Aerosol pirfenidone and pyridone analogue compounds and uses thereof - Patents.com

Abstract

To provide novel formulations for delivering, to the lungs and / or systemic compartment, pirfenidone or a pyridone analog compound useful for treating, e.g., lung diseases represented by idiopathic pulmonary fibrosis.SOLUTION: An aqueous solution for nebulized inhalation administration comprises: water; pirfenidone or a pyridone analog compound at a concentration of 0.1 to 60 mg / mL; and one or more cosolvents; where the osmolality of the aqueous solution is 50 to 6000 mOsmol / kg. Preferably, the cosolvents are ethanol, propylene glycol, or glycerol.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] (Priority Claim) This application is a continuation of U.S. Provisional Patent Application No. 61 / 438,203, filed January 31, 2011, entitled "Aerosol Pirfenidone and Pyridone Analog Compounds and Uses Thereof," U.S. Provisional Patent Application No. 61 / 508,542, filed July 15, 2011, entitled "Aerosol Pirfenidone and Pyridone Analog Compounds and Uses Thereof," U.S. Provisional Patent Application No. 61 / 559,670, filed November 14, 2011, entitled "Aerosol Pirfenidone and Pyridone Analog Compounds and Uses Thereof," U.S. Provisional Patent Application No. 61 / 559,670, filed January 6, 2012, entitled "Aerosol Pirfenidone and Pyridone Analog Compounds and Uses Thereof," U.S. Provisional Patent Application No. This application claims the benefit of U.S. Provisional Patent Application No. 61 / 584,119, entitled "THEREOF," all of which are incorporated herein by reference in their entireties.

[0002] In its embodiments, the present invention relates to liquid, dry powder and metered dose formulations for therapeutic inhalation delivery of pyridone compositions, such as pirfenidone, to a desired anatomical site to treat and / or prevent a variety of pulmonary, neurological, cardiovascular and solid organ disease conditions. [Background technology]

[0003] Many undesirable lung diseases, such as interstitial lung disease (ILD and its subtypes), chronic obstructive pulmonary disease (COPD and its subtypes), asthma, and fibrotic manifestations of the kidney, heart, and eye, are initiated by external insults. By way of non-limiting example, these effectors can include infection, smoking, environmental exposure, radiation exposure, surgical procedures, and transplant rejection. However, other causes related to genetics and the effects of aging may also be attributable. Compositions of pirfenidone or pyridone analog compounds suitable for inhalation delivery to the lung 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, pirfenidone or pyridone analog compound formulation compositions for delivery by oral, pulmonary, or intranasal inhalation are provided, including formulations for aerosol administration of pirfenidone or pyridone analog compounds, for the prevention or treatment of various fibrotic and inflammatory diseases, including diseases associated with the lungs, heart, kidneys, liver, eyes, and central nervous system.

[0005] In one embodiment, described herein is an aqueous solution for nebulized inhalation administration, the aqueous solution comprising water, a pirfenidone or pyridone analog compound at a concentration of about 10 mg / mL to about 50 mg / mL, and one or more cosolvents. In another embodiment, described herein is an aqueous solution for nebulized inhalation administration, the aqueous solution comprising water, a pirfenidone or pyridone analog compound at a concentration of about 10 mg / mL to about 50 mg / mL, optionally one or more buffers for maintaining a pH between about pH 4.0 and about pH 8.0, and one or more cosolvents. In some embodiments, the pH of the aqueous solution is about 4.0 to about 8.0. In some embodiments, the pH of the aqueous solution is 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 pirfenidone or pyridone analog compound at a concentration of about 0.1 mg / mL to about 60 mg / mL, and one or more cosolvents, and the osmolality of the aqueous solution is about 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog compound is at a concentration of about 10 mg / mL to about 60 mg / mL. In some embodiments, the pirfenidone or pyridone analog compound is at a concentration of about 10 mg / mL to about 50 mg / mL. In some embodiments, the pirfenidone or pyridone analog compound is at a concentration of about 15 mg / mL to about 50 mg / mL. In some embodiments, the pirfenidone or pyridone analog compound is at a concentration of about 20 mg / mL to about 50 mg / mL. In some embodiments, the pirfenidone or pyridone analog compound is at a concentration of about 25 mg / mL to about 50 mg / mL. In some embodiments, the pirfenidone or pyridone analog compound is present at a concentration of about 30 mg / mL to about 50 mg / mL. In some embodiments, the aqueous solution has an osmolality of about 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the aqueous solution has an osmolality of about 50 mOsmol / kg to about 5000 mOsmol / kg.In some embodiments, the osmolality of the aqueous solution is about 100 mOsmol / kg to about 5000 mOsmol / kg, about 300 mOsmol / kg to about 5000 mOsmol / kg, about 400 mOsmol / kg to about 5000 mOsmol / kg, about 600 mOsmol / kg to about 5000 mOsmol / kg, about 1000 mOsmol / kg to about 5000 mOsmol / kg, or about 2000 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the total concentration of the co-solvent is about 1% v / v to about 40% v / v. In some embodiments, the total concentration of the co-solvent is about 1% v / v to about 30% v / v. In some embodiments, the total concentration of the co-solvent is about 1% v / v to about 25% v / v. In some embodiments, the one or more co-solvents are selected from ethanol, propylene glycol, and glycerol. In some embodiments, the one or more co-solvents are selected from ethanol and propylene glycol. In some embodiments, the aqueous solution includes both ethanol and propylene glycol. In some embodiments, the aqueous solution further includes one or more additional ingredients selected from a surfactant, a taste-making agent / