rats, hamsters, and mice, prophylactic administration of pirfenidone decreased pulmonary fibrosis as evaluated by both histopathological analysis and quantitative determination of collagen content. Treatment with pirfenidone also decreased pulmonary edema and decreased the levels in the lung of TGF beta, basic fibroblast growth factor (bFGF), and various pro-inflammatory cytokines.

[0088] In rats, pirfenidone decreased collagen production and deposition in liver fibrosis, reversed cardiac and renal fibrosis, and alleviated the increase in diastolic stiffness of the diabetic heart from animals treated with streptozotocin without normalizing myocardial contractility or renal function. In DOCA-salt hypertensive rats, pirfenidone further reversed and prevented cardiac remodeling and prevented the increase in cardiac sclerosis without reducing the increased vascular response to norepinephrine.

[0089] Studies in humans have shown the clinical anti-inflammatory and anti-fibrotic benefits of oral pirfenidone. Test values for phototoxicity, gastrointestinal disorders, and abnormal liver function may also occur in human populations after oral administration of pirfenidone. As a result, dosing of patients must be closely monitored. In a Phase 3 clinical study using orally administered pirfenidone, an initial dose increase was required to establish gastrointestinal tolerance. However, the occurrence of nausea, rash, gastrointestinal disorders, dizziness, vomiting, photosensitivity reactions, anorexia, and elevations in the serum transaminases AST and ALT limit the dose levels during and after the increase. In some cases, oral administration of pirfenidone may result in dose reduction or discontinuation of pirfenidone administration.

[0090] In addition to the dose increase of pirfenidone required to establish gastrointestinal tolerance, dose reduction and use of food have been employed to enable oral administration to individuals who would otherwise be removed from treatment (e.g., dose reductions of up to and more than 50%) due to failure to achieve tolerance. Further, clinical studies utilizing the use of food to enable dosing tolerance may also be attempted. In both cases, plasma Cmax decreases proportionally to the dose. More specifically, the fed state results in a decrease in Cmax of approximately 50%, an increase in Tmax of approximately 7-fold, and a decrease in overall exposure of 10 - 15%. Both the fed and fasted states resulted in a plasma half-life of approximately 2.5 hours. This approach may reduce gastrointestinal-related adverse events, while the lack of clinically significant efficacy in recent orally administered clinical studies may have been affected by these approaches.

[0091] Similar to the observed toxicity, based on clinical observations and adverse events, oral pirfenidone therapy is limited to dosages from about 1800 mg / day to about 2400 mg / day (from 600 mg TID to 801 mg TID, respectively). Thus, while pirfenidone has shown efficacy in a wide range outside of humans, human adverse events and toxicity limit oral administration to the lower end of this range.

[0092] The regulatory risk - benefit analysis between the observed efficacy of orally administered pirfenidone and the associated adverse events has raised concerns that these dosages do not provide sufficient efficacy to guarantee a safety risk, even in end - stage populations where the clinical need is not met. In certain embodiments, methods are provided herein for directly administering an equivalent or increased dosage of pirfenidone or pyridone analogs to the disease site (e.g., inhalation delivery to the lungs) that would provide equivalent or improved efficacy across the oral route. In certain embodiments, the amount of drug administered required for these dosages is less. In certain embodiments, this technique of administering pirfenidone by inhalation may also benefit from a reduction in systemic exposure and an increase in the safety margin compared to oral administration of pirfenidone. Compositions of pirfenidone or pyridone analog compounds suitable for delivery to mammals by inhalation, and methods of using such compositions are described herein.

[0093] Whether the anti - inflammatory or anti - fibrotic mechanism of action of pirfenidone is driven by Cmax or exposure (area under the curve, AUC) is not clear from existing data. In some embodiments, the clinically observed efficacy, observed at low to moderate levels, may be associated with a pirfenidone plasma level of about 5 mcg / mL or greater than 5 mcg / mL, an exposure (AUC 0-無限大 ) of about 50 mg·hr / L or greater than 50 mg·hr / L, and / or a plasma elimination rate of about 2.5 hours.

[0094] In some embodiments, intravenous or oral administration of pirfenidone results in epithelial lining fluid (ELF) levels in the lung that are comparable to the levels observed in plasma, and thus, in some embodiments, a clinically measured plasma Cmax of about 5 mcg / mL or greater than 5 mcg / mL is directly associated with low to moderate clinically observed efficacy in the lung. In some embodiments, plasma levels of pirfenidone resulting from oral administration are associated with low efficacy, and thus, in some embodiments, the resulting ELF and lung tissue levels are also associated with low efficacy. In other embodiments, intravenous or oral administration of pirfenidone may result in ELF levels in the lung that are less than the levels observed to be effective from plasma. In some embodiments, ELF levels that match the effective levels observed in plasma, delivered orally or intravenously, may be from 0.1 mcg / mL to about 5 mcg / mL. In some embodiments, ELF levels that match the effective levels observed in plasma may be from 0.1 mcg / mL to about 1 mcg / mL. In some embodiments, ELF levels that match the effective levels observed in plasma, delivered orally or intravenously, may be from 0.5 mcg / mL to about 5 mcg / mL. In some embodiments, ELF levels that match the effective levels observed in plasma, delivered orally or intravenously, may be from 0.3 mcg / mL to about 3 mcg / mL. In some embodiments, direct administration of pirfenidone to the lung may result in delivering about 5 mcg or more than about 5 mcg of pirfenidone per 1 mL of ELF, resulting in comparable efficacy in the lung without an associated increase in systemic levels related to adverse events and toxicity observed with the administration.By way of non-limiting example, this is accomplished by oral or intranasal inhalation delivery of aerosolized pirfenidone or pyridone analogs to the lungs, providing the ELF with about 0.1 mcg / mL of, or more than about 0.1 mcg / mL of, for example, about 0.2 mcg / mL, 0.4 mcg / mL, 0.6 mcg / mL, 0.8 mcg / mL, 1.0 mcg / mL, 2 mcg / mL, 3 mcg / mL, 4 mcg / mL, 5 mcg / mL, 6 mcg / mL, 7 mcg / mL, 8 mcg / mL, 9 mcg / mL, or more than 10 mcg / mL of pirfenidone or pyridone analog. Once in the ELF, the pirfenidone or pyridone analog, depending on the embodiment, penetrates the lung tissue, resulting in about 0.004 mcg to 0.7 mcg of pirfenidone or pyridone analog per gram of lung tissue (from about 0.1 mcg / mL in about 25 mL of ELF to about 5 mcg / mL in about 75 mL of ELF for an adult lung tissue weight of about 600 grams).

[0095] In some embodiments, pirfenidone may equilibrate readily between plasma and the lungs and / or between other organs. In some embodiments, the pirfenidone levels in the organs may further mimic the plasma levels, for example, in the lungs, heart, kidneys, or the nervous system. In some embodiments, delivering about 0.004 mcg of pirfenidone, or from 0.004 mcg to 0.7 mcg of pirfenidone, per gram of tissue may provide a similar therapeutic effect on other organs. In some embodiments, additional pirfenidone or pyridone analogs may be given to provide further efficacy. In some embodiments, this may be done by inhalation (i.e., oral inhalation or intranasal inhalation) delivery of aerosolized pirfenidone or pyridone analogs to the lungs. In some embodiments, pirfenidone or pyridone analogs delivered to the lungs may be readily available to the heart. In some embodiments, delivering an ELF of from about 0.1 mcg / mL to about 5 mcg / mL, or giving 0.004 mcg / gram or about 0.7 mcg / gram of lung tissue pirfenidone or pyridone analogs to the ELF, or giving 0.2 - 0.7 mcg / gram of lung tissue pirfenidone or pyridone analogs may result in a similar effective dose to the heart without the increased systemic adverse events or toxicity observed with oral administration. In some embodiments, delivery of aerosolized pirfenidone or pyridone analogs to the lungs by intranasal or oral inhalation may result in effective delivery of pirfenidone or pyridone analogs to the liver. In some embodiments, pirfenidone or pyridone analogs delivered to the lungs may be available to the liver. In some embodiments, delivering an ELF of from about 0.1 mcg / mL to about 5 mcg / mL, or giving from about 0.004 mcg / gram to about 0.7 mcg / gram of lung tissue pirfenidone or pyridone analogs may result in a similar effective dose to the liver without the increased systemic adverse events or toxicity observed with oral administration.In some embodiments, delivery of aerosolized pirfenidone or a pyridone analog to the lungs by intranasal or oral inhalation may result in effective delivery of the pirfenidone or pyridone analog to the kidneys. In some embodiments, pirfenidone or a pyridone analog delivered to the lungs becomes available to the kidneys. In some embodiments, by providing an ELF of from about 0.1 mcg / mL to about 5 mcg / mL, or by providing from about 0.004 mcg / gram to about 0.7 mcg / gram of pirfenidone or a pyridone analog in lung tissue, it may result in a similar effective dose to the kidneys without an increase in systemic adverse events or toxicity observed with oral administration. In some embodiments, intranasal inhalation delivery of aerosolized pirfenidone or a pyridone analog to the nasal cavity may result in effective delivery of the pirfenidone or pyridone analog to the central nervous system (CNS). In some embodiments, inhalation delivery of pirfenidone or a pyridone analog to the nasal cavity becomes readily available to the CNS. In some embodiments, by providing a dose to the nasal cavity equivalent to an ELF of from about 0.1 mcg / mL to about 5 mcg / mL, or from about 0.004 mcg / gram to about 0.7 mcg / gram of pirfenidone or a pyridone analog in lung tissue, it may result in a similar effective dose to the CNS without an increase in systemic adverse events or toxicity observed with oral administration.

[0096] In some embodiments, topical delivery of aerosolized liquid or cream of pirfenidone or pyridone analogs to the desired site of action, providing from about 0.004 mcg / gram to about 0.7 mcg / gram of tissue weight, may result in similar effective administration without systemic adverse events or toxicity. In some embodiments, topical delivery of aerosolized liquid or cream of pirfenidone or pyridone analogs to damaged skin epithelium may prevent or reverse scarring, fibrosis, and / or inflammation. This damage can be the result of infection, burns, surgery, acute or chronic injury (such as bedsores), or other events. In some embodiments, topical delivery of liquid or dry powder of pirfenidone or pyridone analogs to the bladder may prevent scarring, fibrosis, and / or inflammation associated with bladder infection, bladder cancer, indwelling catheter, or other events. In some embodiments, topical delivery of liquid pirfenidone or pyridone analogs to the eye may prevent the progression of postoperative fibrosis in the conjunctiva and / or episclera after glaucoma surgery.

[0097] In some embodiments, infusion delivery of liquid pirfenidone or pyridone analogs to the desired site of action, providing from about 0.004 mcg / gram to about 0.7 mcg / gram of tissue weight pirfenidone or pyridone analogs, results in similar effective administration without systemic adverse events or toxicity. In some embodiments, infusion delivery of liquid pirfenidone or pyridone analogs to the skeletal joints may prevent scarring, fibrosis, and / or inflammation associated with autoimmune diseases, arthritis, rheumatoid arthritis, infection, or other events.

[0098] Depending on the embodiment, in addition to Cmax, and in further additional embodiments, pirfenidone exposure (AUC) at the disease site may also be essential for efficacy. In some embodiments, a plasma AUC of about 50 mg·hr / L or 50 mg·hr / L or greater 0-無限大It is also associated with efficacy in the lung. In some embodiments, partial or complete equilibration of pirfenidone between plasma and the lung ELF, and between plasma and lung tissue, may provide an AUC that mimics that in the lung. In other embodiments, the AUC of the lung ELF and tissue may be less.

[0099] In some embodiments, the Cmax, AUC, and / or half-life, individually or in combination, are required for efficacy, and thus, in some embodiments, a conservative model with all three parameters required for efficacy (Cmax, AUC, and half-life) is provided. In some embodiments, by way of non-limiting example, an ELF AUC of about 1.0 mg·hr / L or about 50 mg·hr / L 0-無限大 is provided, and direct inhalation delivery of about 0.1 mcg to about 5 mcg of pirfenidone or a pyridone analog to 1 mL of lung ELF, maintaining these values over the same time as when delivered via the oral route, is equally effective. Similarly, in other embodiments, direct inhalation delivery of about 0.2004 mcg or from 0.2004 mcg to 0.7 mcg of pirfenidone or a pyridone analog to 1 gram of lung tissue 0-無限大 provides a tissue AUC that is less than 0-無限大 to equal or nearly equal to the plasma AUC after oral delivery 0-無限大 and maintaining these values for the same amount of time as when delivered via the oral route is equally effective. In some embodiments, the following assumptions and theoretical calculations are described for inhalation therapy:

[0100] ELF Delivery Assumptions: 1. The total volume of human ELF is 25 mL. 2. The inhalation route of administration depends on the respirable delivery dose (RDD), which is a fraction of the drug inhaled as aerosol particles with a diameter of less than 5 microns. 3. The RDD of typical dry powder, liquid atomization, or metered-dose inhalation devices varies from 10% to 70%. In some embodiments, highly efficient or resistive devices with an RDD greater than 70% and less than 10% are contemplated. 4. The half-life of plasma pirfenidone or pyridone analogs after oral administration is approximately 2.5 hours. In some embodiments, intestinal absorption affects this rule (vule), but for the typical purposes of this model, the pirfenidone half-life in the lung ELF after inhaled delivery is assumed to be halved after oral administration (e.g., 2.5 hours / 2 = 1.25 hours). The half-life value may be supported by measurements indicating that intravenous administration of pirfenidone results in approximately half the lung ELF half-life after oral administration. 5. In some embodiments, a lung ELF level of 5 mcg / mL may be the lower limit of efficacy. And, 6. 801 mg of oral pirfenidone results in plasma levels (human measurements) of 5 mcg / mL or greater than 5 mcg / mL over 4 hours. For the purpose of comparing routes, this model assumes that the pirfenidone value in the ELF after oral administration remains at 5 mcg / mL or approximately 5 mcg / mL in the lung ELF over the same duration as the plasma.

[0101] Typical ELF calculations: Mcg of pirfenidone delivered to 25 mL of ELF to make 1.5 mcg / mL = 125 mcg 2. Based on an RDD efficiency of 30%, the required unit dose is 416 mcg (125 mcg / 0.3 = 416 mcg). 3. Based on an RDD efficiency of 50%, the required unit dose is 250 mcg (125 mcg / 0.5 = 250 mcg). 4. Based on an RDD efficiency of 70%, the required unit dose is 179 mcg (125 mcg / 0.7 = 179 mcg). Correct to maintain these values or above for each 1.25 hour period of 3.2 half-lives (4 hours = 3.2 half-lives at 5 mcg / mL or above with a 1.25 hour lung half-life). For an RDD efficiency of 5.30%, the unit dose required to maintain the lower limit of clinically observed efficacy (416 mcg in this case) for 3.2 half-lives is 3994 mcg. For an RDD efficiency of 6.50%, the unit dose required to maintain the lower limit of clinically observed efficacy (250 mcg in this case) for 3.2 half-lives is 2400 mcg. For an RDD efficiency of 7.70%, the unit dose required to maintain the lower limit of clinically observed efficacy (179 mcg in this case) for 3.2 half-lives is 1718 mcg.

[0102] By way of non-limiting example, based on the above assumptions and in certain embodiments, a dose of about 4 mg of pirfenidone or a pyridone analog delivered by a device with 30% efficiency may result in a pulmonary ELF level of 5 mcg / mL or greater over the same period obtained after 801 mg oral administration. Further, while the minimum effective dose of pirfenidone may be maintained over this duration, local pirfenidone levels may also exhibit a significantly high ELF Cmax level that confers improved efficacy. In some embodiments, delivery of 4 mg of pirfenidone or a pyridone analog using a 30% efficiency device may result in a pulmonary ELF Cmax of up to about 48 mcg / mL (4 mg X 30% = 1.2 mg. 1.2 mg / 25 mL ELF = 48 mcg / mL). In some embodiments, based on the above assumptions, an administration of approximately 66 mg with a device for administering pirfenidone or a pyridone analog with 70% efficiency may result in a pulmonary ELF Cmax of up to 1.85 mg / mL (66 mg X 70% = 46.2 mg. 46.2 mg / 25 mL ELF = 1.85 mg / mL). In some embodiments, based on the above assumptions, an administration of approximately 154 mg with a device for administering pirfenidone or a pyridone analog with 30% efficiency may result in a pulmonary ELF Cmax of up to 1.85 mg / mL (154 mg X 30% = 46.2 mg. 46.2 mg / 25 mL ELF = 1.85 mg / mL). In some embodiments, based on the above assumptions, an administration of approximately 12 mg with a device for administering pirfenidone or a pyridone analog with 70% efficiency may result in a pulmonary ELF Cmax of up to 336 mcg / mL (12 mg X 70% = 8.4 mg. 8.4 mg / 25 mL ELF = 336 mcg / mL). In some embodiments, based on the above assumptions, an administration of approximately 28 mg with a device for administering pirfenidone or a pyridone analog with 30% efficiency may also result in a pulmonary ELF Cmax of up to 336 mcg / mL (28 mg X 30% = 8.4 mg. 8.4 mg / 25 mL ELF = 336 mcg / mL).In some embodiments, this dosage may maintain a minimum effective dosage at 5 mcg / mL, or 5 mcg / mL or more, over about 6 half-lives or about 15 hours. In some embodiments, the embodiments described for inhalation therapy provide beneficial efficacy by an increase in Cmax and maintain drug exposure in the minimum effective range of 5 mcg / mL or more than 5 mcg / mL over a longer time than is currently limited by oral administration. In some embodiments, long-term exposure may allow for a decrease in dosing interval (e.g., once a day or twice a day versus the current three-times-a-day oral dosing regimen). In some embodiments, while delivery is made directly to the lungs, these dosages may result in significantly low systemic plasma levels (e.g., about 2 mcg / mL of pirfenidone). In some embodiments, about 28 mg of pirfenidone or a pyridone analog delivered using an aerosol device with 30% efficiency results in an initial increase in levels in the vasculature and tissue immediately downstream of the lung (or nasal cavity), and the systemic plasma dilution concentration may be about 1.7 mcg / mL (28 mg X 30% = 8.4 mg. 8.4 mg / 5 L of systemic blood = 1.7 mcg / mL). In some embodiments, delivery of about 46 mg of pirfenidone or a pyridone analog may result in a systemic plasma dilution concentration of about 9.3 mcg / mL.

[0103] One of ordinary skill in the art will recognize from the discussion herein that if the actual measured pulmonary ELF half-life for pirfenidone or pyridone analog clearance changes, the dosage calculated with the above model will change. The shorter the half-life, the more pirfenidone or pyridone analog will need to be administered to maintain pulmonary ELF concentrations above what is considered the minimum effective level. Further increases in the administered pirfenidone or pyridone analog may also be desirable to further improve efficacy. Additionally, in addition to delivering the desired pulmonary tissue Cmax and AUC, delivery of aerosolized pirfenidone or pyridone analog by oral inhalation or intranasal inhalation may also serve as an efficient route for systemic delivery. In some embodiments, dosing regimens are contemplated that can achieve the desired pulmonary tissue Cmax and AUC with a plasma half-life slower than the pulmonary ELF by inhaled delivery of pirfenidone or pyridone analog, and by targeting the delivery of specific plasma concentrations, the pulmonary ELF-pirfenidone or pyridone analog exposure may be lengthened in sequence.

[0104] Assumptions for typical pulmonary tissue delivery: 1. The total wet weight of an adult lung is approximately 685 - 1,050 grams (for calculations, conservatively assume approximately 1,000 grams). 2. The adult pulmonary blood volume is approximately 450 mL. 3. The tissue weight of an adult lung is equal to 600 grams by subtracting 450 mL of blood weight (assuming a density of 1.0) from the conservative 1,050 grams of wet weight. 4. In some embodiments, after intravenous injection of pirfenidone in mice, - Plasma pirfenidone Tmax is equivalent to pulmonary Tmax. - Intravenous administration of 40 mg / kg results in a plasma Cmax of approximately 55 mcg / mL and a pulmonary Cmax of 30 mcg / gram wet weight. - Conservatively, blood accounts for approximately 40% of the wet weight of the lung. Depending on the embodiment, if the plasma and the lung have the same Tmax, as a result, most of the 30 mcg / g of pirfenidone measured in the wet lung would be due to the presence of blood. Conservatively, if blood accounts for approximately 40% of the wet weight of the lung, 40% of the plasma Cmax of pirfenidone in the measured lung weight of about 22 mcg / gram (or 40% of 55 mcg / mL X) is due to blood. Taking the difference between the wet lung Cmax and this number (or subtracting 22 mcg / g from 30 mcg / g), approximately 8 mcg / g is in the lung tissue. - A measured wet lung half-life that is approximately 45% longer than the plasma half-life may be considered. Taking up the argument that more than about 40% of the pirfenidone in the wet lung is in the blood, the actual half-life of the lung tissue is 45% longer than that of the plasma. From the above observations and calculations where a plasma Cmax of 5.55 mcg / mL results in a lung tissue Cmax of about 8 mcg / gram, the following comparison for humans can be made. - According to the initial assumption, the lower limit of human efficacy is 5 mcg / mL of plasma pirfenidone. - Assuming that the above ratio (55 mcg / mL of plasma results in 8 mcg / gram of lung tissue) also applies to humans, 5 mcg / mL divided by 55 mcg / mL is approximately 9.1%. 9.1% of 8 mcg / gram is approximately 0.7 mcg / gram. - Together, 5 mcg / mL of plasma pirfenidone may result in 0.7 mcg / gram of lung tissue pirfenidone. Therefore, approximately 0.7 mcg / gram of lung tissue pirfenidone is the lower limit of efficacy. 6. The inhalation route of administration depends on the Respirable Delivery Dose (RDD). The RDD is a portion of the drug inhaled as aerosol particles with a diameter of less than 5 microns. 7. The RDD of typical dry powders, liquid atomization, or metered inhalation devices varies from 10% to 70%. There are also high-efficiency and low-efficiency devices with an RDD greater than 70% and less than 10%. 8. As discussed above, the pirfenidone half-life in lung tissue is much longer (2-4 times or more than 2-4 times) than the plasma pirfenidone half-life delivered intravenously. The plasma pirfenidone half-life after oral administration is approximately 2.5 hours. However, continuous intestinal absorption affects this number and is thus much longer than after intravenous delivery. Therefore, for the purposes of this model, the pirfenidone half-life in lung tissue after inhaled delivery is considered to be equivalent to that after oral administration (e.g., 2.5 hours). 9. From the above observations and calculations, the lower limit of effectiveness in lung tissue is 8 mcg / gram. 10. Combining that 801 mg of oral pirfenidone results in human plasma levels of 5 mcg / mL or greater over 4 hours and that 5 mcg / mL of plasma results in 0.7 mcg / gram of lung tissue pirfenidone, what is delivered by oral or intranasal inhalation must be at least 0.7 mcg / gram or more of lung tissue pirfenidone for at least 4 hours with respect to effectiveness against pulmonary fibrosis equivalent to that of oral administration.

[0105] Typical lung tissue calculations: 1. Mcg pirfenidone delivered to 1000 grams of wet lung tissue (blood plus lung tissue) to make 0.7 mcg / gram = 700 mcg. 2. Based on 30% RDD efficiency, the required unit dose is 2,333 mcg (700 mcg / 0.3 = 2,333 mcg). 3. Based on 50% RDD efficiency, the required unit dose is 1,400 mcg (700 mcg / 0.5 = 1,400 mcg). 4. Based on 70% RDD efficiency, the required unit dose is 1,000 mcg (700 mcg / 0.7 = 1,000 mcg). Correct for maintaining these values or above these values during 2 half-lives of 2.5 hours each (4 hours at 0.7 mcg / gram or more in wet lung tissue with a 2.5-hour lung half-life = 1.6 half-lives) For an RDD efficiency of 5.30%, the unit dose required to match the lower limit of the effectiveness of the oral route clinically observed (in this case 2,333 mcg) over 1.6 half-lives is 3,733 mcg. For an RDD efficiency of 6.50%, the unit dose required to match the lower limit of the effectiveness of the oral route clinically observed (in this case 1,400 mcg) over 1.6 half-lives is 2,240 mcg. For an RDD efficiency of 7.70%, the unit dose required to match the lower limit of the effectiveness of the oral route clinically observed (in this case 1,000 mcg) over 1.6 half-lives is 1,600 mcg.

[0106] By way of non-limiting example, based on the above assumptions, a dose of approximately 3.7 mg in a device for delivering pirfenidone or a pyridone analog with 30% efficiency may result in a wet lung tissue level of 0.7 mcg / gram or more over the same duration obtained after an oral dose of 801 mg. Further, the minimum effective dose of pirfenidone is maintained during this duration, but the local pirfenidone level may also exhibit a significantly higher Cmax level in wet lung tissue that provides improved efficacy. According to a non-limiting example, delivery of 3.7 mg of pirfenidone or a pyridone analog using a device with 30% efficiency may result in a wet lung tissue Cmax of up to approximately 1.1 mcg / gram (3.7 mg X 30% = 1.1 mg. 1.1 mg / 1,050 grams of wet lung weight = 1.1 mcg / gram). This number is nearly about 1.5 times higher than the number delivered after oral delivery. According to another non-limiting example, based on the above assumptions, a dose of approximately 50 mg in a device for delivering pirfenidone or a pyridone analog with 30% efficiency may result in a wet lung tissue Cmax of up to 14.3 mcg / mL (50 mg X 30% = 15 mg. 15 mg / 1,050 grams of wet lung weight = 14.3 mcg / gram), or a lung tissue Cmax that is approximately 20 times higher than when delivered after oral delivery. In this scenario, this dose may result in maintaining the minimum effective dose at 0.7 mcg / gram of wet lung tissue, or more, for at least about 5 half-lives, or over approximately 12.5 hours, compared to 4 hours after an oral dose of 801 mg. Similarly, by way of another non-limiting example, based on the above assumptions, a dose of approximately 15 mg in a device for delivering pirfenidone or a pyridone analog with 70% efficiency may result in a wet lung tissue Cmax of up to 10 mcg / mL (15 mg X 70% = 10.5 mg. 10.5 mg / 1,050 grams of wet lung weight = 10 mcg / gram), or a lung tissue Cmax that is approximately 14 times higher than when delivered after oral delivery.In this scenario, this dosage may result in maintaining the minimum effective dosage at 0.7 mcg / gram of wet lung tissue, or more, for approximately 4.5 half-lives, or at least about 11 hours, compared to 4 hours after an oral dosage of 801 mg. Such a duration exceeding 0.7 mcg / gram of lung tissue may permit twice-daily (BID) dosing. Similarly, by another non-limiting example, based on the above assumptions, a dosage of approximately 75 mg in a device delivering pirfenidone or a pyridone analog with 70% efficiency may result in a wet lung tissue Cmax up to 50 mcg / mL (75 mg X 70% = 52.5 mg. 52.5 mg / 1,050 grams of wet lung weight = 50 mcg / gram), or approximately 71 times higher lung tissue Cmax when delivered after oral delivery. In this scenario, this dosage may result in maintaining the minimum effective dosage at 0.7 mcg / gram of wet lung tissue, or more, for at least about 6 half-lives, or about 15 hours, compared to 4 hours after an oral dosage of 801 mg. Such a duration exceeding 0.7 mcg / gram of lung tissue may permit BID dosing. Similarly, by another non-limiting example, based on the above assumptions, a dosage of approximately 15 mg in a device delivering pirfenidone or a pyridone analog with 30% efficiency may result in a wet lung tissue Cmax up to 4.3 mcg / mL (15 mg X 30% = 4.5 mg. 4.5 mg / 1,050 grams of wet lung weight = 4.3 mcg / gram), or approximately 6 times higher lung tissue Cmax when delivered after oral delivery. In this scenario, this dosage may result in maintaining the minimum effective dosage at 0.7 mcg / gram of wet lung tissue, or more, for at least about 3 half-lives, or about 7.5 hours, compared to 4 hours after an oral dosage of 801 mg. Similarly, by another non-limiting example, based on the above assumptions, a dosage of approximately 75 mg in a device delivering pirfenidone or a pyridone analog with 30% efficiency may result in a 21 mcg / mL (75 mg X 30% = 22.5 mg.22.5 mg / 1,050 grams of wet lung weight = 21 mcg / gram) may also result in a Cmax in wet lung tissue up to, or a lung tissue Cmax approximately 31 times higher when delivered after oral delivery. In this scenario, this dosage may result in maintaining the minimum effective dosage at 0.7 mcg / gram of wet lung tissue or more for at least about 5 half-lives, or about 12.5 hours, compared to 4 hours after an oral dosage of 801 mg. Such a duration exceeding 0.7 mcg / gram of lung tissue may permit BID dosing. Similarly, by another non-limiting example, based on the above assumptions, a dosage of approximately 15 mg in a device delivering pirfenidone or a pyridone analog at 10% efficiency may result in a Cmax in wet lung tissue up to 1.4 mcg / mL (15 mg X 10% = 1.5 mg. 1.5 mg / 1,050 grams of wet lung weight = 1.4 mcg / gram), or a lung tissue Cmax approximately 2 times higher when delivered after oral delivery. In this scenario, this dosage may result in maintaining the minimum effective dosage at 0.7 mcg / gram of wet lung tissue or more for about 1 half-life, or at least about 2.5 hours, compared to 4 hours after an oral dosage of 801 mg. Similarly, by another non-limiting example, based on the above assumptions, a dosage of approximately 75 mg in a device delivering pirfenidone or a pyridone analog at 10% efficiency may result in a Cmax in wet lung tissue up to 7.1 mcg / mL (75 mg X 10% = 7.5 mg. 7.5 mg / 1,050 grams of wet lung weight = 7.1 mcg / gram), or a lung tissue Cmax approximately 2 times higher when delivered after oral delivery. In this scenario, this dosage may result in maintaining the minimum effective dosage at 0.7 mcg / gram of wet lung tissue or more for about 3.5 half-lives, or at least about 8.8 hours, compared to 4 hours after an oral dosage of 801 mg. Such a duration exceeding 0.7 mcg / gram of lung tissue may permit TID dosing.Such an approach can confer efficacy by maintaining drug exposure in the minimum effective range of 0.7 mcg / gram or more of wet lung tissue over an increase in Cmax and a duration longer than the duration currently limited by oral administration. Such long-term exposure may also allow for a shorter dosing interval (e.g., once or twice a day versus the current three-times-a-day oral dosing regimen). Further, while this approach delivers directly to the lung, systemic plasma levels may be reduced (e.g., Cmax from less than 0.6 mcg / mL of pirfenidone from a delivery dose of 4.5 mg to 5000 mL of blood, less than 2 mcg / mL of pirfenidone from a delivery dose of 15 mg, less than 10 mcg / mL of pirfenidone from a dose of 75 mg) by using the above non-limiting examples.

[0107] If the actually measured half-life of pirfenidone or pyridone analog removal in lung tissue changes, the doses calculated with the above model will vary greatly. If the half-life is faster, increasingly more inhaled pirfenidone or pyridone analog will be required to maintain a lung tissue concentration higher than what is considered the minimum effective level. Further increases in inhaled pirfenidone or pyridone analog may be desirable to further improve efficacy. In addition to delivering the desired lung tissue Cmax and AUC, inhaled delivery of aerosolized pirfenidone or pyridone analog may also serve as an efficient route for systemic delivery. In some embodiments, a dosing scheme enabling inhaled delivery of pirfenidone or pyridone analog is contemplated to first achieve the desired lung tissue Cmax and AUC, and since the plasma half-life is expected to be slower than the lung tissue half-life, lung tissue pirfenidone or pyridone analog exposure may be lengthened in turn by targeting delivery of a specific plasma concentration.

[0108] Since the scarring is irreversible, the effectiveness of IPF is the action of protecting the original lung tissue from invasive fibrosis. Therefore, maintaining normal levels of effective drugs in unaffected tissues is essential for improving patient survival. Clinical and non-clinical studies suggest a dose responsiveness ranging from disease improvement to amelioration where the effectiveness of pirfenidone has waned. Unfortunately, due to significant gastrointestinal (GI) side effects and systemic toxicity, the approved oral dose is limited to the lower end of this range. What complicates the situation is that the lung dose is further reduced and the necessary maintenance therapy of this otherwise promising drug is interrupted by recommending food that absorbs the dose or frequently initiating dose reduction / withdrawal procedures to address these tissues. Direct inhalation delivery of aerosolized pirfenidone or pyridone analogs to the lungs reduces or eliminates these safety or durability limitations associated with the oral route of delivery.

[0109] The effectiveness of oral pirfenidone has been somewhat demonstrated in human clinical studies, and the data suggest that this effect increases with increasing dose. Unfortunately, due to severe side effects and toxicity, the oral dosage is limited to the lower limit of this effectiveness range (Esbriet is approved up to 2403 mg / d). The prescription of Esbriet threatens this already low effective dosage, and thus requires an initial dose escalation scheme and administration with the recommended food to obtain minimal GI tolerance and an acceptable side effect / toxicity profile (up to 3 capsules of 267 mg, or 801 mg three times a day (TID)). Unfortunately, not all patients reach this recommended dosage, and furthermore food decreases bioavailability (food reduces Cmax and AUC by ~50% and ~20%, respectively). Additionally, increases in liver enzyme values and skin photosensitivity initiate a procedure of dose reduction and discontinuation under the guidance of a physician. This procedure was observed to be up to a 50% dose reduction prior to discontinuation in phase 3 trials (between 48% and 67% of patients had a reduced dose in these studies). Since long-term pulmonary tissue administration of an effective drug concentration is essential to maintain protection from invasive fibrosis, the prescription and practice of oral pirfenidone are likely to result in a sub-efficacious administration of this otherwise promising drug (a hypothesis that somewhat explains the modest effectiveness observed in phase 3 trials).

[0110] Regarding oral administration in the context of treating pulmonary fibrosis, high oral doses are required to achieve plasma levels necessary for effective lung tissue exposure. However, gastrointestinal side effects and systemic toxicity have limited the approved oral doses to levels restricted to the lower limit of the efficacy and dose - response curve. In one embodiment, inhaled pirfenidone or pyridone analogs improve the efficacy of treatment with pirfenidone by increasing the dose administered to the lungs and improving compliance. In one embodiment, inhalation of pirfenidone or pyridone analogs (e.g., using a nebulizer) delivers pirfenidone or pyridone analogs directly to the lungs, and the systemic distribution of the delivered dose is minimized. In some embodiments, inhalation of pirfenidone reduces or eliminates the GI exposure and / or systemic toxicity common to oral administration of pirfenidone or pyridone analogs. In some embodiments, the inhaled delivery of pirfenidone or pyridone analogs provided herein provides higher lung tissue levels of pirfenidone than are possible through oral administration. In some embodiments, the inhaled delivery of pirfenidone or pyridone analogs serves as an efficient means of delivering pirfenidone or pyridone analogs to the systemic compartment. In some embodiments, the inhaled delivery of pirfenidone or pyridone analogs provides advantages in Cmax and AUC over the oral route. In some embodiments, the inhaled delivery of pirfenidone or pyridone analogs provides advantages in Cmax and AUC over the oral route, and aerosol - delivered pirfenidone or pyridone analogs with plasma recirculation maintain these beneficial properties. In some embodiments, the methods described herein may be used to treat patients diagnosed with mild to moderate IPF. In some embodiments, the methods described herein may be used to treat patients diagnosed with mild to severe IPF. In some embodiments, the methods described herein may be used to treat patients diagnosed with mild to moderate IPF without the need to first increase the dose in the patient. In some embodiments, the methods described herein may be used to treat patients diagnosed with mild to severe IPF without the need to first increase the dose in the patient.In some embodiments, the methods described herein may be used to treat patients diagnosed with mild to moderate IPF without the need to monitor treatment, reduce dosage, or interrupt treatment due to gastrointestinal, phototoxic, or liver enzyme-related adverse events. In some embodiments, the methods described herein may be used to treat patients diagnosed with mild to severe IPF without the need to monitor treatment, reduce dosage, or interrupt treatment due to gastrointestinal, phototoxic, or liver enzyme-related adverse events. In some embodiments, the methods described herein may be used to provide prophylactic treatment to patients diagnosed with mild to moderate IPF. In some embodiments, the methods described herein may be used to provide prophylactic treatment to patients diagnosed with mild to severe IPF. In some embodiments, the methods described herein may be used to provide prophylactic treatment to patients with mild to moderate IPF without first increasing the dosage to the patient. In some embodiments, the methods described herein provide prophylactic treatment to patients diagnosed with mild to severe IPF without first increasing the dosage to the patient. In some embodiments, the methods described herein may be used to provide prophylactic treatment to patients diagnosed with mild to moderate IPF without the need to monitor treatment, reduce dosage, or interrupt treatment due to gastrointestinal, phototoxic, or liver enzyme-related adverse events. In some embodiments, the methods described herein may be used to provide prophylactic treatment to patients diagnosed with mild to severe IPF without the need to monitor treatment, reduce dosage, or interrupt treatment due to gastrointestinal, phototoxic, or liver enzyme-related adverse events. In some embodiments, the methods described herein may be used to delay the progression of the disease in patients diagnosed with mild to moderate IPF without first increasing the dosage to the patient. In some embodiments, the methods described herein may be used to delay the progression of the disease in patients diagnosed with mild to severe IPF without first increasing the dosage to the patient.In some embodiments, the methods described herein may be used to slow the progression of disease in patients diagnosed with mild to moderate IPF without the need to monitor treatment, reduce dosage, or interrupt treatment due to gastrointestinal, phototoxic, or liver enzyme-related adverse events. In some embodiments, the methods described herein may be used to slow the progression of disease in patients diagnosed with mild to severe IPF without the need to monitor treatment, reduce dosage, or interrupt treatment due to gastrointestinal, phototoxic, or liver enzyme-related adverse events. By way of non-limiting example, clinical endpoints of IPF efficacy include reduction in the decline of forced vital capacity (FVC), reduction in the decline of distance walked in a six-minute interval (six-minute walk test; 6MWT), gradual reduction in diffusing capacity of the lung for carbon monoxide (DL. CO ), monitoring changes in biomarkers such as MMP7 and CCL18, including a gentle decrease, improvement in progression-free survival (PFS), reduction in mortality. In some embodiments, a comparison of the observed oral and inhaled aerosol properties is shown in Table A.

[0111]

Table 1

[0112] In some embodiments, the methods described herein provide delivery of a high concentration of readily bioavailable compounds of pirfenidone or pyridone analogs, which provide improved efficacy over pirfenidone or pyridone analog compounds administered by the oral route or by inhalation of a gradually dissolving or otherwise gradually bioavailable compound formulation. In some embodiments, gradually dissolving or otherwise gradually bioavailable compound formulations for inhalation include, but are not limited to, dry powder formulations, liposome formulations, nano-suspension formulations, or micro-suspension formulations. In some embodiments, the aqueous solutions of pirfenidone or pyridone analogs described and contemplated herein for administration by inhalation are completely homogeneous and soluble.

[0113] In some embodiments, a barrier for patients to comply with oral pirfenidone therapy is the intolerance to the GI tract. Pirfenidone blood concentration is also important because it has been involved in other observed toxicities. Therefore, factors contributing to the increase in blood concentration must be considered. Regarding the oral route of administration, due to toxicity and intolerance to the GI tract, the dosage was limited to three times a day at 801 mg. Elevated liver enzymes, photosensitivity reactions, and phototoxicity occur at this dosage, and more frequently and severely with higher dosages. Second, pirfenidone is mainly metabolized by CYP1A2. In vitro metabolism studies using liver microsomes indicate that approximately 48% of pirfenidone is metabolized by CYP1A2 using other CYP isoenzymes including CYP2C9, 2C19, 2D6, and 2E1, each contributing less than 13%. Therefore, inhibition of these enzyme systems results in an increase in pirfenidone blood concentration and an increase in the incidence and severity of toxicity. To achieve this objective, items such as grapefruit juice, fluvoxamine, and other inhibitors of CYP1A2 must be avoided during oral treatment with pirfenidone.

[0114] Oral administration of pirfenidone is contraindicated in patients taking fluvoxamine concomitantly. Fluvoxamine must be discontinued before the initiation of Esbriet therapy and avoided during Esbriet therapy due to the decreased clearance of pirfenidone. Other therapies that are inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of pirfenidone (e.g., CYP2C9, 2C19, and 2D6) must also be avoided during pirfenidone treatment.

[0115] Similarly, for oral administration, special care must be taken when a CYP1A2 inhibitor is used in combination with a potent inhibitor of one or more other CYP isoenzymes involved in the metabolism of pirfenidone, such as CYP2C9 (e.g., amiodarone, fluconazole), 2C19 (e.g., chloramphenicol), and 2D6 (e.g., fluoxetine, paroxetine).

[0116] Oral products should be used with caution in patients being treated with other mild or potent inhibitors of CYP1A2 (e.g., ciprofloxacin, amiodarone, propafenone).

[0117] Since many products that result in CYP enzymes are useful for patients with fibrosis, it is beneficial to permit their use. While the oral route is already at the maximum allowable dose (which provides only moderate effectiveness), any inhibition of the enzymes described above raises the pirfenidone blood concentration, accelerates the rate of the toxic events described herein, and worsens the severity. In some embodiments, delivery of pirfenidone or a pyridone analog by oral inhalation and intranasal inhalation can achieve effective tissue levels with far less drug than required by oral drug products, and in some embodiments, results in significantly lower blood concentrations, excluding the results related to the CYP enzyme inhibition properties described herein. In some embodiments, the use of these CYP inhibitory enzyme products, which are currently contraindicated for use with oral medications, may be administered using pirfenidone or a pyridone analog.

[0118] The primary metabolite of pirfenidone is 5-carboxy-pirfenidone. After oral or intravenous administration, this metabolite appears immediately at high concentrations in the blood. 5-carboxy-pirfenidone does not appear to have antifibrotic or anti-inflammatory effects, and its high blood concentration results from the decrease in the pirfenidone blood concentration. Thus, while the oral product is administered at the highest possible blood concentration, once pirfenidone enters the blood, it is immediately metabolized into inactive species, further reducing the amount of drug that can achieve sufficient lung levels required for significant efficacy. In some embodiments, delivery of pirfenidone or a pyridone analog by oral inhalation and intranasal inhalation can directly achieve effective lung tissue levels, thus minimizing extra-pulmonary metabolism.

[0119] In some embodiments, administration of a pirfenidone or pyridone analog compound by inhalation reduces gastrointestinal side effects compared to oral administration. In some embodiments, due to the reduced gastrointestinal side effects with inhaled administration, there is no longer a need for an initial dose titration. In some embodiments, administration of pirfenidone or a pyridone analog by inhalation bypasses or substantially bypasses the gastrointestinal tract, and thus, the effects observed with oral administration of the pirfenidone or pyridone analog compound are minimized or eliminated. In some embodiments, the lack of food effects with inhaled administration allows for delivery of the total dose.

[0120] In some embodiments, the pharmaceutical compositions described herein are used in the treatment of mammalian lung diseases. In some embodiments, the pharmaceutical compositions described herein are administered to a mammal by the method of oral inhalation or nasal inhalation for the purpose of treating mammalian lung diseases. In some embodiments, lung diseases include, but are not limited to, asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation-induced fibrosis, silicosis, asbestos-induced pulmonary fibrosis or pleural fibrosis, acute lung injury, acute respiratory distress syndrome (ARDS), sarcoidosis, usual interstitial pneumonia (UIP), cystic fibrosis, fibrosis associated with chronic lymphocytic leukemia (CLL), Hamman-Rich syndrome, Caplan syndrome, coal worker's pneumoconiosis, cryptogenic fibrosing alveolitis, bronchiolitis obliterans, chronic bronchitis, emphysema, interstitial pneumonia, Wegner's granulomatosis, scleroderma of the lung, silicosis, interstitial lung disease, asbestos-induced pulmonary fibrosis and / or pleural fibrosis. In some embodiments, the lung disease is pulmonary fibrosis (i.e., lung fibrosis). In some embodiments, the lung disease is idiopathic pulmonary fibrosis.

[0121] (Pulmonary fibrosis) In some embodiments, the compositions and methods described herein can treat pulmonary fibrosis, slow the progression of pulmonary fibrosis, or prevent pulmonary fibrosis. In some embodiments, pulmonary fibrosis includes interstitial pulmonary fibrosis. This group of disorders is characterized by scarring of the deep lung tissue, leading to shortness of breath and lack of functional alveoli, thus limiting oxygen exchange. The etiologies include inhalation of inorganic and organic powders, gases, fumes, and vapors, drug use, radiation exposure, and progression of disorders such as hypersensitivity pneumonitis, coal worker's pneumoconiosis, radiation, chemotherapy, transplant rejection, silicosis, byssinosis, and genetic factors.

[0122] The IPF described in this specification refers to "idiopathic pulmonary fibrosis", which, in some embodiments, is a chronic disease that manifests over several years and is characterized by scar tissue in the lungs without known inciting factors. Exercise-induced shortness of breath and chronic dry cough may be prominent symptoms. IPF belongs to a family of lung disorders known as interstitial lung disease (ILD), or more precisely, diffuse parenchymal lung disease. Within this broad category of diffuse lung diseases, IPF belongs to a subgroup known as idiopathic interstitial pneumonia (IIP). There are seven characteristic IIPs distinguished by specific clinical features and pathological patterns. IPF is the most common form of IIP. IPF is associated with a pathological pattern known as usual interstitial pneumonia (UIP). Therefore, IPF is often referred to as IPF / UIP. IPF is usually fatal, with an average survival period of approximately three years from the time of diagnosis. There is no single test for diagnosing pulmonary fibrosis, and a combination of different tests, including chest X-ray, pulmonary function tests, exercise tests, bronchoscopy, and lung biopsy, are used in conjunction with the methods described in this specification.

[0123] Idiopathic pulmonary fibrosis (also known as cryptogenic fibrosing alveolitis) is the most common form of interstitial lung disease and may be characterized by chronic progressive fibrosis of the lung parenchyma. Idiopathic pulmonary fibrosis is a progressive clinical syndrome with unknown etiology and often has a fatal prognosis because there is no effective treatment. In some embodiments, pirfenidone inhibits the proliferation and differentiation of fibroblasts associated with collagen synthesis, inhibits the production and activity of TGF-beta, reduces the production of fibronectin and connective tissue growth factor, inhibits TNF-alpha and I-CAM, increases the production of IL-10, and / or reduces the levels of platelet-derived growth factor (PDGF) A and B in bleomycin-induced pulmonary fibrosis. The pirfenidone methods and compositions described herein may confer durability and utility in patients with severe idiopathic pulmonary fibrosis and other lung diseases. In some embodiments, the pirfenidone methods and compositions described herein may confer durability and utility in patients with mild to moderate idiopathic pulmonary fibrosis. In some embodiments, an increase in patient survival, enhancement of vital capacity, decrease in the episodes of acute exacerbation (compared to placebo), and / or delay in the progression of the disease are observed with the following pirfenidone treatment.

[0124] In some embodiments, inhaled delivery of pirfenidone or a pyridone analog may be an effective means for preventing, managing, or treating idiopathic pulmonary fibrosis or other fibrotic lung diseases. The term "fibrotic lung disease" includes all interstitial lung diseases associated with fibrosis. In some embodiments, fibrotic lung disease includes the terms "idiopathic pulmonary fibrosis" or "IPF". In some embodiments, fibrotic lung disease may, by way of non-limiting example, result from the inhalation of inorganic and organic powders, gases, fumes, and vapors, the use of drugs, exposure to radiation or radiotherapy, and the progression of disorders such as hypersensitivity pneumonitis, coal worker's pneumoconiosis, radiation, chemotherapy, transplant rejection, silicosis, asbestosis, and genetic factors.

[0125] Typical lung diseases treated or prevented using the methods described herein include, but are not limited to, idiopathic pulmonary fibrosis, pulmonary fibrosis secondary to systemic inflammatory diseases such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), sarcoidosis, scleroderma, chronic asthma, silicosis, asbestos-induced pulmonary fibrosis or pleural fibrosis, acute lung injury and acute respiratory distress syndrome (including those induced by bacterial pneumonia, trauma, viral pneumonia, ventilator-induced, non-pulmonary sepsis, and aspiration).

[0126] (Renal fibrosis) In some embodiments, the compositions and methods described herein can treat renal fibrosis, slow the progression of renal fibrosis, or prevent renal fibrosis. Renal fibrosis can progress as a result of chronic infections, ureteral obstruction by stones, malignant hypertension, radiation therapy, transplant rejection, severe diabetic conditions, or long-term exposure to heavy metals. In addition, idiopathic glomerulosclerosis and interstitial renal fibrosis have been reported in children and adults. Renal fibrosis is often associated with an overall decline in renal function. Studies have shown that oral pirfenidone provides a protective effect against heavy metal challenge and reversal of fibrosis after diabetes induction in rats. Furthermore, the antifibrotic effect of pirfenidone in renal fibrosis after partial nephrectomy in rats was also demonstrated. In addition, clinical studies administering oral pirfenidone have shown that the decline in renal function was delayed in patients with focal segmental glomerulosclerosis. In some embodiments, because the blood vessels of the kidney are immediately downstream of the lungs, delivery by inhalation of pirfenidone or pyridone analogs may be an effective means to prevent, manage, or treat renal fibrosis resulting from various medical conditions or procedures without exposing the systemic compartment to otherwise harmful drugs associated with oral administration.

[0127] The term "renal fibrosis" may relate to remodeling associated with, or resulting from, chronic infections, ureteral obstruction by stones, malignant hypertension, radiation therapy, transplant rejection, severe diabetic conditions, or long-term exposure to heavy metals, by way of non-limiting examples.

[0128] <Cardiac and renal toxicity> In some embodiments, the compositions and methods described herein can treat, slow the progression of, or prevent cardiac and / or renal toxicity. Chemotherapeutic agents have toxicity to multiple organs during treatment. By way of non-limiting examples, doxorubicin has broad therapeutic activity against various tumors. However, its clinical use is limited by its undesirable systemic toxicity, particularly in the heart and kidneys. Treatment with pirfenidone decreased the severity of doxorubicin-induced toxicity as evaluated by decreased mortality, decreased the amount of fluid recovered in the abdomen, and decreased the severity of cardiac and renal lesions at biochemical and morphological levels. In some embodiments, because the cardiac and renal vasculature is immediately downstream of the lungs, inhaled delivery of pirfenidone or pyridone analogs can be an effective means of preventing, managing, or treating chemotherapy-induced cardiac and / or renal inflammation without exposing the systemic compartment to other toxic drug concentrations associated with oral administration. In some embodiments, inhaled delivery of a compound of pirfenidone or a pyridone analog is used for the treatment of cardiac toxicity and / or renal toxicity associated with chemotherapeutic agents or other therapeutic agents in humans.

[0129] The term "cardiac toxicity", by way of non-limiting examples, may be related to or caused by exposure to a chemotherapeutic agent having toxicity. By way of non-limiting examples, doxorubicin has broad therapeutic activity against various tumors. However, its clinical use is limited by its undesirable systemic toxicity, particularly in the heart and kidneys.

[0130] The term "nephrotoxicity", by way of non-limiting example, can be related to or caused by exposure to a chemotherapeutic agent having toxicity. By way of non-limiting example, doxorubicin has broad therapeutic activity against various tumors. However, its clinical use is limited by its undesirable systemic toxicity, particularly in the heart and kidneys.

[0131] <Cardiac fibrosis> In some embodiments, the compositions and methods described herein can treat or slow the progression of, or prevent, cardiac fibrosis. Cardiac remodeling, such as in chronic hypertension, is associated with myocyte hypertrophy and fibrosis, increased and non-uniform deposition of extracellular matrix proteins. The extracellular matrix connects myocytes, arranges contractile elements, prevents overstretching and disruption of myocytes, transmits force, and provides tensile strength to prevent rupture. Fibrosis occurs in many models of hypertension that lead to increased diastolic stiffness, decreased cardiac function, and increased risk of arrhythmia. Fibrosis, rather than myocyte hypertrophy, is a major factor in impaired cardiovascular function, and cardiac function can return to normal by reversal of the fibrosis itself. Because collagen deposition is a dynamic process, appropriate drug loading can selectively reverse existing fibrosis, prevent further fibrosis, and thereby improve function even if increased systolic blood pressure remains unchanged.

[0132] Treatment of DOCA-salt hypertensive rats with pirfenidone reversed and prevented fibrosis. Treatment with that pirfenidone or pyridone analogs may be an effective means of reducing cardiac fibrosis associated with chronic hypertension and cardiac dysfunction in humans with hypertension, suggesting that. Furthermore, reversal of fibrosis following pirfenidone treatment of streptozotocin-diabetic rats was also shown. (Miric et al., 2001). In summary, because the cardiac vasculature is immediately downstream of the lungs, delivery by inhalation of pirfenidone or pyridone analogs may be an effective means of preventing, managing, or treating cardiac fibrosis resulting from a variety of medical conditions or procedures, including, by way of non-limiting example, viral or bacterial infection, surgery, Duchenne muscular dystrophy, radiation, chemotherapy, and transplant rejection.

[0133] By way of non-limiting example, the term "cardiac fibrosis" relates to remodeling associated with or resulting from chronic hypertension, in which viral or bacterial infection, surgery, Duchenne muscular dystrophy, radiation therapy, chemotherapy, transplant rejection, and cardiomyocyte hypertrophy and fibrosis are involved and increased, non-identical depositions of extracellular matrix proteins occur. Fibrosis occurs in many models of hypertension that lead to increased diastolic stiffness, decreased cardiac function, increased risk of arrhythmia, and impairment of cardiovascular function.

[0134] <Liver fibrosis> In some embodiments, the compositions and methods described herein can treat, slow the progression of, or prevent liver fibrosis. Liver fibrosis results from severe liver injury in patients with chronic liver disease caused, by way of non-limiting example, by persistent viral hepatitis, alcohol overconsumption, and autoimmune diseases. Liver fibrosis is associated with abnormal accumulation of extracellular matrix components, particularly collagen. Hepatic stellate cells are non-parenchymal liver cells that reside in the perisinusoidal space. These cells have been shown to be the major cellular source of the extracellular matrix in liver fibrosis. Studies have shown that oral pirfenidone provides a protective effect against dimethylnitrosamine-induced liver fibrosis in terms of prevention of weight loss, suppression of reduction in liver weight, suppression of induction of liver fibrosis measured by histological evaluation, and decrease in hepatic hydroxyproline levels. The expression of mRNA for type I collagen and transforming growth factor beta in the liver was also suppressed by pirfenidone treatment. Furthermore, clinical studies administering oral pirfenidone have shown a decrease in fibrosis and an improvement in quality of life in patients with hepatitis C virus-related liver disease. Collectively, because the hepatic vasculature is immediately downstream of the lung, these results suggest that delivery by inhalation of pirfenidone or pyridone analogs may be an effective means to prevent, manage, or treat liver fibrosis resulting from various medical conditions or procedures without exposing the systemic compartment to other toxic drug concentrations associated with oral administration.

[0135] The term "liver fibrosis", by way of non-limiting example, can be associated with or caused by severe liver injury in patients with chronic liver disease caused, by way of non-limiting example, by persistent viral hepatitis, alcohol overconsumption, and autoimmune diseases. Liver fibrosis is associated with abnormal accumulation of extracellular matrix components, particularly collagen. Hepatic stellate cells are non-parenchymal liver cells that reside in the perisinusoidal space.

[0136] <Multiple Sclerosis> In some embodiments, the compositions and methods described herein can treat, slow the progression of, or prevent multiple sclerosis. Multiple sclerosis is a demyelinating disease characterized by neurological deficits resulting from demyelinating lesions and progressive axonal loss in the white matter. Evidence that TNF alpha plays an important role in the etiology of multiple sclerosis led to the evaluation of pirfenidone in this indication. In clinical studies, oral pirfenidone improved the Scripps Neurological Rating Scale score more than placebo. Additionally, pirfenidone was associated with a reduction in relapses and a significant improvement in bladder dysfunction. Overall, because the central nervous system vasculature is immediately downstream of the lungs, these studies suggest that delivery of pirfenidone or pyridone analogs by inhalation may be an effective means to prevent, manage, or treat multiple sclerosis without exposing the systemic compartment to other toxic drug concentrations associated with oral administration.

[0137] The term "multiple sclerosis" is a demyelinating disease characterized by neurological deficits resulting from demyelinating lesions and progressive axonal loss in the white matter.

[0138] <Chronic Obstructive Pulmonary Disease (COPD)> In some embodiments, the compositions and methods described herein can treat, slow the progression of, or prevent COPD. By way of non-limiting example, oxidants and oxidative stress caused by cigarette smoking promote lung inflammation that is at least partially mediated by activation of the transcription factors nuclear factor (NF)-κB and activator protein (AP)-1. These regulate the expression of several genes thought to be important in COPD, such as interleukin (IL)-8 and TNFα. These inflammation-promoting cytokines and chemokines, together with IL-1β, strongly activate the p38 subgroup of mitogen-activated protein kinases (MAPK), a family of signaling enzymes that also includes extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK). Members of JNK and p38 are mainly activated by cytokines involved in inflammation and apoptosis. Within the MAPK family, both the JNK and p38 subgroups are involved in mediating the inflammation-promoting response, but p38 appears to play a prominent role in COPD. Pirfenidone has been shown to inhibit both TNF alpha and p38-gamma MAPK. Furthermore, silencing of p38-gamma MAPK has been demonstrated to have the potential to restore COPD sensitivity to corticosteroids (Mercado et al., 2007). In some embodiments, delivery by inhalation of pirfenidone or a pyridone analog compound is used for the treatment of COPD in humans. In some embodiments, delivery by inhalation of pirfenidone or a pyridone analog can be an effective means for preventing, managing, or treating COPD or related diseases without exposing the systemic compartment to other toxic drug concentrations associated with oral administration. Furthermore, delivery by inhalation of pirfenidone or a pyridone analog can function as a conjunctive therapy with corticosteroids to restore their usefulness in this indication.

[0139] The term "chronic obstructive pulmonary disease" or "COPD", by way of non-limiting example, may be related to or caused by exposure to tobacco smoke and existing asthma. COPD represents a wide range of airway diseases ranging from simple chronic bronchitis (cough due to excessive smoking) to more severe chronic obstructive bronchitis. When episodes of airway hypersensitivity are added to the above syndrome, a diagnosis of chronic asthmatic bronchitis is established. Chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis, emphysema, and / or pulmonary hypertension, among others.

[0140] <Asthma> In some embodiments, the compositions and methods described herein can treat asthma, slow its progression, or prevent it. TNF-alpha has been shown to be a highly pro-inflammatory cytokine in asthma, as it upregulates adhesion molecules, increases mucin secretion, and promotes airway remodeling. TNF-alpha is produced by a large number of cells in the airway, including mast cells, smooth muscle cells, epithelial cells, monocytes, and macrophages. This cytokine has been associated with and shown to be increased in patients with asthma. Clinical studies using anti-TNF-alpha therapy have produced promising results. In a series of studies using the soluble form of recombinant human TNF-alpha receptor (etanercept), the drug improved FEV1 and improved quality of life. Another clinical study administering an anti-TNF-alpha antibody decreased asthma exacerbations (infliximab). However, due to problems related to adverse events, future studies of these treatments in asthma are unlikely to be conducted. Since pirfenidone has been shown to inhibit TNF-alpha, delivery by inhalation of pirfenidone or pyridone analogs can be an effective means for managing or treating asthma or related diseases without exposing the systemic compartment to other toxic drug concentrations associated with oral administration. In some embodiments, delivery by inhalation of a compound of pirfenidone or a pyridone analog is used for the treatment of asthma in humans. Further, delivery by inhalation of pirfenidone or a pyridone analog can function as combination therapy with corticosteroids to restore their usefulness in asthmatic patients who exhibit steroid resistance.

[0141] The term "asthma" is related to or caused by environmental and genetic factors. Asthma is a chronic inflammatory disease of the common airway characterized by variable and recurrent symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath. The term "asthma" can be used with one or more adjectives to indicate the cause. Non-limiting examples of asthma include, but are not limited to, allergic asthma, non-allergic asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, neutrophilic asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, asthma onset in infancy, asthma onset in adulthood, cough-variant asthma, occupational asthma, steroid-resistant asthma, or seasonal asthma.

[0142] <Pulmonary inflammation> In some embodiments, the compositions and methods described herein can treat or slow the progression of, or prevent, pulmonary inflammation. Pirfenidone treatment has been shown to have an anti-inflammatory effect in addition to its antifibrotic effect. In some embodiments, a compound of pirfenidone or a pyridone analog is administered to a human for treating pulmonary inflammation. Pulmonary inflammation is related to or contributes to the symptoms of bronchitis, asthma, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and interstitial pneumonia.

[0143] <Fibrosis after glaucoma surgery> The success of glaucoma filtration surgery depends on the degree of postoperative wound healing and the amount of scar tissue formation. Filtering bleb failure occurs when fibroblasts proliferate, migrate into the wound, and ultimately cause scarring and closure of the fistula. This often leads to poor postoperative intraocular pressure control with subsequent progressive optic nerve damage. The use of adjunctive antifibrotic agents such as 5-fluorouracil and mitomycin C has significantly improved the success rate of filtration surgery. However, due to the non-specific mechanism of their action, these agents can cause extensive cell death and apoptosis, and consequently lead to potentially vision-threatening complications such as severe postoperative hypotony, bleb leaks, and endophthalmitis. Therefore, alternative antifibrotic agents are needed. For this purpose, the antifibrotic agent, pirfenidone or pyridone analogs, may prove to be beneficial.

[0144] In some embodiments as disclosed herein, the present invention provides compositions and methods for compound formulations of pirfenidone and pyridone analogs that offer unprecedented advantages with respect to the topical delivery of pirfenidone or pyridone analogs in a manner that enables rapid and sustained availability of therapeutically useful levels of pirfenidone or pyridone analogs to one or more desired tissues.

[0145] In certain preferred embodiments, and as described in more detail below, the compound formulations of pirfenidone or pyridone analogs are delivered to airway tissues in a mammalian subject, e.g., to the central airways and / or pulmonary beds (e.g., alveolar capillary beds) via the respiratory airway in a human patient. Delivery to these regions of the lung can, according to certain particularly preferred embodiments, be accomplished by inhalation therapy of the compound formulations of pirfenidone or pyridone analogs, as described herein.

[0146] These and related embodiments provide beneficial therapeutic and / or prophylactic benefits by making a therapeutically effective amount of pirfenidone or a pyridone analog available to the desired tissue shortly after administration, but the same administration event also surprisingly provides a sustained period during which the locally delivered pirfenidone or pyridone analog is available for an extended therapeutic effect.

[0147] The compositions and methods disclosed herein provide such rapid and sustained local delivery of a pirfenidone or pyridone analog compound to a variety of tissues. Embodiments for the treatment of a number of clinically significant diseases are contemplated, including, but not limited to, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, cardiac fibrosis, transplantation (e.g., lung, liver, kidney, heart, etc.), vascular grafts, and / or other diseases such as multiple sclerosis, and in relation thereto, treatment with a rapid and sustained biologically available pirfenidone or pyridone analog may be shown.

[0148] Accordingly, various embodiments provide compositions and methods for optimal prophylactic and therapeutic activity in the prevention and treatment of pulmonary fibrosis in human and / or veterinary subjects using aerosol administration and via high concentration delivery (or dry formulations) (direct exposure to tissue affected by the sustained release of the active drug). In particular, in certain preferred embodiments, a concentrated dose of a pirfenidone or pyridone analog is delivered.

[0149] Without being bound by theory, according to certain of these and related embodiments as described in more detail herein, pirfenidone or a pyridone analog is provided in a formulation having components selected to deliver an effective dose of pirfenidone or a pyridone analog after aerosol administration of a liquid, dry powder or metered formulation that provides rapid and sustained local delivery of the pirfenidone or pyridone analog to the site of the desired effect.

[0150] According to certain related embodiments, by controlling the total amount of solute dissolved in a formulation of a compound of pirfenidone or a pyridone analog, a formulation of an aqueous compound of pirfenidone or a pyridone analog having therapeutically beneficial properties, including the properties of atomized liquid particles formed from an aqueous solution of such a formulation, is consequently provided. Further, as disclosed herein, within the parameters provided herein regarding the concentration, pH, and total solute concentration of a compound of pirfenidone or a pyridone analog, it has been discovered that the tolerance of the formulation at or near the upper portion of the total solute concentration range can be increased by the inclusion of a flavoring agent, as provided herein.

[0151] Unexpectedly, exposure of inhaled pirfenidone to the lung surface resulted in a lack of lung surface cations and an increased tendency towards acute toxicity. The obvious mechanism for this deficiency is the ability of pirfenidone to chelate ions such as iron(III) at a ratio of three pirfenidone molecules per iron(III) ion. Chelation of iron(III) occurs at half the strength of chelation of EDTA. One way to prevent ion deficiency on the lung surface is to formulate pirfenidone with polyvalent ions. By way of non-limiting example, such polyvalent cations can include iron(II), iron(III), calcium, magnesium, and the like. By way of non-limiting example, it has been found that formulations of pirfenidone chelate magnesium at a ratio of one magnesium ion to two pirfenidone molecules. Thus, formulation between about two and ten pirfenidone molecules by one magnesium molecule results in the chelation capacity of pirfenidone being filled or saturated and the ability of pirfenidone to deplete lung surface cations being reduced. By coupling this solution with the need to adjust the osmotic pressure and permeable ionic content of the formulation, the salt form of the polyvalent ion can also be beneficial. By way of non-limiting example, using magnesium chloride to formulate pirfenidone reduces the ability of pirfenidone to deplete essential lung surface cations, contributes to the adjustment of the osmotic pressure of the formulation, and serves to provide chloride-permeable ions to the formulation. In certain such embodiments, for example, compound formulations of pirfenidone or pyridone analogs, including those formulated with pirfenidone alone or pyridone analogs or excipients, can be aerosolized and injected into the nasal or lung compartments or dissolved in a simple aqueous solution that can be inhaled. Such formulations can include polyvalent cations and / or have a total osmotic pressure of at least 34 mcg / mL to about 463 mg / mL and at least 100 mOsmol / kg to about 6000 mOsmol / kg, or 300 to about 5000 mOsmol / kg, and can be buffered to a pH of from about 4.0 to about 11.0, more preferably from a pH of about 4.0 to a pH of about 8.0.Such simple aqueous formulations may further contain flavoring agents, thereby rendering them acceptable for inhalation administration (i.e., superior to undesirable taste or irritation characteristics that would otherwise impede effective therapeutic administration). Thus, as described in more detail herein, specific therapeutic and other advantages are provided by controlling formulation conditions regarding pH, type of buffer, concentration of pirfenidone or pyridone analogs, total osmotic pressure, and potential flavoring agents.

[0152] In certain such embodiments, for example, a compound formulation of pirfenidone or a pyridone analog contains pirfenidone or a pyridone analog, alone or formulated with an excipient such as a polyvalent cation that provides improved stability and / or dispersibility, such that at least 0.1 mg to about 100 mg can be dispersed and infused or inhaled into the nasal or pulmonary compartments. Thus, as described in more detail herein, specific therapeutic and other advantages are provided by controlling formulation conditions regarding dispersion excipient, stability of pirfenidone or pyridone analogs (including, by way of non-limiting example, polymorphs, amorphic content, and moisture), amount of pirfenidone or pyridone analogs, and potential flavoring agents.

[0153] In certain such embodiments, for example, a compound formulation of pirfenidone or a pyridone analog contains pirfenidone or a pyridone analog in a pressurized metered-dose inhaler configuration that provides improved stability and / or aerosol characteristics such that at least 0.1 mg to about 100 mg can be aerosolized and infused or inhaled into the nasal or pulmonary compartments. Thus, as described in more detail herein, specific therapeutic and other advantages are provided by controlling formulation conditions regarding propellant, appropriate pressurized metered-dose inhaler canister, and stability of pirfenidone or pyridone analogs.

[0154] In certain preferred embodiments, the compound formulations of pirfenidone or pyridone analogs or salts thereof can function as prodrugs, sustained release or active substances in the formulations and compositions disclosed herein, and can be delivered under conditions and for a sufficient time to provide maximum concentrations of sustained release or active drugs to the airways (including the lung bed, nose and sinuses), and other parenteral local compartments including, but not limited to, the skin, rectum, vagina, urethra, bladder, eye, and ear. As disclosed herein, certain particularly preferred embodiments relate to the administration of pirfenidone or pyridone analog compounds to the lower airways, i.e., the lungs or lung compartments (e.g., respiratory bronchioles, alveolar ducts, and / or alveoli), via oral and / or nasal inhalation, such that following pulmonary delivery of the pirfenidone or pyridone analog compound to the pulmonary vasculature, an effective amount of the pirfenidone or pyridone analog compound can reach the lung compartments and / or other tissues and organs via the circulatory system.

[0155] Since different formulations are known to have different efficacies depending on dosage, form, concentration, and delivery characteristics, certain embodiments disclosed herein provide specific formulation and delivery parameters that result in anti-inflammatory, anti-fibrotic, anti-demyelinating and / or tissue remodeling outcomes that are prophylactically or therapeutically important. Accordingly, these and related embodiments preferably include compounds of pirfenidone or pyridone analogs, such as pirfenidone or pyridone analogs alone or salts thereof. However, as indicated above, the invention is not so intended to be limited and can relate to pirfenidone or its salts according to particularly preferred embodiments. Other contemplated embodiments can relate to other pyridone analog compounds, such as the pyridone analog compounds disclosed herein.

[0156] By way of non-limiting example, in preferred embodiments, compounds of pyridone analogs as provided herein (e.g., pirfenidone) are formulated to enable administration of a mist, gas-liquid suspension or nebulized liquid, dry powder and / or metered aerosol to supply an effective concentration or amount that confers the desired anti-inflammatory, antifibrotic or tissue remodeling benefits, for example, for preventing, managing or treating patients with pulmonary fibrosis.

[0157] Since different formulations are known to differ in efficacy depending on dosage, shape, concentration and delivery characteristics, the embodiments disclosed herein provide, by way of non-limiting example, specific formulations and delivery parameters that provide protection against and treatment for pulmonary fibrosis associated with infection, radiation therapy, chemotherapy, inhalation of environmental pollutants (e.g., dust, vapors, fumes, and inorganic and organic fibers), allergies, silicosis, asbestosis, genetic factors and transplant rejection. These and related applications are also contemplated for use in diseased lungs, cavities, nasal passages, heart, kidneys, liver, nervous system and related blood vessels. The formulations and methods of compounds of pirfenidone or pyridone analogs described herein can be used with commercially available inhalation devices or other devices for the administration of aerosolized therapeutic agents.

[0158] By way of non-limiting example, in preferred embodiments, compounds of pyridone analogs as provided herein (e.g., pirfenidone) are formulated to enable administration of a mist, gas-liquid suspension or nebulized liquid, dry powder and / or metered aerosol to supply an effective concentration or amount that confers the desired anti-inflammatory, antifibrotic or tissue remodeling benefits, for example, for preventing, managing or treating cardiac fibrosis in human and / or veterinary subjects. Such embodiments provide direct and high-concentration delivery of pirfenidone or compounds of pyridone analogs to the pulmonary vasculature immediately upstream of the left atrium and thus to the arterial system of the coronary arteries with exposure of the atria and ventricles within the vagina.

[0159] Because different formulations are known to differ in efficacy depending on dosage, shape, concentration, and delivery characteristics, the embodiments disclosed herein provide, by way of non-limiting example, specific formulations and delivery parameters that provide protection against and treatment for cardiac fibrosis associated with infection, surgery, radiation therapy, chemotherapy, and transplant rejection.

[0160] By way of non-limiting example, in a preferred embodiment, a compound of a pyridone analog as provided herein (e.g., pirfenidone) is formulated to enable administration of a mist, gas-liquid suspension or nebulized liquid, dry powder and / or metered aerosol to supply an effective concentration or amount that confers the desired anti-inflammatory, antifibrotic or tissue remodeling benefits, for example, to prevent, manage, or treat renal fibrosis. Such embodiments provide direct and high-concentration delivery of pirfenidone or a compound of a pyridone analog to the pulmonary vasculature immediately upstream of the left atrium and, thus, to the renal vasculature.

[0161] Because different formulations are known to differ in efficacy depending on dosage, shape, concentration, and delivery characteristics, the embodiments disclosed herein provide, by way of non-limiting example, specific formulations and delivery parameters that provide protection against and treatment for renal fibrosis associated with infection, ureteral calculi, malignant hypertension, radiation therapy, diabetes, heavy metal exposure, chemotherapy and transplant rejection.

[0162] As a non-limiting example, in a preferred embodiment, a compound of a pyridone analog as provided herein (e.g., pirfenidone) is formulated to enable administration of a mist, gas-liquid suspension or nebulized liquid, dry powder and / or metered aerosol to supply an effective concentration or amount that provides the desired anti-inflammatory benefit, for example, to prevent, manage, or treat heart or kidney toxicity. Such embodiments provide direct and high-concentration delivery of pirfenidone or a compound of a pyridone analog to the pulmonary vasculature immediately upstream of the left atrium and left ventricle and thus to the vasculature of the heart and kidneys.

[0163] Since different formulations are known to differ in efficacy depending on dosage, shape, concentration and delivery characteristics, the embodiments disclosed herein provide, by way of non-limiting example, specific formulations and delivery parameters that provide protection against and treatment for heart or kidney toxicity associated with chemotherapy.

[0164] As a non-limiting example, in a preferred embodiment, a compound of a pyridone analog as provided herein (e.g., pirfenidone) is formulated to enable administration of a mist, gas-liquid suspension or nebulized liquid, dry powder and / or metered aerosol to supply an effective concentration or amount that provides the desired anti-inflammatory, antifibrotic or tissue remodeling benefit, for example, to prevent, manage, or treat liver fibrosis. Such embodiments provide direct and high-concentration delivery of pirfenidone or a compound of a pyridone analog to the pulmonary vasculature immediately upstream of the left atrium and left ventricle and thus to the vasculature of the liver.

[0165] Because different formulations are known to differ in effectiveness depending on dosage, shape, concentration, and delivery characteristics, the embodiments disclosed herein provide, by way of non-limiting example, certain formulations and delivery parameters that result in protection against and treatment of liver fibrosis associated with liver infection, hepatitis, alcohol overconsumption, autoimmune diseases, radiation therapy, chemotherapy, and transplant rejection.

[0166] By way of non-limiting example, in a preferred embodiment, a compound of a pyridone analog as provided herein (e.g., pirfenidone) is formulated to enable administration of an aerosol that is nebulized, a gas-liquid suspension, or a liquid, dry powder, and / or metered dose that is insufflated or inhaled into the nose or orally inhaled to provide an effective concentration or amount that confers the desired anti-inflammatory and / or anti-demyelinating benefits for preventing, managing, or treating multiple sclerosis. In the case of oral inhalation, such embodiments provide direct and high-concentration delivery of pirfenidone or a compound of a pyridone analog to the pulmonary vasculature immediately upstream of the left atrium and left ventricle and thus to the central nervous system. In the case of nasal insufflation or nasal inhalation, such embodiments provide direct and high-concentration delivery of pirfenidone or a compound of a pyridone analog to the nasal and sinus vasculature immediately upstream of the central nervous system.

[0167] Because different formulations are known to differ in effectiveness depending on dosage, shape, concentration, and delivery characteristics, the embodiments disclosed herein provide certain formulations and delivery parameters that result in protection against and treatment of multiple sclerosis.

[0168] By way of non-limiting example, in preferred embodiments, a compound of a pyridone analog as provided herein (e.g., pirfenidone) is formulated to enable administration of a mist, gas-liquid suspension or nebulized liquid, dry powder and / or metered aerosol to supply an effective concentration or amount that confers the desired anti-inflammatory, anti-fibrotic or tissue remodeling benefits for the prevention, management, or treatment of patients having a disease associated with chronic obstructive pulmonary disease (COPD), such as emphysema and chronic bronchitis.

[0169] Since different formulations are known to vary in effectiveness depending on dosage, shape, concentration and delivery characteristics, the embodiments disclosed herein provide, by way of non-limiting example, specific formulations and delivery parameters that provide protection against and treatment for COPD associated with pipe, cigar and cigarette smoke, secondhand smoke, air pollution, and exposure to chemical fumes or dust, and / or COPD associated with alpha-1 antitrypsin deficiency.

[0170] By way of non-limiting example, in preferred embodiments, a compound of a pyridone analog as provided herein (e.g., pirfenidone) is formulated to enable administration of a mist, gas-liquid suspension or nebulized liquid, dry powder and / or metered aerosol to supply an effective concentration or amount that confers the desired anti-inflammatory benefits for the prevention, management, or treatment of patients having asthma.

[0171] Since different formulations are known to vary in effectiveness depending on dosage, shape, concentration and delivery characteristics, the embodiments disclosed herein provide, by way of non-limiting example, specific formulations and delivery parameters that provide protection against and treatment for asthma associated with exercise, genetic traits, airborne allergens, inhaled irritants such as pipe, cigar and cigarette smoke, and childhood respiratory infections.

[0172] By way of non-limiting example, in a preferred embodiment, a compound of a pyridone analog as provided herein (e.g., pirfenidone) is formulated to enable administration as a mist, gas-liquid suspension or nebulized liquid, dry powder and / or metered aerosol to supply an effective concentration or amount to provide the desired anti-inflammatory, anti-fibrotic or tissue remodeling benefits, for example, to prevent, manage or treat a patient having cystic fibrosis. Such embodiments may include co-formulation or co-administration of the pyridone analog compound with an antibiotic, steroid, hypertonic solution, DNAse or other mucolytic agent, or other agents.

[0173] Since different formulations are known to vary in effectiveness depending on dosage, shape, concentration and delivery characteristics, the embodiments disclosed herein provide specific formulations and delivery parameters that provide protection against and treatment for cystic fibrosis.

[0174] For the applications described herein, the compound (or a salt thereof) of pifenedone or a pyridone analog in the form of an atomized liquid, dry powder or metered aerosol may be administered simultaneously, administered sequentially, or in combination with an antibacterial agent (e.g., other aminoglycosides such as tobramycin and / or amikacin, aztreonam and / or other beta or mono-bactams, ciprofloxacin, levofloxacin and / or others, fluoroquinolones, azithromycin and / or other macrolides or ketolides, tetracycline and / or other tetracyclines, quinupristin and / or other streptogramins, linezolid and / or other oxazolidinones, vancomycin and / or other glycopeptides, and chloramphenicol and / or other phenicols, and colistin and / or other polymyxins), a bronchodilator (e.g., beta-2 agonists and muscarinic antagonists), a corticosteroid (e.g., salmeterol, fluticasone and budesonide), a glucocorticoid (e.g., prednisone), cromolyn, nedocromil, a leukotriene modifier (e.g., montelukast, zafirlukast and zileuton), a hypertonic solution, a DNAse or other agent to thin mucus, interferon gamma, cyclophosphamide, colchicine, N-acetylcysteine, azathioprine, bromhexine, an endothelin receptor antagonist (e.g., bosentan and ambrisentan), a PDE5 inhibitor (e.g., sildenafil, vardenafil and tadalafil), a PDE4 inhibitor (e.g., roflumilast, cilomilast, oglemilast, tetomilast and SB256066), a prostinoid (e.g., epoprostenol, iloprost and treprostinin), nitric oxide or a nitric oxide donating compound, an IL-13 blocker, an IL-10 blocker, a CTGF specific antibody, a CCN2 inhibitor, an angiotensin converting enzyme inhibitor, an angiotensin receptor antagonist, a PDGF inhibitor, a PPAR antagonist, imatinib, a CCL2 specific antibody, a CXCR2 antagonist, a triple growth factor kinase inhibitor, an anticoagulant, a TNF blocker, a tetracycline or a tetracycline derivative,5-Lipoxygenase inhibitors, pituitary hormone inhibitors, TGF-β-neutralizing antibodies, copper chelating agents, angiotensin II receptor antagonists, chemokine inhibitors, NF-kappaB inhibitors, NF-kappaB antisense oligonucleotides, IKK-1 and -2 inhibitors (e.g., imidazoquinoxaline or derivatives, and quinazoline or derivatives), JNK2 and / or p38 MAPK inhibitors (e.g., pyridylimidazolbutyn-I-ol, SB856553, SB681323, diaryl ureas or derivatives, and indole-5-carboxamide), PI3K inhibitors, LTB4 inhibitors, antioxidants (e.g., Mn-pentaazatetracyclohexacosatriene, M40419, N-acetyl-L-cysteine, mucolyst, fluimucil, nacistelin, erdosteine), Ebeselen, thioredoxin, glutathione peroxidase mimetic, curcumin C3 complex, resveratrol and analogs, tempol, catalytic antioxidants, and OxSODrol), TNF scavengers (e.g., infliximab, ethercept, adalumimab, PEG-sTNFR1, afeclumomab, and antisense TNF-alpha oligonucleotides), It can be prepared in a fixed combination with interferon beta-1a (Avonex, Betaseron, or Rebif), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), natalizumab (Tysabri), methotrexate, azathioprine (Imuran), intravenous immunoglobulin (IVIg), cyclophosphamide (Cytoxan), riorexal (baclofen), tizanidine (Zanaflex), benzodiazepines, cholinergic agents, antidepressants and amantadine.

[0175] As shown as a promising approach for treating cancer and pulmonary hypertension, in order to enable "cocktail therapy" or "cocktail prophylaxis" in fibrotic diseases, more specifically idiopathic pulmonary fibrosis and other fibrotic lung diseases, in combination with agents targeting fibrotic or inflammatory diseases, either co-administered, sequentially administered, or co-prescribed (as required by the prescribing physician in some sequences as combination therapy for drugs treating the same disease), a method of administering pirfenidone or a pyridone analog is described. By way of non-limiting examples, pirfenidone or a pyridone analog is administered in a fixed combination with, co-administered with, sequentially administered with, or co-prescribed with monoclonal GS-6624 (formerly known as AB0024), an analog, or another antibody targeting the LOXL2 protein related to the biosynthesis of connective tissue for reducing inflammation and / or fibrosis. By another non-limiting example, pirfenidone or a pyridone analog is administered in a fixed combination with, co-administered with, sequentially administered with, or co-prescribed with IW001 (Type V collagen), an analog, or another collagen targeting immunogenicity for reducing inflammation and / or fibrosis. By another non-limiting example, pirfenidone or a pyridone analog is administered in a fixed combination with, co-administered with, sequentially administered with, or co-prescribed with PRM-151 (recombinant pentraxin-2), an analog, or another molecule targeting the control of the injury response for reducing inflammation and / or fibrosis. By another non-limiting example, pirfenidone or a pyridone analog is administered in a fixed combination with, co-administered with, sequentially administered with, or co-prescribed with CC-903 (Jun kinase inhibitor), an analog, or another Jun kinase inhibitor for reducing the inflammatory response.By another non-limiting example, pirfenidone or a pyridone analog is administered in a fixed combination with, co-administered with, sequentially administered with, or co-formulated with STX-100 (a monoclonal antibody targeting integrin alpha-v beta-6), an analog, or another antibody targeting integrin alpha-v beta-6 or other integrin to reduce fibrosis. By another non-limiting example, pirfenidone or a pyridone analog is administered in a fixed combination with, co-administered with, sequentially administered with, or co-formulated with QAX576 (a monoclonal antibody targeting interleukin 13 [IL-13]), an analog, or another antibody targeting IL-13 to reduce inflammation. By another non-limiting example, pirfenidone or a pyridone analog is administered in a fixed combination with, co-administered with, sequentially administered with, or co-formulated with FG-3019 (a monoclonal antibody targeting connective tissue growth factor [CTGF]), an analog, or another antibody targeting CTGF to reduce fibrosis. By another non-limiting example, pirfenidone or a pyridone analog is administered in a fixed combination with, co-administered with, sequentially administered with, or co-formulated with CNTO-888 (a monoclonal antibody targeting chemokine [C-C motif] ligand 2 [CCL2]), an analog, or another antibody targeting CCL2 to reduce fibrosis. By another non-limiting example, pirfenidone or a pyridone analog is administered in a fixed combination with, co-administered with, sequentially administered with, or co-formulated with Esbriet, Pirespa or Pirfenex (trade names of pirfenidone), or an analog targeting inflammation and fibrosis.By another non-limiting example, pirfenidone or a pyridone analog is administered in a fixed combination with, co-administered with, sequentially administered with, or co-formulated with BIBF-1120 (also known as Vargatef, a triple kinase inhibitor that targets vascular endothelial growth factor [VEGF], platelet-derived growth factor [PDGF], and fibroblast growth factor [FGF]), an analog or other triple kinase inhibitor for reducing fibrosis and / or inflammation.

[0176] Oral and parenteral (by way of non-limiting examples, intravenous and subcutaneous) routes of administration of other compounds, molecules, and antibodies that target a reduction in inflammation and / or fibrosis with the administration of pirfenidone are often, by way of non-limiting examples, associated with adverse reactions such as gastrointestinal side effects, liver, kidney, skin, cardiovascular, or other toxicities. As described herein with respect to pirfenidone or pyridone analogs, the benefits of direct oral or intranasal inhalation to the lung or tissues immediately downstream of the nasal and / or lung compartments are also useful for these compounds. Thus, by way of non-limiting examples, monoclonal GS-6624 (formerly known as AB0024), an analog, or another antibody that targets the LOXL2 protein associated with the biosynthesis of connective tissue to reduce inflammation and / or fibrosis can be administered by oral or intranasal inhalation for direct delivery to the lung or tissues immediately downstream of the nasal or lung compartments. By way of another non-limiting example, PRM-151 (recombinant pentraxin-2), an analog, or other molecule that targets the regulation of the injury response to reduce inflammation and / or fibrosis can be administered by oral or intranasal inhalation for direct delivery to the lung or tissues immediately downstream of the nasal or lung compartments. By way of another non-limiting example, CC-903 (Jun kinase inhibitor), an analog, or other Jun kinase inhibitor for reducing the inflammatory response can be administered by oral or intranasal inhalation for direct delivery to the lung or tissues immediately downstream of the nasal or lung compartments. By way of another non-limiting example, STX-100 (monoclonal antibody targeting integrin alpha-v beta-6), an analog, or another antibody that targets integrin alpha-v beta-6 or other integrins to reduce fibrosis can be administered by oral or intranasal inhalation for direct delivery to the lung or tissues immediately downstream of the nasal or lung compartments.By another non-limiting example, QAX576 (a monoclonal antibody targeting interleukin 13 [IL-13]), an analog, or other antibody targeting IL-13 for reducing inflammation can be administered by oral or intranasal inhalation for direct delivery to the lung or tissue immediately downstream of the nasal or lung compartment. By another non-limiting example, FG-3019 (a monoclonal antibody targeting connective tissue growth factor [CTGF]), an analog, or other antibody targeting CTGF for reducing fibrosis can be administered by oral or intranasal inhalation for direct delivery to the lung or tissue immediately downstream of the nasal or lung compartment. By another non-limiting example, CNTO-888 (a monoclonal antibody targeting chemokine [C-C motif] ligand 2 [CCL2]), an analog, or other antibody targeting CCL2 for reducing fibrosis can be administered by oral or intranasal inhalation for direct delivery to the lung or tissue immediately downstream of the nasal or lung compartment. By another non-limiting example, BIBF-1120 (also known as Vargatef, a triple kinase inhibitor targeting vascular endothelial growth factor [VEGF], platelet-derived growth factor [PDGF] and fibroblast growth factor [FGF]), an analog, or other triple kinase inhibitor for reducing inflammation and / or fibrosis can be administered by oral or intranasal inhalation for direct delivery to the lung or tissue immediately downstream of the nasal or lung compartment.

[0177] Direct aerosol administration to one or more desired regions of the airway, including the upper airway (e.g., the nasal, sinus, and pharyngeal compartments), the respiratory airway (e.g., the laryngeal, tracheal, and bronchial compartments), and the lung or lung compartments (e.g., the respiratory bronchioles, alveolar ducts, alveoli), can be achieved in certain preferred embodiments via nasal or oral inhalation (e.g., "lung delivery") to obtain delivery of high and titrated concentrations of a drug, prodrug active, or sustained release, to the site of a respiratory pathology. Aerosol administration, such as by nasal or oral inhalation, can also reduce the risk of extra-respiratory toxicity associated with non-respiratory routes of drug delivery and provide delivery of a drug, prodrug active, or sustained release (e.g., further lung delivery) via the pulmonary vasculature to reach other tissues or organs, by way of non-limiting example, the heart, brain, central nervous system of the liver, and / or the kidneys. Thus, because the effectiveness of therapeutic compositions of certain pyridone compounds (e.g., pirfenidone) can vary depending on formulation and delivery parameters, the specific embodiments described herein reflect reformulations of the compositions and new delivery methods for the recognized active drug compounds. Other embodiments contemplate local pathologies and / or infections that may benefit from the discoveries described herein through direct exposure to a compound formulation of pirfenidone or a pyridone analog as provided herein, including, for example, aerosol delivery to burn wounds to prevent scarring, to diseased skin, rectum, vagina, urethra, bladder, eye, and / or ear.

[0178] In addition to clinical and pharmacological criteria, in accordance with which any composition intended for therapeutic administration (such as a formulation of a compound of pirfenidone or a pyridone analog described herein) can be characterized, those skilled in the art will recognize many physicochemical factors specific to a given pharmaceutical composition. These include, but are not limited to, water solubility, viscosity, partitioning coefficient (LogP), predicted stability in various formulations, osmotic pressure, surface tension, pH, pKa, pKb, dissolution rate, mucus permeability, mucus binding / inactivation, taste, throat irritation and acute tolerance.

[0179] Other factors to consider when selecting the shape of a particular product include the physicochemistry of the formulation (e.g., a formulation of a compound of pirlfenidone or a pyridone analog), the intended disease target for which the formulation is to be used, clinical acceptability, and patient compliance. By way of non-limiting example, a desired formulation of a compound of pirlfenidone or a pyridone analog for aerosol delivery (e.g., by oral and / or intranasal inhalation of a mist such as a nebulized suspension of liquid particles, a dry powder formulation produced by a metered-dose inhaler, or a dispersion of an aerosol) may be a simple liquid such as an aqueous liquid (e.g., a soluble compound of pirlfenidone or a pyridone analog having an unencapsulated soluble excipient / salt) for packaging and administration using an inhaler such as a metered-dose inhaler, a complex liquid such as an aqueous liquid (e.g., a compound of pirlfenidone or a pyridone analog encapsulated or complexed with a soluble excipient such as a lipid, liposome, cyclodextrin, microencapsulation, and emulsion), a complex suspension (e.g., a compound of pirlfenidone or a pyridone analog having a low solubility lipid as a low solubility, stable nano-suspension alone, as a co-crystal / coprecipitate complex, and / or as a mixture with solid lipid nanoparticles), a dry powder (e.g., a dry powder of a compound of pirlfenidone or a pyridone analog alone or in a mixture having a co-crystal / coprecipitate / spray-dried complex or a highly soluble formulation with a low solubility excipient / salt or lactose), or a solution of an organic soluble or organic suspension, may be provided in the form of.

[0180] The selection of a compound formulation of a specific pirfenidone or pyridone analog, or a composition of a compound formulation of a pirfenidone or pyridone analog, as provided herein according to certain preferred embodiments, is influenced by the packaging of the desired product. Factors considered in selecting the packaging include, for example, inherent product stability, whether the formulation is susceptible to lyophilization, device selection (e.g., liquid nebulizer, dry powder inhaler, metered inhaler), and / or packaging form (e.g., simple liquid, complex liquid formulation), whether it is provided in a vial as a liquid to be dissolved before insertion into the device or as a lyophilized product, whether it is a complex suspension formulation, whether it is provided in a vial as a liquid or as a lyophilized product, and whether it has components of soluble salts / excipients that dissolve before or after insertion into the device, or separate packaging of liquid and solid components, dry powder formulation in a vial, capsule or blister pack, and other formulations packaged separately in separate containers alone or with a highly soluble or low solubility solid drug as a highly soluble or low solubility solid drug in a separate container with a highly soluble or low solubility solid drug, may be included.

[0181] A packaged medicament can be made in a manner that provides a composition of a compound formulation of a pirfenidone or pyridone analog for pulmonary delivery, comprising a solution provided as an aqueous solution of a compound of a pirfenidone or pyridone analog having a concentration of at least 0.1 mg / mL to about 50 mg / mL, a pH of about 3.0 to about 11.0, more preferably a pH of about 4 to 8, and a total osmotic pressure of at least 50 mOsmol / kg to about 1000 mOsmol / kg, more preferably from about 200 to about 500 mOsmol / kg.

[0182] In some embodiments, the present invention relates to aerosol delivery and / or topical delivery of pyridone analog compounds (e.g., pirfenidone). Pirfenidone has a favorable solubility that enables clinically desirable levels of administration by aerosol (e.g., via atomization of a liquid, dispersion of a dry powder, or metered dosing) or topically (e.g., as an aqueous suspension, an oil formulation, etc., or as a drip, spray, suppository, ointment, or cream), and can be used in a method for the acute or prophylactic treatment of a subject having pulmonary fibrosis or a subject at risk of having pulmonary fibrosis. Clinical criteria for determining when pulmonary fibrosis is present or when a subject is at risk of having pulmonary fibrosis are known to those of skill in the art. Pulmonary delivery by inhalation allows for direct, immediate, and titrated administration directly to the clinically desired site, thereby reducing systemic exposure.

[0183] In a preferred embodiment, the method treats or functions as a prophylaxis against interstitial lung disease (ILD) by administering to a subject having or suspected of having interstitial lung disease an aerosol formulation (e.g., a suspension of liquid particles in air or another gas) of a compound of pirfenidone or a pyridone analog. Interstitial lung disease includes those diseases of idiopathic interstitial pneumonia as defined by the American Thoracic Society / European Respiratory Society international multidisciplinary consensus classification, Am. J. Respir. Crit. Care Med. 165, 277-304 (2002). These include ILD related to known causes or connective tissue diseases, occupational causes or side effects of drugs, idiopathic interstitial pneumonia (e.g., idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis-ILD, idiopathic organizing pneumonia, acute interstitial pneumonia and lymphocytic interstitial pneumonia), granulomatous lung diseases (e.g., sarcoidosis, hypersensitivity interstitial pneumonia and infections), and other forms of ILD (e.g., lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, eosinophilic pneumonia and alveolar proteinosis).

[0184] The treatment method may also include a diagnostic step, such as identifying a subject having or suspected of having ILD. In some embodiments, the method further subclassifies idiopathic pulmonary fibrosis. In some embodiments, the delivered amount of the aerosol formulation of the compound of pirfenidone or a pyridone analog (or a salt thereof) is sufficient to provide acute, subacute, or chronic symptom relief, delay the progression of fibrosis, halt the progression of fibrosis, reverse fibrotic damage, and / or increase subsequent survival rate and / or improve quality of life.

[0185] The treatment method may also include a diagnostic step, such as identifying a subject having or suspected of having fibrosis in other tissues, by way of non-limiting example, the heart, liver, kidney or skin. In some embodiments, the delivered amount of a formulation of a compound of pirfenidone or a pyridone analog (or a salt thereof) in a nebulized liquid, dry powder or metered aerosol is sufficient to provide acute, subacute, or chronic symptom relief, delay the progression of fibrosis, halt the progression of fibrosis, reverse fibrotic damage, and / or increase subsequent survival rate and / or improve quality of life.

[0186] The treatment method may also include a diagnostic step, such as identifying a subject having or suspected of having multiple sclerosis. In some embodiments, the delivered amount of a formulation of a compound of pirfenidone or a pyridone analog (or a salt thereof) in a nebulized liquid, dry powder or metered aerosol is sufficient to provide acute, subacute, or chronic symptom relief, delay the progression of demyelination, halt the progression of demyelination, reverse demyelination damage, and / or increase subsequent survival rate and / or improve quality of life.

[0187] In another embodiment, the atomized liquid, dry powder or measured dose of aerosol of a compound of pifenedone or a pyridone analog (or a salt thereof) can be co-administered, can be administered sequentially, or can be formulated in a fixed combination with an antibacterial agent to also provide treatment of co-existing bacterial infections. By way of non-limiting example, the bacteria may also be Pseudomonas - aeruginosa, Pseudomonas - fluorescens, Pseudomonas - acidovorans, Pseudomonas - alcaligenes, Pseudomonas - putida, Stenotrophomonas - maltophilia, Burkholderia - cepacia, Aeromonas - hydrophila, Escherichia - coli, Citrobacter - freundii, Salmonella - typhimurium, Salmonella - typhi, Salmonella - paratyphi, Salmonella - enteritidis, Shigella - dysenteriae, Shigella - flexneri, Shigella - sonnei, Enterobacter - cloacae, Enterobacter - aerogenes, Klebsiella - pneumoniae, Klebsiella - oxytoca, Serratia - marcescens, Francisella - tularensis, Morganella - morganii, Proteus - mirabilis, Proteus - vulgaris, Providencia - alcalifaciens, Providencia - rettgeri, Providencia - stuartii, Acinetobacter - calcoaceticus, Acinetobacter - haemolyticus, Yersinia - enterocolitica, Yersinia - pestis, Yersinia - pseudotuberculosis, Yersinia - intermedia, Bordetella - pertussis, Bordetella - parapertussis, Bordetella - bronchiseptica, Haemophilus - influenzae, Haemophilus - parainfluenzae, Haemophilus - haemolyticus, Haemophilus - parahemolyticus, Haemophilus - ducreyi, Pasteurella - multocida, Pasteurella - haemolytica, Branhamella - catarrhalis, Helicobacter - pylori, Campylobacter - fetus, Campylobacter - jejuni, Campylobacter - coli, Borrelia - burgdorferi, Vibrio - cholerae, Vibrio - parahaemolyticus, Legionella - pneumophila, Listeria - monocytogenes, Neisseria - gonorrhoeae,It can be Gram-negative bacteria such as Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides bivius, Bacteroides vulgatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides spragnicus. In some embodiments of the methods described above, the bacteria are Gram-negative anaerobic bacteria, which include, by way of non-limiting example, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides bivius, Bacteroides vulgatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides spragnicus. In some embodiments of the methods described above, the bacteria are Gram-positive bacteria, which include, by way of non-limiting example, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus milleri; Streptococcus (Group G); Streptococcus (Group C / F); Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, and Staphylococcus saccharolyticus. In some embodiments of the methods described above, the bacteria are Gram-positive anaerobic bacteria, which include, by way of non-limiting example, Clostridium difficile, Clostridium perfringens, Clostridium tetani (Clostridiuminclude Clostridium tetani and Clostridium botulinum. In some embodiments of the methods described above, the bacteria are acid-fast bacteria, which include, by way of non-limiting example, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium leprae. In some embodiments of the methods described above, the bacteria are heterotypic bacteria, which include, by way of non-limiting example, Chlamydia pneumoniae and Mycoplasma pneumoniae.

[0188] By way of non-limiting example, in a preferred embodiment, a compound of a pyridone analog as provided herein (e.g., pirfenidone) is formulated to enable administration of a mist, gas-liquid suspension or nebulized liquid, dry powder and / or metered aerosol to provide an effective concentration or amount that results in and maintains a threshold drug concentration in the lung and / or targeted downstream tissues, as measured by drug concentration in epithelial lining fluid (ELF), sputum, lung tissue, bronchoalveolar lavage fluid (BAL), or analysis of blood concentration via pharmacokinetic analysis. One embodiment includes the use of aerosol administration to provide direct high or titrated concentrations of drug exposure to affected tissues for the treatment of pulmonary fibrosis, and inflammation associated with ILD (including idiopathic pulmonary fibrosis), COPD and asthma in animals and humans. In one such embodiment, the peak lung ELF level achieved after aerosol administration to the lung is a level of pirfenidone or a pyridone analog between 0.1 mg / mL and about 50 mg / mL. In another embodiment, the peak wet lung tissue level achieved after aerosol administration to the lung is a level of pirfenidone or a pyridone analog between 0.004 mcg / gram of lung tissue and about 500 mcg / gram of lung tissue.

[0189] As a non-limiting example, in a preferred embodiment, a compound of a pyridone analog as provided herein (e.g., pirfenidone) is formulated to enable administration of a mist, gas-liquid suspension or nebulized liquid, dry powder and / or metered aerosol to provide an effective concentration or amount that results in and maintains a threshold drug concentration in blood and / or lung, as measured by pharmacokinetic analysis of drug concentration in epithelial lining fluid (ELF), sputum, lung tissue, bronchoalveolar lavage fluid (BAL), or absorbed into the pulmonary vasculature to provide a drug concentration sufficient for extra-pulmonary treatment, maintenance or prevention. One embodiment includes, but is not limited to, the use of aerosol administration to provide high drug exposure in the pulmonary vasculature and subsequent tissues for the treatment, maintenance and / or prevention of cardiac fibrosis, renal fibrosis, hepatic fibrosis, cardiac or renal toxicity, or multiple sclerosis. In one such embodiment, peak tissue-specific plasma levels (e.g., heart, kidney and liver) or cerebrospinal fluid levels (e.g., central nervous system) achieved after aerosol administration to the lung after oral inhalation or to the lung or nasal cavity after nasal administration are levels of pirfenidone or pyridone analog between 0.1 mcg / mL and about 50 mcg / mL. In another embodiment, peak wet lung tissue values achieved after aerosol administration to the lung are levels of pirfenidone or pyridone analog between 0.004 mcg / gram lung tissue and about 500 mcg / gram lung tissue.

[0190] In another embodiment, a method for the acute or prophylactic treatment of a patient is provided via parenteral or non-nasal topical administration of a formulation of a compound of pirfenidone or a pyridone analog (or a salt thereof) to provide and maintain a threshold drug concentration at the site of a burn. One embodiment includes the use of aerosol administration to provide direct high drug exposure to affected tissue for the treatment or prevention of skin scarring. For example, according to these and related embodiments, the term aerosol can include forms of sprays, mists, or other nucleated liquids or dry powders.

[0191] In another embodiment, a method for the acute or prophylactic treatment of a patient is provided via parenteral or non-nasal topical administration of a compound formulation of pirfenidone or a pyridone analog (or a salt thereof) to effect and maintain a threshold drug concentration at the burn site. One embodiment involves the use of aerosol administration or drops of the formulation to effect a direct high concentration drug exposure to the affected tissue for the treatment or prevention of scarring following surgical glaucoma procedures (such as bleb fibrosis). For example, according to these and related embodiments, the term aerosol can include sprays, mists, or other nucleated liquid or dry powder forms. Drops can be simple liquid or suspension formulations.

[0192] In another embodiment, a pyridone analog compound (such as pirfenidone) as provided herein is formulated for inhalation, where the inhaled liquid aerosol or dry powder aerosol (such as after liquid atomization or metered dosing) has an average particle size of the aerodynamic mass median particle of from about 1 micron to 10 microns and a particle size geometric standard deviation of about 3 microns or less. In another embodiment, the particle size is an aerodynamic mass median particle of from 2 microns to about 5 microns and a particle size geometric standard deviation of about 3 microns or less. In one embodiment, the particle size geometric standard deviation is about 2 microns or less.

[0193] By way of non-limiting example, in a preferred embodiment, a compound of a pyridone analog as provided herein (e.g., pirfenidone) remains at a therapeutically effective concentration at the site of a pulmonary condition, a suspected site of a pulmonary condition, and / or the site of pulmonary absorption into the pulmonary vasculature for at least about 1 minute, at least about 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least about 1 hour, at least 2 hours, at least about 4 hours, at least 8 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, or for at least 1 week. An effective pirfenidone or pyridone analog concentration is sufficient to produce a therapeutic effect, and the effect can be localized to the site of the pulmonary condition or act broadly from the site of the pulmonary condition.

[0194] By way of non-limiting example, in a preferred embodiment, a compound of a pyridone analog as provided herein (e.g., pirfenidone or a salt thereof) remains at a therapeutically effective concentration at the site of cardiac fibrosis, renal fibrosis, hepatic fibrosis, cardiac or renal toxicity, or demyelination in multiple sclerosis for at least about 1 minute, at least about 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least about 1 hour, at least 2 hours, at least about 4 hours, at least 8 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, or for at least 1 week after inhaled administration. An effective pirfenidone or pyridone analog concentration is sufficient to produce a therapeutic effect, and the effect can be localized to the site of the extrapulmonary condition or act broadly from the site of the extrapulmonary condition.

[0195] In some embodiments, at a delivery site such as a lung site, a compound formulation of pirfenidone or a pyridone analog as provided herein is administered in one or more administrations to achieve a daily breathing-appropriate delivery dosage of pirfenidone or a pyridone analog of at least about 0.1 mg to about 50 mg, including all integer values such as 0.1, 0.2, 0.4, 0.8, 1, 2, 4, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50 milligrams. In some embodiments, a compound formulation of pirfenidone or a pyridone analog as provided herein is administered in one or more administrations to achieve a daily breathing-appropriate delivery dosage of pirfenidone or a pyridone analog of at least about 0.1 mg to about 30 mg, including all integer values such as 0.1, 0.2, 0.4, 0.8, 1, 2, 4, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300 milligrams. The pirfenidone or pyridone analog formulation is administered at a delivery dosage appropriate for the described breathing in less than 60 minutes, less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes, less than 3 minutes, less than 2 minutes, less than 1 minute, 10 inspiratory breaths, 8 inspiratory breaths, 6 inspiratory breaths, 4 inspiratory breaths, 3 inspiratory breaths, 2 inspiratory breaths, or 1 inspiratory breath. In some embodiments, the pirfenidone or pyridone analog formulation is administered at a delivery dosage appropriate for the described breathing using a breathing pattern of 1 second of inhalation and 2 seconds of exhalation, 2 seconds of inhalation and 2 seconds of exhalation, 3 seconds of inhalation and 2 seconds of exhalation, 4 seconds of inhalation and 2 seconds of exhalation, 5 seconds of inhalation and 2 seconds of exhalation, 6 seconds of inhalation and 2 seconds of exhalation, 7 seconds of inhalation and 2 seconds of exhalation, or 8 seconds of inhalation and 2 seconds of exhalation.

[0196] In some embodiments, at a delivery site such as the nasal cavity or sinus, a compound formulation of pirfenidone or a pyridone analog (or a salt thereof) is administered in one or more administrations to achieve a daily nasal or sinus deposited dose of pirfenidone or a pyridone analog of at least about 0.1 mg to about 50 mg, including all integer values such as 0.1, 0.2, 0.4, 0.8, 1, 2, 4, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50 milligrams. In some embodiments, at a delivery site such as the nasal cavity or sinus, a compound formulation of pirfenidone or a pyridone analog (or a salt thereof) is administered in one or more administrations to achieve a daily nasal or sinus deposited dose of pirfenidone or a pyridone analog of at least about 0.1 mg to about 300 mg, including all integer values such as 0.1, 0.2, 0.4, 0.8, 1, 2, 4, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300 milligrams. The pirfenidone or pyridone analog formulation is administered at the described nasal or sinus deposited dose with less than 20 breaths, less than 15 breaths, less than 10 breaths, less than 7 breaths, less than 5 breaths, less than 3 breaths, less than 2 breaths, less than 1 breath, 10 nasal inhalations, 8 nasal inhalations, 6 nasal inhalations, 4 nasal inhalations, 3 nasal inhalations, 2 nasal inhalations or 1 nasal inhalation. In some embodiments, the pirfenidone or pyridone analog formulation is administered at a delivery dose suitable for the described breath using a breathing pattern of 1 second inhalation and 2 second exhalation, 2 second inhalation and 2 second exhalation, 3 second inhalation and 2 second exhalation, 4 second inhalation and 2 second exhalation, 5 second inhalation and 2 second exhalation, 6 second inhalation and 2 second exhalation, 7 second inhalation and 2 second exhalation, 8 second inhalation and 2 second exhalation.

[0197] In some embodiments of the methods described above, the subject is a human. In some embodiments of the methods described above, the subject is a human having ILD. In some embodiments, the method further subclassifies idiopathic pulmonary fibrosis. In some embodiments of the methods described above, the human subject may be wearing a ventilator.

[0198] In embodiments where the human is wearing a ventilator, aerosol administration is performed using a device with an in-line device (by way of non-limiting example, the Nektar Aeroneb Pro) or a similar adapter with a device for liquid atomization. Aerosol administration can also be performed using an in-line adapter for the generation and delivery of dry powder or metered aerosol.

[0199] In some embodiments of the methods described above, the subject is a human. In some embodiments of the methods described above, the subject is a human in need of treatment for cardiac fibrosis. In some embodiments of the methods described above, the human subject may be wearing a ventilator.

[0200] In some embodiments of the methods described above, the subject is a human. In some embodiments of the methods described above, the subject is a human in need of treatment for renal fibrosis. In some embodiments of the methods described above, the human subject may be wearing a ventilator.

[0201] In some embodiments of the methods described above, the subject is a human. In some embodiments of the methods described above, the subject is a human in need of treatment for hepatic fibrosis. In some embodiments of the methods described above, the human subject may be wearing a ventilator.

[0202] In some embodiments of the methods described above, the subject is a human. In some embodiments of the methods described above, the subject is a human in need of treatment for cardiac or renal toxicity. In some embodiments of the methods described above, the human subject may be wearing a ventilator.

[0203] In some embodiments of the methods described above, the subject is a human. In some embodiments of the methods described above, the subject is a human in need of treatment for COPD. In some embodiments of the methods described above, the human subject may be wearing a ventilator.

[0204] In some embodiments of the methods described above, the subject is a human. In some embodiments of the methods described above, the subject is a human in need of treatment for asthma. In some embodiments of the methods described above, the human subject may be wearing a ventilator.

[0205] In some embodiments of the methods described above, the subject is a human. In some embodiments of the methods described above, the subject is a human in need of treatment for multiple sclerosis. In some embodiments of the methods described above, the human subject may be wearing a ventilator.

[0206] In another embodiment, the pharmaceutical composition comprises a formulation of a compound of simple liquid pirlidone or pyridone analog (or a salt thereof) having an unencapsulated water-soluble excipient as described above, having an osmotic pressure of from about 50 mOsmol / kg to about 6000 mOsmol / kg. In one embodiment, the osmotic pressure is from about 50 mOsmol / kg to about 1000 mOsmol / kg. In one embodiment, the osmotic pressure is from about 400 mOsmol / kg to about 5000 mOsmol / kg. In other embodiments, the osmotic pressure is from about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500 mOsmol / kg to about 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2400, 2600, 2800, 3000, 3200, 3400, 3600, 3800, 4000, 4200, 4400, 4600, 4800, 5000, 5200, 5400, 5600, 5800 and 6000 mOsmol / kg. For osmotic pressure, and for any of the others in this application, "about", when used to refer to a quantitative value, means that the stated quantity can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 20 percent more or less than the stated numerical value.

[0207] In another embodiment, the pharmaceutical composition comprises a formulation of a compound of simple liquid pirlidone or pyridone analog (or a salt thereof) having an osmotic ionic concentration between about 30 mM and about 300 mM, preferably between 50 mM and 200 mM. In one such embodiment, one or more of the osmotic ions in the composition are selected from the group consisting of chloride and bromide.

[0208] In another embodiment, the pharmaceutical composition comprises a compound formulation of a complex liquid pilaphenidone or a pyridone analog (or a salt thereof) encapsulated and complexed with a water-soluble excipient, such as lipids, liposomes, cyclodextrins, microencapsulation, and emulsions, having a solution osmotic pressure of from about 50 mOsmol / kg to about 6000 mOsmol / kg, as described above. In one embodiment, the osmotic pressure is from about 50 mOsmol / kg to about 1000 mOsmol / kg. In one embodiment, the osmotic pressure is from about 100 mOsmol / kg to about 500 mOsmol / kg. In one embodiment, the osmotic pressure is from about 400 mOsmol / kg to about 5000 mOsmol / kg.

[0209] In another embodiment, the pharmaceutical composition comprises a compound formulation of a complex liquid pilaphenidone or a pyridone analog (or a salt thereof) having an osmotic ion concentration of from about 30 mM to about 300 mM. In one such embodiment, one or more of the osmotic ions in the composition are selected from the group consisting of chloride and bromide.

[0210] In another embodiment, the pharmaceutical composition comprises a compound formulation of a complex liquid pilaphenidone or a pyridone analog (or a salt thereof) having an osmotic ion concentration of from about 50 mM to about 200 mM. In one such embodiment, one or more of the osmotic ions in the composition are selected from the group consisting of chloride and bromide.

[0211] In another embodiment, the pharmaceutical composition provided includes a formulation of a simple liquid of a compound of a compound of pirfenidone or a pyridone analog (or a salt thereof) having a molar ratio of pirfenidone or a pyridone analog to the positive charge of a polyvalent cation of about two pirfenidone or pyridone analog compounds to about 0.1 to about 4 of the positive charges of the polyvalent cation. By way of non-limiting example, two compounds of pirfenidone or a pyridone analog for one magnesium ion (two cation positive charges), three compounds of pirfenidone or a pyridone analog for one magnesium ion, four compounds of pirfenidone or a pyridone analog for one magnesium ion, and two compounds of pirfenidone or a pyridone analog for two magnesium ions.

[0212] An unexpected finding was that a divalent cation, by way of non-limiting example, magnesium, decreased the dissolution time of pirfenidone and increased the aqueous solubility of pirfenidone in a molar ratio-dependent manner. This increased saturated solubility enables the delivery of a predicted sufficient amount of inhaled liquid atomized pirfenidone to the lungs. By way of example, one pirfenidone molecule for three magnesium molecules showed a slower dissolution time and reduced saturated solubility than one pirfenidone molecule for one magnesium molecule. Further, one pirfenidone molecule for one magnesium molecule showed a faster dissolution time and greater aqueous solubility than the equimolar ratio of pirfenidone to sodium.

[0213] In another embodiment, the pharmaceutical composition is provided comprising a complex liquid formulation of a compound formulation of pirfenidone or a pyridone analog (or a salt thereof) having pirfenidone or a pyridone analog relative to the positive charge of a polyvalent cation of from about 0.1 to about 4. By way of non-limiting example, a compound of two pirfenidone or pyridone analogs relative to one magnesium ion (2 cation positive charges), a compound of three pirfenidone or pyridone analogs relative to one magnesium ion, a compound of four pirfenidone or pyridone analogs relative to one magnesium ion, and a compound of two pirfenidone or pyridone analogs relative to two magnesium ions.

[0214] In another embodiment, the pharmaceutical composition is provided comprising a complex liquid formulation of a compound formulation of pirfenidone or a pyridone analog (or a salt thereof) as a stable nano-suspension of low water solubility in a single, or complex of co-crystals / co-precipitates, or a mixture having a low solubility lipid such as a nano-suspension of lipid, having a solution osmotic pressure of from about 50 mOsmol / kg to about 6000 mOsmol / kg as described above. In one embodiment, the osmotic pressure is from about 100 mOsmol / kg to about 500 mOsmol / kg. In one embodiment, the osmotic pressure is from about 400 mOsmol / kg to about 5000 mOsmol / kg.

[0215] In another embodiment, the pharmaceutical composition is provided comprising a complex suspension of a compound formulation of pirfenidone or a pyridone analog (or a salt thereof) having an osmotic ion concentration of from about 30 mM to about 300 mM. In one such embodiment, one or more of the osmotic ions in the composition are selected from the group consisting of chloride and bromide.

[0216] In another embodiment, the pharmaceutical composition is provided comprising a complex suspension of a compound formulation of pifidone or a pyridone analog (or a salt thereof) having an osmotic ionic concentration from about 50 mM to about 200 mM. In one such embodiment, one or more of the osmotic ions in the composition are selected from the group consisting of chloride and bromide.

[0217] In another embodiment, the pharmaceutical composition is provided comprising a complex suspension of a compound formulation of pifidone or a pyridone analog (or a salt thereof) having a molar ratio of pifidone or pyridone analog to the positive charge of a polyvalent cation from about 1 pifidone or pyridone analog compound to about 0.1 to about 4 positive charges of the polyvalent cation. By way of non-limiting example, two pifidone or pyridone analog compounds for one magnesium ion (2 cation positive charges), three pifidone or pyridone analog compounds for one magnesium ion, four pifidone or pyridone analog compounds for one magnesium ion, and two pifidone or pyridone analog compounds for two magnesium ions.

[0218] In other embodiments, a compound formulation of pifidone or a pyridone analog (or a salt thereof) as provided herein, or a pharmaceutical composition, is provided comprising a flavoring agent. By way of non-limiting example, the flavoring agent may include sugar, saccharin (e.g., sodium saccharin), sweeteners, or other compounds or agents that beneficially affect taste, aftertaste, perceived unpleasant saltiness, sourness or bitterness, or that reduce the tendency of an oral or inhaled formulation to stimulate the recipient (e.g., by causing coughing or pharyngitis or other unwanted side effects such as may reduce the delivered dose or adversely affect compliance of a patient having a prescribed treatment regimen). Certain flavoring agents may form a complex with a compound of pifidone or a pyridone analog (or a salt thereof).

[0219] In certain preferred embodiments related to compound formulations of the pifidone or pyridone analog (or a salt thereof) disclosed herein, the formulation comprises a compound of pifidone or pyridone analog (or a salt thereof) and a flavoring agent and can be optimized with respect to a desired osmotic pressure and / or an optimized osmotic ion concentration. In certain such embodiments, the flavoring agent comprises saccharin (e.g., sodium saccharin), which, according to non-limiting theory, provides a desirable taste effect even when present at very low concentrations, such that it may have little or no effect on the detectable osmotic pressure of the solution, thereby providing certain advantages related to the ability of this flavoring agent to provide a desirable taste effect, whereby the formulations described herein can deliver aqueous solutions, organic formulations, or dry powder formulations in a highly resistant manner. In certain such embodiments, the flavoring agent comprises a chelating agent (e.g., a divalent cation such as EDTA or magnesium), which, according to non-limiting theory, provides certain advantages related to the ability of this flavoring agent to provide a desirable taste effect by masking chemical moieties that stimulate taste on the pifidone or pyridone analog. Together with the divalent cation, inclusion as a flavoring agent can also serve as a substitute as an osmotic pressure regulator, and by retaining the salt form, osmotic ions (e.g., magnesium chloride) can also be provided, whereby the formulations described herein can deliver aqueous solutions, organic formulations, or dry powder formulations in a highly resistant manner. Non-limiting examples of these and related embodiments include compound formulations of pifidone or pyridone analog (or a salt thereof) for pulmonary delivery as described herein, including aqueous solutions having a pH of from about 4 to about 8 and an osmotic pressure of from about 50 to about 1000 mOsmol / kg (e.g., adjusted with sodium chloride), the aqueous solution comprising a compound of pifidone or pyridone analog (or a salt thereof) and sodium saccharin, wherein the aqueous solution contains from about 0.1 mM to about 2.0 mM saccharin. Related non-limiting examples further include citrate (e.g., citric acid) in an aqueous solution containing from about 1 mM to about 100 mM citrate.Related non-limiting examples include further containing citrate or exchanging citrate with phosphate (e.g., sodium phosphate) in an aqueous solution containing from about 0.0 mM to about 100 mM of phosphate. Another related non-limiting example includes further containing citrate or exchanging citrate with phosphate (e.g., sodium phosphate) in an aqueous solution containing from about 0.5 mM to about 100 mM of phosphate. By another non-limiting example, these and related embodiments include an aqueous solution having a pH of from about 4 to about 8 and an osmotic pressure of from about 50 to about 5000 mOsmol / kg (adjusted, for example, with magnesium chloride), a compound formulation of pirfenidone or a pyridone analog (or a salt thereof) for pulmonary delivery as described herein, the aqueous solution containing a compound of pirfenidone or a pyridone analog (or a salt thereof), wherein a divalent cation (e.g., berilium, magnesium or calcium) functions to adjust the osmotic pressure and also as a flavoring agent. When included as a flavoring agent, the divalent cation (e.g., magnesium) is added stoichiometrically with pirfenidone or a pyridone analog. For example, 1 mol of divalent ion per 2 mol of pirfenidone or a pyridone analog, 1.5 mol of divalent ion per 2 mol of pirfenidone or a pyridone analog, 2 mol of divalent ion per 2 mol of pirfenidone or a pyridone analog, 3 mol of divalent ion per 2 mol of pirfenidone or a pyridone analog or 4 mol of divalent ion per 2 mol of pirfenidone or a pyridone analog. If it is necessary to further increase the osmotic pressure, sodium chloride or an additional divalent salt can be used. Related non-limiting examples include further containing citrate (e.g., citric acid) in an aqueous solution containing from about 1 mM to about 100 mM of citrate. The citrate of a related non-limiting example is exchanged with phosphate (e.g., sodium phosphate) in an aqueous solution containing from about 0.0 mM to about 100 mM of phosphate. The citrate of another related non-limiting example is exchanged with phosphate (e.g., sodium phosphate) in an aqueous solution containing from about 0.0 mM to about 100 mM of phosphate.

[0220] In another embodiment, by including an exact molar ratio of magnesium to pirfenidone, the dissolution time is reduced and the saturation solubility increases to a level necessary for sufficient nebulized delivery of liquid to the lungs. An unexpected finding was that this formulation further required a flavoring agent due to acute tolerance after inhalation of the nebulized solution. For this purpose, saccharin between 0.1 and 1.0 micromoles enables the use of formulations that allow this solubility.

[0221] In another embodiment, the pharmaceutical composition can be protected from light to avoid photodegradation. By way of non-limiting example, this can occur by light-protected vials, ampoules, blisters, capsules or other colored or light-protected primary packaging. By way of another non-limiting example, this can occur by the use of secondary packaging such as aluminum or other light-protected over-pouches, boxes or other secondary packaging.

[0222] In another embodiment, the pharmaceutical composition can be protected from oxygen to protect against oxidation. By way of non-limiting example, in solution, this can occur by removing oxygen from the solution before and / or during mixing (e.g., spraying), and / or by controlling the headspace gas of the primary packaging (e.g., use of an inert gas such as argon or nitrogen in the headspace). Similarly, by way of another non-limiting example, control of the contained secondary packaging gas (e.g., having an inert gas) may also be required. For powder formulations, this can be controlled by the use of an inserted gas in the primary and / or secondary packaging. Metered-dose inhaled products can benefit from the same means as described above for solution products.

[0223] In another embodiment, the pirfenidone or pyridone analog in the pharmaceutical composition can be protected from hydrolysis by including cationic metal ions. By way of non-limiting example, the acid hydrolysis of the amide bond decreases as the salt concentration increases. Specifically, the hydration number is important for this decrease in rate, because the hydration of the electrolyte decreases the availability of free water for the reaction. Thus, the rate decreases as the salt and the hydration number increase. The order of increasing hydration number is potassium < sodium < lithium < magnesium. The rate decrease is also approximately similar to the ionic strength. By way of non-limiting example, the addition of magnesium stabilizes the 2-pyridone structure of pirfenidone. Pirfenidone is known to chelate Fe(III) in a ratio of three pirfenidone molecules to 1 Fe(III). From this, pirfenidone will chelate magnesium with two pirfenidone molecules for 1 magnesium +2 charge. Thus, for this purpose, the addition of magnesium or other cationic metal ions can be in a fixed ratio to the amount of pirfenidone or pyridone analog.By way of non-limiting example, two pillphenidone molecules for 0.1 magnesium molecules, two pillphenidone molecules for 0.25 magnesium molecules, two pillphenidone molecules for 0.5 magnesium molecules, two pillphenidone molecules for 0.75 magnesium molecules, two pillphenidone molecules for one magnesium molecule, two pillphenidone molecules for 1.5 magnesium molecules, two pillphenidone molecules for two magnesium molecules, two pillphenidone molecules for three magnesium molecules, two pillphenidone molecules for four magnesium molecules, two pillphenidone molecules for five magnesium molecules, two pillphenidone molecules for six magnesium molecules, two pillphenidone molecules for seven magnesium molecules, two pillphenidone molecules for eight magnesium molecules, two pillphenidone molecules for nine magnesium molecules, two pillphenidone molecules for ten magnesium molecules, two pillphenidone molecules for twelve magnesium molecules, two pillphenidone molecules for fourteen magnesium molecules, two pillphenidone molecules for sixteen magnesium molecules, two pillphenidone molecules for eighteen magnesium molecules, or two pillphenidone molecules for twenty magnesium molecules. Potassium, sodium, lithium or iron can substitute for magnesium in these ratios and in the pharmaceutical composition. The above pharmaceutical composition includes the maintenance of the buffer solution described herein at a pH of from about 4.0 to about 8.0, and the buffer solution contains MgCl2 or its cation salt at a level that provides an osmotic pressure of 300 mOsmo / kg and 600 mOsmo / kg. 300 mOsmo / kg has been discussed in the literature as important for the acute tolerance after inhalation of this in the nebulized solution, while 600 mOsmo / kg has been shown in unpublished studies to be sufficiently tolerant with other pharmaceutical solutions. However, the osmotic pressure of the final solution up to 6000 mOsmo / kg is considered. Unexpectedly, the formulations described herein have demonstrated excellent tolerance at high osmotic pressures.

[0224] In another embodiment, a pharmaceutical composition of liquid pirfenidone or a pyridone analog may contain a solubility enhancer or co-solvent. By way of non-limiting examples, these may include ethanol, cetylpyridinium chloride, glycerin, lecithin, propylene glycol, polysorbates (including polysorbate 20, 40, 60, 80, and 85), sorbitan trioleate, and the like. By way of further examples, cetylpyridinium chloride may be used in pharmaceutical compositions from about 0.01 mg / mL to about 4 mg / mL. Similarly, by way of another non-limiting example, ethanol may be used in pharmaceutical compositions from about 0.01% to about 30%. Similarly, by way of another non-limiting example, glycerin may be used in pharmaceutical compositions from about 0.01% to about 25%. Similarly, by way of another non-limiting example, lecithin may be used in pharmaceutical compositions from about 0.01% to about 4%. Similarly, by way of another non-limiting example, propylene glycol may be used in pharmaceutical compositions from about 0.01% to about 30%. Similarly, by way of another non-limiting example, polysorbates may also be used in pharmaceutical compositions from about 0.01% to about 10%. Similarly, by way of another non-limiting example, sorbitan trioleate may be used in pharmaceutical compositions from about 0.01% to about 20%.

[0225] In another embodiment, a pharmaceutical composition of liquid or dry powder pirfenidone or a pyridone analog may contain chelated metal ions to assist in the solubility and / or dissolution of the pirfenidone or pyridone analog. By way of non-limiting examples, these may include iron, magnesium, or calcium.

[0226] In another embodiment, a pharmaceutical composition of a liquid or dry powder of pifenedone or a pyridone analog may contain chelated metal ions to assist in the removal of reactive oxygen species. By way of non-limiting example, these may include iron, magnesium, or calcium. By way of non-limiting example, for this purpose, the addition of metal ions of magnesium or other cations may be in a fixed ratio to the amount of pifenedone or pyridone analog. By way of non-limiting example, two pifenedone molecules per 0.1 magnesium molecule, two pifenedone molecules per 0.25 magnesium molecule, two pifenedone molecules per 0.5 magnesium molecule, two pifenedone molecules per 0.75 magnesium molecule, two pifenedone molecules per one magnesium molecule, two pifenedone molecules per 1.5 magnesium molecules, two pifenedone molecules per two magnesium molecules, two pifenedone molecules per three magnesium molecules, two pifenedone molecules per four magnesium molecules, two pifenedone molecules per five magnesium molecules, two pifenedone molecules per six magnesium molecules, two pifenedone molecules per seven magnesium molecules, two pifenedone molecules per eight magnesium molecules, two pifenedone molecules per nine magnesium molecules, two pifenedone molecules per ten magnesium molecules, two pifenedone molecules per twelve magnesium molecules, two pifenedone molecules per fourteen magnesium molecules, two pifenedone molecules per sixteen magnesium molecules, two pifenedone molecules per eighteen magnesium molecules, or two pifenedone molecules per twenty magnesium molecules. Potassium, sodium, lithium, or iron may substitute for magnesium in these ratios and in the pharmaceutical composition. The pharmaceutical composition described above includes the maintenance of a buffer as described herein at a pH from about 4.0 to about 8.0, the buffer including MgCl2 or its cationic salts at levels that provide osmotic pressures of 300 mOsmo / kg and 600 mOsmo / kg.300 mOsmo / kg has been discussed in the literature as important for this acute tolerance after inhalation in the atomized solution, while 600 mOsmo / kg has been shown in unpublished studies to be sufficiently tolerant with other pharmaceutical solutions. However, the osmotic pressure of the final solution up to 5000 mOsmo / kg is considered.

[0227] In some embodiments, the present specification describes a pharmaceutical composition comprising pirfenidone; water; a phosphate buffer or a citrate buffer; and optionally sodium chloride or magnesium chloride. In other embodiments, the present specification describes a pharmaceutical composition comprising pirfenidone; water; a buffer; and at least one additional component selected from sodium chloride, magnesium chloride, ethanol, propylene glycol, glycerol, polysorbate 80, and ethylpyridinium bromide chloride (or chloride). In some embodiments, the buffer is a phosphate buffer. In other embodiments, the buffer is a citrate buffer. In some embodiments, the pharmaceutical composition comprises from 1 mg to 500 mg of pirfenidone, such as 5 mg, 10 mg, 15 mg, 25 mg, 37.5 mg, 75 mg, 100 mg, 115 mg, 150 mg, 190 mg, 220 mg, or 500 mg of pirfenidone. In some embodiments, the osmotic pressure of the pharmaceutical composition described herein is between about 50 mOsmo / kg and 6000 mOsmo / kg. In some embodiments, the pharmaceutical composition optionally comprises saccharin (e.g., the sodium salt). Non-limiting examples of the pharmaceutical composition described herein include any one of the pharmaceutical compositions described in Tables 1-1 to 1-11 of Example 1.

[0228] The solution of pirfenidone should remain protected from light because the API in the solution is prone to decomposition.

[0229] In another embodiment, the pharmaceutical composition is provided in the form of a dry powder, with or without additives such as lactose, and contains solely a simple dry powder of pirfenidone or a compound of a pyridone analog (or a salt thereof).

[0230] In another embodiment, a pharmaceutical composition for use in a liquid, dry powder or metered dose inhaler is provided such that the pirfenidone or pyridone analog is not in salt form.

[0231] In another embodiment, the pharmaceutical composition, with or without additives such as lactose, is provided in a co-crystal / co-precipitate / spray dried composite or in a mixture with a low water solubility excipient / salt in dry powder form, comprising a compound formulation of a composite dry powder pirfenidone or pyridone analog (or a salt thereof).

[0232] In another embodiment, a system for administering a compound of pirfenidone or a pyridone analog (or a salt thereof) is provided, the system comprising a container containing a solution of a compound formulation of pirfenidone or a pyridone analog (or a salt thereof), and a nebulizer physically coupled to or packaged together with the container and suitable for generating an aerosol of the solution, having a particle size of mean mass aerodynamic diameter from about 1 micron to about 5 microns, volume median diameter (VMD) or mass median diameter (MMD) and a geometric standard deviation of particle size of mean mass aerodynamic diameter of about 2.5 microns or less. In one embodiment, the geometric standard deviation of particle size is about 3.0 microns or less. In one embodiment, the geometric standard deviation of particle size is about 2.0 microns or less.

[0233] In another embodiment, a system for administering a dry powder of a compound of pirfenidone or a pyridone analog (or a salt thereof) is provided, the system comprising a container containing the compound of pirfenidone or a pyridone analog (or a salt thereof), and a dry powder inhaler coupled to the container and suitable for generating a dispersed dry powder aerosol having an aerodynamic diameter of particle size with an average mass from about 1 micron to about 5 microns and a standard deviation of particle size of about 3.0 microns or less. In one embodiment, the standard deviation of the particle size is about 2.5 microns or less. In one embodiment, the standard deviation of the particle size is about 2.0 microns or less.

[0234] In another embodiment, the kit comprises a container containing a pharmaceutical formulation comprising a compound of pirfenidone or a pyridone analog (or a salt thereof), and an aerosolizer (e.g., in certain preferred embodiments, a liquid nebulizer) suitable for aerosolizing the pharmaceutical formulation and delivering it to the lower respiratory tract, such as to lung compartments such as alveoli, alveolar ducts and / or bronchioles, after administration in the mouth. The formulation can also be delivered as a dry powder or via a metered dose inhaler.

[0235] In another embodiment, the kit comprises a container containing a pharmaceutical formulation comprising a compound of pirfenidone or a pyridone analog (or a salt thereof), and an aerosolizer (e.g., in certain preferred embodiments, a liquid nebulizer) suitable for aerosolizing the pharmaceutical formulation and delivering it to the nasal cavity after administration in the nasal cavity. The formulation can also be delivered as a dry powder or via a metered dose inhaler.

[0236] It should be understood that many carriers and excipients can perform some functions even within the same formulation.

[0237] The contemplated pharmaceutical composition provides a therapeutically effective amount of a compound of pirfenidone or a pyridone analog that allows for administration, for example, once a day, twice a day, three times a day, etc. In some embodiments, the pharmaceutical composition for delivery by inhalation provides an effective amount of a compound of pirfenidone or a pyridone analog that allows for once-daily administration. In some embodiments, the pharmaceutical composition for delivery by inhalation provides an effective amount of a compound of pirfenidone or a pyridone analog that allows for twice-daily administration. In some embodiments, the pharmaceutical composition for delivery by inhalation provides an effective amount of a compound of pirfenidone or a pyridone analog that allows for three-times-daily administration.

[0238] It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.

[0239] <Specific technical terms> The term "mg" refers to milligram.

[0240] The term "mcg" refers to microgram.

[0241] The term "microM" refers to micromole.

[0242] The term "QD" refers to once-daily administration.

[0243] The term "BID" refers to twice-daily administration.

[0244] The term "TID" refers to three-times-daily administration.

[0245] The term "QID" refers to four-times-daily administration.

[0246] As used herein, the term "about" is used synonymously with the term "approximately". By way of illustration, the use of the term "about" with respect to a particular therapeutically effective dosage amount refers to that value which is slightly different from the recited value, e.g., ±0.1% to ±10% which is also effective and safe.

[0247] As used herein, the terms "comprising", "including", "such as", and "for example" are used in a broad, non-limiting sense.

[0248] The terms "administration" or "administering" and "delivery" or "delivering" refer to a method of giving a dosage of a therapeutic or prophylactic formulation, such as, for example, a pharmaceutical composition that is anti-inflammatory, anti-fibrotic and / or anti-demyelinating, or for other purposes, a compound formulation of the pirfenidone or pyridone analog (or a salt thereof) described herein, to a mammal. Preferred methods of delivery or administration can vary depending on various factors, such as the components of the pharmaceutical composition, the desired site where the formulation is introduced, delivered or administered, the site where a therapeutic effect is sought, or the proximity to the site of initial delivery to a downstream diseased organ (e.g., aerosol delivery to the lungs for absorption and second delivery to the heart, kidney, liver, central nervous system or other diseased location). In some embodiments, the pharmaceutical compositions described herein are administered by pulmonary administration.

[0249] The terms "pulmonary administration", "inhalatio", "pulmonary delivery", "oral inhalation", "intranasal inhalation" and other related terms refer to a method of administering a dosage of a therapeutic or prophylactic formulation, such as a compound formulation of pirfenidone or a pyridone analog (or a salt thereof) described herein, to a mammal by a route such that the desired therapeutic or prophylactic agent is delivered to the lungs of the mammal. Such delivery to the lungs can occur by intranasal administration, oral inhalation administration. Each of these administration routes can occur as an inhalation of an aerosol of the formulation described herein. In some embodiments, pulmonary administration occurs by passively delivering an aerosol described herein by a ventilator.

[0250] The terms "intranasal inhalation administration" and "intranasal inhalation delivery" refer to a method of administering a dosage of a therapeutic or prophylactic formulation, such as a compound formulation of pirfenidone or a pyridone analog (or a salt thereof) described herein, to a mammal by a route such that the formulation targets direct therapeutic formulation delivery and absorption in the lungs of the mammal through the nasal cavity. In some embodiments, intranasal inhalation administration is performed by a nebulizer.

[0251] The terms "intranasal administration" and "intranasal delivery" refer to a method of administering a dosage of a therapeutic or prophylactic formulation, such as a compound formulation of pirfenidone or a pyridone analog (or a salt thereof) described herein, to a mammal by a route such that the desired therapeutic or prophylactic agent is delivered to the nasal cavity or a downstream diseased organ (e.g., aerosol delivery to the nasal cavity for absorption and secondary delivery to the central nervous system or other diseased sites). Such delivery to the nasal cavity can occur by intranasal administration, where this route of administration can occur by inhalation of an aerosol of the formulation described herein, injection of an aerosol of the formulation described herein, enteral nutrition of the formulation described herein, or passive delivery by a ventilator.

[0252] The terms "intraoccular administration" and "intraoccular delivery" refer to a method of administering a dosage of a therapeutic or prophylactic formulation, such as a compound formulation of pirfenidone or a pyridone analog (or a salt thereof) described herein, to a mammal by a route such that the desired therapeutic or prophylactic agent is delivered to the eye. Such delivery to the eye can occur by direct administration to the eye. This route of administration can occur by spraying an aerosol of the formulation described herein, injecting an aerosol of the formulation described herein, or dropping the formulation described herein.

[0253] "Oral administration" or "orally" or "oral" is a route of administration by which a substance (e.g., a pharmaceutical composition) is obtained through the oral cavity. In some embodiments, when used without any further recitation, it refers to the direct administration of a substance through the oral cavity into the gastrointestinal tract. Oral administration generally includes many forms such as tablets, pills, capsules, and solutions.

[0254] The terms "oral inhalation administration" or "oral inhalation delivery" or "oral inhalation" refer to a method of administering a therapeutically or prophylactically effective amount of a compound formulation such as the pirfenidone or pyridone analog (or a salt thereof) described herein to a mammal through the oral cavity for direct delivery and absorption of the formulation into the lungs of the mammal. In some embodiments, oral inhalation administration is effected by use of a nebulizer.

[0255] The term "abnormal liver function" may manifest as abnormal at the level of biomarkers of liver function, including alanine transaminase, aspartate transaminase, bilirubin, and / or alkaline phosphatase, and may be an indicator of drug-induced liver injury. See FDA Draft Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation, October 2007.

[0256] "Grade 2 liver function abnormalities" include elevations of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), or gamma-glutamyltransferase (GGT) that are greater than 2.5 times and less than or equal to 5 times the upper limit of normal (ULN). Grade 2 liver function abnormalities also include elevations of bilirubin levels that are greater than 1.5 times and less than or equal to 3 times the ULN.

[0257] "Gastrointestinal adverse events" include, but are not limited to, any one or more of the following: dyspepsia, nausea, diarrhea, gastroesophageal reflux disease (GERD), and vomiting.

[0258] A "carrier" or "excipient" is a compound or substance used to facilitate the administration of a compound, for example, to increase the solubility of the compound. Solid carriers include, for example, starch, lactose, dicalcium phosphate, sucrose, and kaolin. Liquid carriers include, for example, sterile water, physiological saline, buffer solutions, nonionic surfactants, and oils, such as edible oils like peanut and sesame oil. Additionally, various adjuvants as commonly used in the art may be included. These and other such compounds are described in the literature, for example, Merck Index, Merck & Company, Rahway, NJ. Consideration of the inclusion of various components in pharmaceutical compositions is described, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.

[0259] "Diagnostic" as used herein is a compound, method, system or device that aids in the identification and characterization of the state of health or disease. A diagnostic can be used in standard assays as known in the art.

[0260] "Patient" or "subject" is used interchangeably and refers to a mammal.

[0261] The term "mammal" is used in its ordinary biological sense. In some embodiments, the mammal is a human.

[0262] The term "ex vivo" refers to an experiment or manipulation performed in or on a biological tissue in an artificial environment outside of an organism.

[0263] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in a therapeutic composition is contemplated. Supplementary active ingredients can also be incorporated into the composition.

[0264] The term "pharmaceutically acceptable salts" refers to salts that retain the biological effects and properties of the compounds of the present invention and are not biologically or otherwise undesirable. In many cases, the compounds of the present invention can form acids and / or base salts due to the presence of amino groups and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed by inorganic acids and organic acids. Inorganic acids from which the salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which the salts can be derived include, for example, acetic acid, propionic acid, naphthoic acid, oleic acid, palmitic acid, pamoic acid (embonic acid), stearic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, glucoheptonic acid, glucuronic acid, lactic acid, lactobionic acid, tartaric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed by inorganic bases and organic bases. Inorganic bases from which the salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, and particularly, ammonium, potassium, sodium, calcium, and magnesium salts are preferred. Organic bases from which the salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and particularly, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, histidine, arginine, lysine, benethamine, N-methyl-glucamine, and ethanolamine, and the like. Other acids include dodecylsufuric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, and saccharin.

[0265] The term "pH-reducing acid" refers to an acid that retains the biological effects and properties of the compounds of the present invention, which is not necessarily undesirable biologically or otherwise. Pharmaceutically acceptable pH-reducing acids include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. By way of non-limiting example, pH-reducing acids may also include organic acids such as citric acid, acetic acid, propionic acid, naphthoic acid, oleic acid, palmitic acid, pamoic acid (embonic acid), stearic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, glucopeptonic acid, glucuronic acid, lactic acid, lactobionic acid, tartaric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0266] According to certain embodiments disclosed herein, a compound formulation of pirfenidone or a pyridone analog may include an "acidic excipient" that is typically present as an aqueous solution of an acidic excipient. Examples include acid salts such as phosphates, sulfates, nitrates, acetates, formates, citrates, tartrates, propionates, and sorbates, organic acids such as carboxylic acids, sulfonic acids, phosphonic acids, phosphinic acids, phosphoric acid monoesters, and phosphoric acid diesters, and / or other organic acids including 1 to 12 carbon atoms, citric acid, acetic acid, formic acid, propionic acid, butyric acid, benzoic acid, monochloroacetic acid, dichloroacetic acid, and trichloroacetic acid, salicylic acid, trifluoroacetic acid, benzenesulfonic acid, toluenesulfonic acid, methylphosphonic acid, methylphosphinic acid, dimethylphosphinic acid, and phosphonic acid monobutyl ester.

[0267] "Buffer solution" refers to a compound that functions to adjust pH. In certain related embodiments, the pH buffer is present under conditions and in sufficient amounts to maintain a pH that is an "about" detailed pH value. Such an "about" pH refers to the functional presence of the buffer, which, as known in the art, can result from various factors including the pKa value of the buffer, buffer concentration, processing temperature, the effect of other components of the composition on the pKa (i.e., the pH at which the buffer is in an equilibrium state between its protonated and deprotonated forms, typically the center of the effective buffering range of the pH value), and other factors.

[0268] Thus, "about" in the context of pH can be understood to represent a quantitative variation in pH that can be greater than or less than the detailed value by up to 0.5 pH units or less, more preferably up to 0.4 pH units or less, more preferably up to 0.3 pH units or less, even more preferably up to 0.2 pH units or less, and most preferably up to 0.1 - 0.15 pH units or less. As shown above, in certain embodiments, a substantially constant pH (e.g., a pH maintained within the detailed range for an extended period) can be from about pH 4.0 to about pH 8.0, from about pH 4.0 to about pH 7.0, or from about pH 4.0 to about pH 6.8, or any other pH or pH range as described herein, which in a preferred embodiment can be from about pH 4.0 to about pH 8.0 for a compound formulation of pirlfenidone or a pyridone analog, and can be greater than pH 8.0 for an aqueous solution of a compound of pirlfenidone or a pyridone analog.

[0269] Therefore, a pH buffer is typically a composition that can maintain a desired pH level such that it can be selected by one of ordinary skill in the art when present under appropriate conditions and in sufficient amounts, for example, citrate, formate, malate, formate, pyridine, piperazine, succinate, histidine, maleate, bis-tris, pyrophosphate, PIPES, ACES, histidine, MES, cacodylic acid, H2CO3 / NaHCO3, and buffers containing N-(2-acetamido)-2-imino diacetic acid (ADA), or other buffers for maintaining, preserving, enhancing, protecting, or promoting the desired biological or pharmacological activity of a compound of pirlfenidone or a pyridone analog, based on the disclosure herein. Suitable buffers can include those in Table 1 or known in the art (see, e.g., Calbiochem® Biochemicals & Immunochemicals Catalog 2004 / 2005, pp. 68-69 and the catalog pages cited therein, EMD Biosciences, La Jolla, CA).

[0270] Non-limiting examples of buffers that can be used in accordance with certain embodiments disclosed herein include, but are not limited to, formate (pKa 3.77), citrate (pKa2 4.76), malate (pKa2 5.13), pyridine (pKa 5.23), piperazine ((pKa1) 5.33), succinate ((pKa2) 5.64), histidine (pKa 6.04), maleate ((pKa2) 6.24), citrate ((pKa3) 6.40), bis-tris (pKa 6.46), pyrophosphate ((pKa3) 6.70), PIPES (pKa 6.76), ACES (pKa 6.78), histidine (pKa 6.80), MES (pKa 6.15), cacodylic acid (pKa 6.27), H2CO3 / NaHCO3 (pKa1) (6.37), ADA (N-(2-acetamido)-2-imino diacetic acid) (pKa 6.60). In some embodiments, the pharmaceutical compositions disclosed herein comprise a citrate buffer or a phosphate buffer. In some embodiments, the pharmaceutical compositions disclosed herein comprise a citrate buffer. In some embodiments, the pharmaceutical compositions disclosed herein comprise a phosphate buffer.

[0271] "Solvate" refers to a compound formed by the interaction of a solvent with a compound, metabolite, or salt thereof of pirlfenidone or a pyridone analog. Suitable solvates are pharmaceutically acceptable solvates, including hydrates.

[0272] By "therapeutically effective amount" or "pharmaceutically effective amount" is meant those amounts of a compound of pirfenidone or a pyridone analog as disclosed herein with a therapeutic effect. The dosage of a compound of pirfenidone or a pyridone analog useful in treatment is a therapeutically effective amount. Thus, as used herein, a therapeutically effective amount is that amount of a compound of pirfenidone or a pyridone analog that produces the desired therapeutic effect as determined by clinical trial results and / or in model animals for pulmonary fibrosis, cardiac fibrosis, renal fibrosis, hepatic fibrosis, cardiac or renal toxicity, multiple sclerosis, COPD or asthma. In a specific embodiment, a compound of pirfenidone or a pyridone analog is administered in a predetermined dosage, and thus, the therapeutically effective amount is the amount of the dosage administered. This amount and the amount of the compound of pirfenidone or a pyridone analog can be routinely determined by one of ordinary skill in the art and depends on various factors such as whether a therapeutic or prophylactic effect against fibrotic, inflammatory, demyelinating lesions results, and how far the site of the disease is from the site of the first breath receiving the initially inhaled aerosol dosage. This amount further depends on the patient's height, weight, sex, age and medical history. For prophylactic treatment, a therapeutically effective amount is an amount that will be effective to prevent fibrotic, inflammatory or demyelinating injury.

[0273] "Therapeutic effect" reduces, to some extent, one or more of the symptoms related to inflammation, fibrosis and / or demyelination. This includes delaying, preventing or reducing the progression of further inflammation, fibrosis and / or demyelination. For IPF, "therapeutic effect" is defined as an improvement in quality of life reported by the patient and / or a statistically significant increase or stabilization of exercise stress test and related blood oxygen saturation, a decrease in the decline of baseline forced vital capacity, a decrease in the incidence of acute exacerbation, an increase in progression-free survival, an increase in time-to-death or improvement of the disease, and / or a decrease in pulmonary fibrosis. For cardiac fibrosis, "therapeutic effect" is defined as an improvement in quality of life reported by the patient and / or a statistically significant improvement in cardiac function, a decrease in fibrosis, a reduction in cardiac stiffness, a reduction or reversal of valvular stenosis, a decrease in the incidence of arrhythmia, and / or a reduction in atrial or ventricular remodeling. For renal fibrosis, "therapeutic effect" is defined as an improvement in quality of life reported by the patient and / or a statistically significant improvement in glomerular filtration rate and related markers. For liver fibrosis, "therapeutic effect" is defined as an improvement in quality of life reported by the patient and / or a statistically significant decrease in the elevation of aminotransferases (e.g., AST and ALT), alkaline phosphatase, gamma-glutamyl transferase, bilirubin, prothrombin time, globulin, in addition to reversal of thrombocytopenia, leukopenia and neutropenia and coagulation disorders. Furthermore, potential reversal of imaging, endoscopic or other pathological findings. For COPD, "therapeutic effect" is defined as an improvement in quality of life reported by the patient and / or a statistically significant improvement in exercise capacity and related blood oxygen saturation, FEV1 and / or FVC, similarly, a delay or halt in the progression of progression-free survival, an increase in lifespan or improvement of the disease, and / or a decrease in the incidence of acute exacerbation. For asthma, "therapeutic effect" is defined as an improvement in quality of life reported by the patient and / or a statistically significant improvement in exercise capacity, improvement of FEV1 and / or FVC, and / or a decrease in the incidence of acute exacerbation.Regarding multiple sclerosis, "treatment effect" is defined as an improvement in quality of life reported by the patient and / or a statistically significant improvement in the Scripps Neurological Rating Scale score, improvement in bladder dysfunction, improvement in Disability Status Socres, MRI lesion count, and / or delay or arrest of disease progression.

[0274] "Treat", "treatment", or "treating", as used herein, refers to administering a pharmaceutical composition for therapeutic purposes. In some embodiments, treating refers to reducing, alleviating, or improving at least one symptom of a disease or disorder, preventing any additional symptoms from occurring, arresting the progression of at least one current symptom of a disease or disorder, removing at least one symptom of a disease or disorder, causing regression of a disease or disorder, removing a disease caused by a disease or disorder, or arresting the symptoms of a disease or disorder. In some embodiments, the compositions described herein are used for prophylactic treatment. The term "prophylactic treatment" refers to treating patients who are not yet ill but are susceptible to or at risk of a particular disease or who are ill but whose symptoms do not worsen while being treated with the pharmaceutical compositions described herein. The term "therapeutic treatment" refers to treating patients who are already suffering from a disease. Thus, in a preferred embodiment, treating is the administration to a mammal of a therapeutically effective amount of a compound of pifenedone or a pyridone analog (for therapeutic or prophylactic purposes).

[0275] "To treat", "treatment", or "treating" as used herein refers to administering a pharmaceutical composition for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a patient who has not yet developed a disease but is susceptible to or at risk of a particular disease. The term "therapeutic treatment" refers to treating a patient who is already suffering from a disease. Thus, in preferred embodiments, treating comprises administering to a mammal a therapeutically effective amount of a compound of pirfenidone or a pyridone analog for therapeutic or prophylactic purposes.

[0276] The term "dosing interval" refers to the time between administrations of two consecutive doses of a pharmaceutical in a plurality of dosing regimens.

[0277] "Respirable delivered dose" is the amount of aerosolized particles of a compound of pirfenidone or a pyridone analog that are inhaled in the inspiratory phase of a respiratory simulator that are 5 microns or less.

[0278] "Lung deposition" as used herein refers to a small nominal dose of an active pharmaceutical ingredient (API) that deposits on the inner surface of the lungs.

[0279] "Nominal dose", or "loaded dose" refers to the amount of drug that is placed in a nebulizer prior to administration to a mammal. The amount of solution containing the nominal dose is referred to as the "fill volume".

[0280] "Enhanced pharmacokinetic properties" means an improvement in several pharmacokinetic parameters. Pharmacokinetic parameters that can be improved are AUC last 、AUC (0-∞)、 T max 、and optionally C maxIt includes. In some embodiments, the enhanced pharmacokinetic properties can be quantitatively measured by comparing the pharmacokinetic parameters obtained for a nominal dose of an active pharmaceutical ingredient (API) administered by one type of inhaler device with the same pharmacokinetic parameters obtained by oral administration of a composition of the same active pharmaceutical ingredient (API).

[0281] "Plasma concentration" refers to the concentration of an active pharmaceutical ingredient in the plasma component of the blood of a subject or patient population.

[0282] "Respiratory disease" as used herein refers to a disease or disorder that is physically manifest in the airways, including but not limited to pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), bronchitis, chronic bronchitis, emphysema, or asthma.

[0283] "Nebulizer" as used herein refers to a device that converts a medicine, composition, formulation, suspension, and mixture, etc. into a mist or aerosol for delivery to the lungs. A nebulizer can also be referred to as an atomizer.

[0284] "Drug absorption" or simply "absorption" typically refers to the process of drug movement from the site of delivery of a drug (e.g., a drug being absorbed in the alveolar pulmonary capillary bed) across a barrier to a blood vessel or site of action.

[0285] <Pirfenidone and pyridone analog compounds> As also shown elsewhere herein, in preferred embodiments, the pyridone compounds for use in the formulations of pyridone compounds as described herein include pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) or a salt thereof. Although various embodiments are described with the use of pirfenidone, it is noted that other pyridone analog compounds, or salts thereof, can be used in place of pirfenidone.

[0286] Pirfenidone is also known as 5-methyl-1-phenyl-2-(1H)-pyridone and has the following structure:

[0287]

Chemical formula

[0288] "Pyridone analog" or "pyridone compound" refers to a compound having the same type of biological activity and effectiveness as pirfenidone. Such pyridone analog compounds are compounds that, after administration to a mammal, provide anti-inflammatory, anti-fibrotic and / or demyelinating activity for therapeutic or prophylactic purposes. In some embodiments, the pyridone analog is a compound having a core structure of a substituted 2-(1H) pyridone or 3-(1H) pyridone. In some embodiments, the pyridone analog is a compound having a core structure of a substituted 2-(2h) pyridone.

[0289] 1-Phenyl-2-(1H)pyridone, 5-methyl-1-(4-methylphenyl)-2-(1h)-pyridone, 5-methyl-1-(4-hydroxyphenyl)-2-(1H)-pyridone, 5-methyl-1-(4-methoxyphenyl)-2-(1H)-pyridone, 5-methyl-1-(2’-pyridyl)-2-(1H)pyridone, 6-methyl-1-phenyl-3-(1H)pyridone, 6-methyl-1-phenyl-2-(1H)pyridone, 5-methyl-1-p-tolyl-3-(1H)pyridone, 5-methyl-3-phenyl-1-(2’-thienyl)-2-(1H)pyridone, 5-methyl-1-(2’-naphthyl)-3-(1H)pyridone, 5-methyl-1-(2’-naphthyl)-2-(1H)pyridone, 5-methyl-1-phenyl-3-(1H)pyridone, 5-methyl-1-p-tolyl-2-(1H)pyridone, 5-methyl-1-(1’-naphthyl)-2-(1H)pyridone, 5-methyl-1-(5’-quinolyl)-3-(1H)pyridone, 5-ethyl-1-phenyl-2-(1H)pyridone, 5-ethyl-1-phenyl-3-(1H)pyridone, 5-methyl-1-(5’-quinolyl)-2-(1H)pyridone, 5-methyl-1-(4’-methoxyphenyl)-3-(1H)pyridone, 5-methyl-1-(4’-quinolyl)-2-(1H)pyridone, 4-methyl-1-phenyl-3-(1H)pyridone, 5-methyl-1-(4’-pyridyl)-2-(1H)pyridone, 5-methyl-1-(3’-pyridyl)-3-(1H)pyridone, 3-methyl-1-phenyl-2-(1H)pyridone, 5-methyl-1-(4’-methoxyphenyl)-2-(1H)pyridone, 5-methyl-1-(2’-thienyl)-3-(1H)pyridone, 5-methyl-1-(2’-pyridyl)-3-(1H)pyridone, 1,3-diphenyl-2-(1H)pyridone, 1,3-Diphenyl-5-methyl-2-(1H)pyridone, 5-methyl-1-(2'-quinolyl)-3-(1H)pyridone, 5-methyl-1-(3'-trifluoromethylphenyl)-2-(1H)pyridone, 1-phenyl-3-(1H)pyridone, 1-(2'-furyl)-5-methyl-3-(1H)-pyridone, 3-ethyl-1-phenyl-2-(1H)pyridone, 1-(4'-chlorophenyl)-5-methyl(1H)pyridone, 5-methyl-1-(3'-pyridyl)-2-3-(1H)pyridone, 5-methyl-1-(3-nitrophenyl)-2-(1H)pyridone, 3-(4'-chlorophenyl)-5-methyl-1-phenyl-2-(1H)pyridone, 5-methyl-1-(2'-thienyl)-2-(1H)pyridone, 5-methyl-1-(2'-thiazolyl)-2-(1H)pyridone, 3,6-dimethyl-1-phenyl-2-(1H)pyridone, 1-(4'chlorophenyl)-5-methyl-2-(1H)pyridone, 1-(2'-imidazolyl)-5-methyl-2-(1H)pyridone, 1-(4'-nitrophenyl)-2-(1H)pyridone, 1-(2'-furyl)-5-methyl-2-(1H)pyridone, 1-phenyl-3-(4'-chlorophenyl)-2-(1H)pyridone.,

[0290] In some embodiments, the pyridone analog compound is a compound described in U.S. Patent Publication No. US20090005424; U.S. Patent Publication No. 20070092488; U.S. Patent No. 8,022,087; U.S. Patent No. 6,090,822; U.S. Patent No. 5,716,632; U.S. Patent No. 5,518,729; U.S. Patent No. 5,310,562; U.S. Patent No. 4,052,509; U.S. Patent No. 4,042,699; U.S. Patent No. 3,839,346; or U.S. Patent No. 3,974,281.

[0291] In some embodiments, the pyridone analog is a deuterated pirfenidone compound in which one or more hydrogen atoms of pirfenidone are replaced with deuterium.

[0292] By certain other different embodiments of the compositions and methods described herein, the pyridone compounds are bis(2-hydroxyethyl)azanium; 2-(3,5-diiodo-4-oxopyridin-1-yl)acetic acid, propyl 2-(3,5-diiodo-4-oxopyridin-1-yl)acetate, 2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl][1,2,4]triazolo[4,3-a]pyridin-3-one hydrochloride, 2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one, 3-anilin-1-phenylpropan-1-one, 2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one hydrochloride, 2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3a]pyridin-3-one, (2S)-2-amino-3-(3-hydroxy-4-oxopyridin-1-yl)propanoic acid, 2-[3-[4(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one, 2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one hydrochloride, 2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one hydrochloride, (2S)-2-[(3-hydroxy-4-oxopyridin-1-yl)amino]propanoic acid, 2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one hydrochloride, 2-amino-3-(3-hydroxy-4-oxopyridin-1-yl)propanoic acid, 2-[3-[4-(3chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one hydrochloride, propyl 2-(3,5-diiodo-4-oxopyridin-1-yl)acetate, 2-(3,5-Iodo-4-oxopyridin-1-yl)acetic acid; 2-(2-hydroxyethylamino)ethanol, (2S)-2-amino-3-(3-hydroxy-4-oxopyridin-1-yl)propanoic acid, (2R)-2-amino-3-(3-hydroxy-4-oxopyridin-1-yl)propanoic acid, 2-amino-3-(3-hydroxy-4-oxopyridin-1-yl)propanoic acid, 5-cyano-6-methyl-N-[4(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 6-methyl-N-[4-(methylsulfonyl)benzyl]-5-nitro-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-(1-butoxyvinyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-acetyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-[(1E)-N-methoxyethanimidoyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-[(1E)-N-hydroxyethanimidoyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(pyridin-3-ylethynyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(2-pyridin-3-ylethynyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-5-vinyl-1,2-Dihydropyridine-3-carboxamide, ethyl 2-methyl-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydropyridine-3-carboxylate, 5-(4-methanesulfonyl-benzylcarbamoyl)-2-methyl-6-oxo-1-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-3-carboxylic acid, 6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 5-dimethylamide 3-(4-methanesulfonyl-benzylamide), 6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 5-amide 3-(4-methanesulfonyl-benzylamide), 6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 3-(4-methanesulfonyl-benzylamide) 5-methylamide, 6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 5-[(2-hydroxy-ethyl)-methyl-amide] 3-(4-methanesulfonyl-benzylamide), 6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 3-(4-methanesulfonyl-benzylamide) 5-(methyl-propyl-amide), 6-methyl-2-oxo-5-(pyrrolidine-1-carbonyl)-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 3-(4-methanesulfonyl-benzylamide), 6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 5-[(2-dimethylamino-ethyl)-methyl-amide] 3-(4-methanesulfonyl-benzylamide), 5-((2R)-2-hydroxymethyl-pyrrolidine-1-carbonyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-Dihydro-pyridine-3-carboxylic acid 3-(4-methanesulfonyl-benzylamide), 5-(3-hydroxy-pyrrolidine-1-carbonyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 3-(4-methanesulfonyl-benzylamide), N, 3 -[(1,1-dioxide-2,3-dihydro-1-benzothien-5-yl)methyl]-N 5 、N 5 ,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, 5-(N 1 -acetyl-hydrazinocarbonyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide, 5-[N 1-[-(2-Cyano-acetyl)-hydrazinocarbonyl]-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide, 5-{[2-(aminocarbonothioyl)hydrazino]carbonyl}-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-hydrazinocarbonyl-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide, 5-({2-[(ethylamino)carbonyl]hydrazino}carbonyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-({2-[(N,N-dimethylamino)carbonyl]hydrazino}carbonyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-(3,3-dimethyl-ureido)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide, 6-methyl-5-(3-methyl-ureido)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide, 6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-5-ureido-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide, 5-amino-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide, 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-propionyl-1-[3-(trifluoromethyl)phenyl]-1,2-Dihydropyridine-3-carboxamide, 5-formyl-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(3-oxobutyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-acetyl-N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-acetyl-1-(3-cyano-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide, 5-acetyl-1-(3-chloro-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide, 5-acetyl-6-methyl-2-oxo-1-m-tolyl-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide, 5-(1-hydroxyethyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-(1-azidoethyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 6-methyl-N-[4-(methylsulfonyl)benzyl]-5-(1-morpholin-4-ylethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-(1-hydroxypropyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-(1-hydroxyethyl)-N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid, Levobroxamide, N-[4-(Cyclopropylsulfonyl)benzyl]-5-formyl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-[(E)-(Methoxyimino)methyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-(Hydroxymethyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-[(Dimethylamino)methyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 6-methyl-5-[(methylamino)methyl]-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 6-methyl-N-[4-(methylsulfonyl)benzyl]-5-(morpholin-4-ylmethyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-{[(2-Furylmethyl)amino]methyl}-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-[(Cyclopropylamino)methyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-{[(2-Hydroxypropyl)amino]methyl}-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-[(Cyclopentylamino)methyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-Dihydropyridine-3-carboxamide, 5-{[(2-hydroxyethyl)(methyl)amino]methyl}-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(pyrrolidin-1-ylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-{[methoxy(methyl)amino]methyl}-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-{[(cyanomethyl)amino]methyl}-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-{[(cyclopropylmethyl)amino]methyl}-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-[(3-hydroxypyrrolidin-1-yl)methyl]-6-methyl-N―[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-(2-hydroxyethoxy)-N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 2-methyl-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydropyridine-3-ylacetic acid, 5-methoxy-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-(3-methoxypropoxy)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-Dihydropyridine-3-carboxamide, 2-methyl-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydropyridine-3-yl methanesulfonic acid, 5-ethoxy-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(...

Claims

**Claim 1** An aqueous solution for nebulized inhalation administration comprising water, a compound of pirlfenidone or a pyridone analog at a concentration of from about 0.1 mg / mL to about 60 mg / mL, and one or more co-solvents, wherein the osmotic pressure of the aqueous solution is from about 50 mOsmol / kg to about 6000 mOsmol / kg. **Claim 2** The aqueous solution according to claim 1, wherein the one or more co-solvents are selected from ethanol, propylene glycol, and glycerol. **Claim 3** The aqueous solution according to claim 1 or 2, further comprising one or more additional components selected from surfactants, buffers, and salts. **Claim 4** The surfactant is polysorbate 80 or cetylpyridinium bromide, the buffer is a citrate buffer or a phosphate buffer, and, the salt is sodium chloride or magnesium chloride, for the aqueous solution according to claim 3. **Claim 5** The aqueous solution comprises water, a compound of pirlfenidone or a pyridone analog at a concentration of from about 10 mg / mL to about 60 mg / mL, one or more co-solvents, wherein the total amount of the one or more co-solvents is from about 1% v / v to about 40% v / v, and the one or more co-solvents are selected from ethanol at from about 1% v / v to about 25% v / v, propylene glycol at from about 1% v / v to about 25% v / v, and glycerol at from about 1% v / v to about 25% v / v, optionally, the aqueous solution further comprises a phosphate buffer that maintains the pH of the solution at from pH about 6.0 to pH about 8.0, for the aqueous solution according to claim 1. **Claim 6** The aqueous solution comprises water, a compound of pirlfenidone or a pyridone analog at a concentration of from about 15 mg / mL to about 50 mg / mL, one or more co-solvents, wherein the total amount of the one or more co-solvents is from about 1% v / v to about 30% v / v, and the one or more co-solvents are selected from ethanol at from about 1% v / v to about 10% v / v and propylene glycol at from about 1% v / v to about 20% v / v, optionally, the aqueous solution further comprises a phosphate buffer that maintains the pH of the solution at from pH about 6.0 to pH about 8.0, wherein the osmotic pressure of the aqueous solution is from about 400 mOsmol / kg to about 6000 mOsmol / kg, for the aqueous solution according to claim 1. **Claim 7** A unit dose suitable for use in a liquid nebulizer, comprising an aqueous solution of from about 0.5 mL to about 6 mL of a compound of pirlfenidone or a pyridone analog, wherein the concentration of the compound of pirlfenidone or a pyridone analog in the aqueous solution is from about 0.1 mg / mL to about 60 mg / mL, characterized by the unit dose. **Claim 8** The aqueous solution further comprises one or more additional components selected from co-solvents, isotonic agents, sweeteners, surfactants, wetting agents, chelating agents, antioxidants, salts, and buffers, wherein the osmotic pressure of the aqueous solution is from about 50 mOsmol / kg to about 6000 mOsmol / kg, characterized by the unit dose according to claim 7. **Claim 9** The aqueous solution further comprises one or more co-solvents selected from ethanol, propylene glycol, and glycerol, and one or both of a citrate buffer or a phosphate buffer, characterized by the unit dose according to claim 7. **Claim 10** The aqueous solution is water, a compound of pirlfenidone or a pyridone analog at a concentration of from about 15 mg / mL to about 50 mg / mL, comprises one or more co-solvents, wherein the total amount of the one or more co-solvents is from about 1% v / v to about 30% v / v, and the one or more co-solvents are selected from ethanol at from about 1% v / v to about 10% v / v and propylene glycol at from about 1% v / v to about 20% v / v, optionally, the aqueous solution comprises a phosphate buffer that maintains the pH of the solution at from about pH 6.0 to about pH 8.0, wherein the osmotic pressure of the aqueous solution is from about 400 mOsmol / kg to about 6000 mOsmol / kg, characterized by the unit dose according to claim 7. **Claim 11** A kit comprising the unit dose according to any one of claims 7 - 10 in a container suitable for use in a liquid nebulizer. **Claim 12** An aqueous aerosol comprising a plurality of water droplets of a compound of pirlfenidone or a pyridone analog, wherein the plurality of water droplets have a volume median diameter (VMD), an aerodynamic mass median diameter (MMAD), and / or a mass median diameter (MMD) of less than about 5.0 μm, characterized by the aqueous aerosol. **Claim 13** The plurality of water droplets are produced from a liquid nebulizer and an aqueous solution of a compound of pirlfenidone or a pyridone analog, characterized by the aqueous aerosol according to claim 12. **Claim 14** The aqueous solution has a concentration of about 10 mg / mL to about 60 mg / mL of a compound of pirlfenidone or a pyridone analog and an osmotic pressure of from about 50 mOsmol / kg to about 6000 mOsmol / kg, the aqueous aerosol according to claim 13, characterized in that.

15. At least 30% of the water droplets in the aerosol have a diameter of less than about 5 μm, the aqueous aerosol according to claim 12, characterized in that.

16. The aqueous aerosol is produced by spraying the aqueous solution according to any one of claims 1-6 using a liquid nebulizer, the aqueous aerosol according to claim 12, characterized in that.

17. A method for treating a pulmonary disease in a mammal, Said method is, Comprising the step of administering an aqueous solution containing a compound of pirlfenidone or a pyridone analog to a mammal in need thereof using a liquid nebulizer, The aqueous solution contains water, a compound of pirlfenidone or a pyridone analog at a concentration of from about 0.1 mg / mL to about 60 mg / mL, and one or more co-solvents, and the osmotic pressure of the aqueous solution is from about 50 mOsmol / kg to about 6000 mOsmol / kg, a method characterized in that.

18. The aqueous solution contains water, a compound of pirlfenidone or a pyridone analog at a concentration of from about 10 mg / mL to about 60 mg / mL, and one or more co-solvents, wherein the total amount of the one or more co-solvents is from about 1% v / v to about 40% v / v, and the one or more co-solvents are selected from about 1% v / v to about 25% v / v ethanol, about 1% v / v to about 25% v / v propylene glycol, or about 1% v / v to about 25% v / v glycerol, and the aqueous solution optionally contains a phosphate buffer that maintains the pH of the aqueous solution at pH about 6.0 to pH about 8.0, the method according to claim 17, characterized in that.

19. The aqueous solution contains water, a compound of pirlfenidone or a pyridone analog at a concentration from about 15 mg / mL to about 50 mg / mL, and one or more co-solvents, where the total amount of the one or more co-solvents is from about 1% v / v to about 30% v / v, and the one or more co-solvents are selected from ethanol at from about 1% v / v to about 10% v / v, or propylene glycol at from about 1% v / v to about 20% v / v. The aqueous solution optionally contains a phosphate buffer to maintain the pH of the aqueous solution at from about pH 6.0 to about pH 8.0, where the osmotic pressure of the aqueous solution is from about 400 mOsmol / kg to about 6000 mOsmol / kg. The method according to claim 17, characterized by the above.

20. The nebulizer is a jet nebulizer, an ultrasonic nebulizer, a flutter membrane type nebulizer, a nebulizer including a vibrating mesh or plate with many holes, or a nebulizer including a vibration generator and an aqueous chamber. The method according to any one of claims 17 - 19, characterized by the above.

21. The liquid nebulizer (i) achieves at least 7% lung deposition of the compound of pirlfenidone or a pyridone analog administered to a mammal, (ii) provides a geometric standard deviation (GSD) of the droplet size distribution of the aqueous solution released from about 1.0 μm to about 2.5 μm, (iii) a) an aerodynamic mass median diameter (MMAD) of the droplet size of the aqueous solution released by a high-efficiency liquid nebulizer from about 1 μm to about 5 μm, b) a volume median diameter (VMD) from about 1 μm to about 5 μm, and / or c) a mass median diameter (MMD) from about 1 μm to about 5 μm, (iv) provides at least about 30% fine particle fraction (FPF = % ≤ 5 microns) of the droplets released from the liquid nebulizer, (v) provides an output rate of at least 0.1 mL / min, and / or (vi) administers at least about 25% of the aqueous solution to a mammal. The method according to any one of claims 17 - 19, characterized by the above.

22. The lung disease is pulmonary fibrosis, and the mammal is a human. The method according to claim 17, characterized by the above.

23. The lung disease is idiopathic pulmonary fibrosis, and the mammal is a human. The method according to claim 17, characterized by the above.

24. The method according to claim 17, wherein the liquid nebulizer delivers a compound of pirfenidone or a pyridone analog in an amount from about 0.1 mg to about 360 mg to the lungs of a mammal at a mass median aerodynamic diameter (MMAD) particle size from about 1 micron to about 5 microns in less than about 20 minutes. **Claim 25** (I) The Cmax and / or AUC of the compound of pirfenidone or a pyridone analog in lung tissue obtained after a single administration of an aqueous solution to a mammal using a liquid nebulizer is approximately the same as, or greater than, the Cmax and / or AUC of the compound of pirfenidone or a pyridone analog in lung tissue obtained after a single oral administration of the compound of pirfenidone or a pyridone analog at a dose that is about 80% to about 120% of the dose administered using the liquid nebulizer, and / or (II) The Cmax and / or AUC of the compound of pirfenidone or a pyridone analog in plasma obtained after a single administration of an aqueous solution to a mammal using a liquid nebulizer is at least 10% of, or higher than, the Cmax and / or AUC of the compound of pirfenidone or a pyridone analog in plasma obtained after a single oral administration of the compound of pirfenidone or a pyridone analog at a dose that is about 80% to about 120% of the dose administered using the liquid nebulizer, the method according to claim 17. **Claim 26** The method according to claim 17, wherein administration using a liquid nebulizer does not include an initial dose titration period. **Claim 27** A method for reducing the risk of gastrointestinal (GI) adverse events in the treatment of humans with a compound of pirfenidone or a pyridone analog, wherein the method comprises administering to a human a nebulized aqueous solution comprising a pirfenidone human or a pyridone analog compound using a liquid nebulizer, wherein the aqueous solution comprises water, a compound of pirfenidone or a pyridone analog at a concentration from about 0.1 mg / mL to about 60 mg / mL, and one or more co-solvents, and the osmotic pressure of the aqueous solution is from about 50 mOsmol / kg to about 6000 mOsmol / kg. **Claim 28** The aqueous solution contains water, a compound of pirfenidone or a pyridone analog at a concentration from about 10 mg / mL to about 60 mg / mL, and one or more co-solvents, wherein the total amount of the one or more co-solvents is from about 1% v / v to about 40% v / v, and the one or more co-solvents are selected from about 1% v / v to about 25% v / v ethanol, about 1% v / v to about 25% v / v propylene glycol, or about 1% v / v to about 25% v / v glycerol, and the aqueous solution optionally contains a phosphate buffer that maintains the pH of the aqueous solution from pH about 6.0 to pH about 8.0, The method according to claim 27, characterized in that.

29. The aqueous solution contains water, a compound of pirfenidone or a pyridone analog at a concentration from about 15 mg / mL to about 50 mg / mL, and one or more co-solvents, wherein the total amount of the one or more co-solvents is from about 1% v / v to about 30% v / v, and the one or more co-solvents are selected from about 1% v / v to about 10% v / v ethanol, or about 1% v / v to about 20% v / v propylene glycol, and the aqueous solution optionally contains a phosphate buffer that maintains the pH of the aqueous solution from pH about 6.0 to pH about 8.0, wherein the osmotic pressure of the aqueous solution is from about 400 mOsmol / kg to about 6000 mOsmol / kg, The method according to claim 27, characterized in that.

30. The compound of pirfenidone or a pyridone analog is administered for treating idiopathic pulmonary fibrosis, (I) The pulmonary tissue Cmax and / or AUC of the compound of pirfenidone or a pyridone analog obtained after a single administration of the aqueous solution to a mammal using a liquid nebulizer is approximately 80% to about 120% of the dose administered using the liquid nebulizer. It is approximately the same as, or greater than, the pulmonary tissue Cmax and / or AUC of the compound of pirfenidone or a pyridone analog obtained after a single oral administration of the compound of pirfenidone or a pyridone analog at a dose, and / or The plasma Cmax and / or AUC of the compound of pirfenidone or a pyridone analog obtained after a single administration of an aqueous solution to a mammal using a liquid sprayer is at least 10% of, or higher than, the plasma Cmax and / or AUC of the compound of pirfenidone or a pyridone analog obtained after a single oral administration of the compound of pirfenidone or a pyridone analog at a dose that is about 80% to about 120% of the dose administered using the liquid sprayer. The method according to claim 27, characterized in that.

31. The liquid sprayer is (i) achieving at least 7% pulmonary deposition of the compound of pirfenidone or a pyridone analog administered to a mammal, (ii) providing a geometric standard deviation (GSD) of the particle size distribution of the aqueous solution droplets released of from about 1.0 μm to about 2.5 μm, (iii) a) an aerodynamic mass median diameter (MMAD) of the droplet size of the aqueous solution released using a high-efficiency liquid sprayer from about 1 μm to about 5 μm, b) a volume median diameter (VMD) from about 1 μm to about 5 μm, and / or c) providing a mass median diameter (MMD) from about 1 μm to about 5 μm, (iv) providing at least about 30% fine particle fraction (FPF = % ≤ 5 microns) of the droplets released from the liquid sprayer, (v) providing an output rate of at least 0.1 mL / min, and / or (vi) giving at least about 25% of the aqueous solution to a mammal. The method according to claim 27, characterized in that.

32. The liquid sprayer delivers from about 0.1 mg to about 360 mg of the compound of pirfenidone or a pyridone analog to the lung in less than about 20 minutes at a mass median diameter (MMAD) particle size from about 1 micron to about 5 microns. The method according to claim 27, characterized in that.

33. Administration using a liquid sprayer does not include an initial dose titration period. The method according to claim 27, characterized in that.

34. An inhalation system for administering a compound of pirfenidone or a pyridone analog to the human airway, wherein the inhalation system is (a) an aqueous solution of from about 0.5 mL to about 6 mL of the compound of pirfenidone or a pyridone analog, and (b) includes a high-efficiency liquid sprayer. An inhalation system, characterized in that.

35. The aqueous solution of a compound of pirfenidone or a pyridone analog is the aqueous solution according to any one of claims 1 - 6, characterized in that it is an inhalation system according to claim 34.

36. A high - efficiency liquid nebulizer (i) achieves at least 7% pulmonary deposition of a compound of pirfenidone or a pyridone analog administered to a mammal, (ii) provides a geometric standard deviation (GSD) of the released droplet size distribution of the aqueous solution from about 1.0 μm to about 2.5 μm, (iii) a) an aerodynamic mass median diameter (MMAD) of the droplet size of the aqueous solution released by a high - efficiency liquid nebulizer from about 1 μm to about 5 μm, b) a volume median diameter (VMD) from about 1 μm to about 5 μm, and / or c) a mass median diameter (MMD) from about 1 μm to about 5 μm, (iv) provides at least about 30% fine particle fraction (FPF = % ≤ 5 microns) of the droplets released from the liquid nebulizer, (v) provides an output rate of at least 0.1 mL / min, and / or (vi) administers at least about 25% of the aqueous solution to a mammal, characterized in that it is an inhalation system according to claim 34 or 35.

37. A method for achieving a pulmonary tissue Cmax of a compound of pirfenidone or a pyridone analog that is at least equal to or higher than the Cmax of an orally administered amount of the compound of pirfenidone or a pyridone analog up to 801 mg, wherein the method comprises the step of atomizing an aqueous solution containing a compound of pirfenidone or a pyridone analog, and the step of administering the atomized aqueous solution to a human, characterized by the method.

38. The AUC of a compound of pirfenidone or a pyridone analog in an orally administered amount up to 801 mg ０－２４ is at least equivalent to, or greater than, the lung tissue AUC of a compound of pirfenidone or a pyridone analog ０－２４ and a method of achieving the same The method comprises the step of atomizing an aqueous solution containing a compound of pirfenidone or a pyridone analog, and the step of administering the atomized aqueous solution to a human, characterized by the method.

39. A method for administering a compound of pirfenidone or a pyridone analog to a human, wherein the method comprises the step of administering an atomized aqueous solution containing pirfenidone or a pyridone analog, The lung tissue Cmax achieved with the nebulized aqueous solution is at least equivalent to, or higher than, the lung tissue Cmax achieved with the oral dosage of the compound of pirfenidone or a pyridone analog, which is 80% to 120% of the dosage of the compound of pirfenidone or a pyridone analog in the nebulized aqueous solution of the compound of pirfenidone or a pyridone analog to be administered. A method characterized by this.

40. A method of administering a compound of pirfenidone or a pyridone analog to a human, The method includes a step of administering a nebulized aqueous solution containing pirfenidone or a pyridone analog, The plasma Cmax achieved with the nebulized aqueous solution is at least 10% of, or higher than, the plasma Cmax achieved with the oral dosage of the compound of pirfenidone or a pyridone analog, which is 80% to 120% of the dosage of the compound of pirfenidone or a pyridone analog in the nebulized aqueous solution of the compound of pirfenidone or a pyridone analog to be administered. A method characterized by this.

41. A method of administering a compound of pirfenidone or a pyridone analog to a human, The method includes a step of administering a nebulized aqueous solution containing pirfenidone or a pyridone analog, Plasma AUC achieved with an atomized aqueous solution ０－２４ is at least 10% of, or greater than, the plasma AUC achieved with the dose of the compound of pirfenidone or a pyridone analog administered orally, which is from 80% to 120% of the dose of the compound of pirfenidone or a pyridone analog in the atomized aqueous solution of the compound of pirfenidone or a pyridone analog to be administered ０－２４ A method characterized by being at least 10% or greater than that.

42. A method of administering a compound of pirfenidone or a pyridone analog to a human, The method includes a step of administering a nebulized aqueous solution containing pirfenidone or a pyridone analog, Lung tissue AUC achieved with an atomized aqueous solution ０－２４ is 80% to 120% of the dose of the pirfenidone or pyridone analog compound in the atomized aqueous solution of the pirfenidone or pyridone analog compound to be administered, the lung tissue AUC achieved with the dose of the orally administered pirfenidone or pyridone analog compound ０－２４ and is at least equal to or greater than that, a method characterized by that.

43. The nebulization is performed by the inhalation system according to any one of claims 34 - 36. The method according to any one of claims 37 - 42, characterized by this.

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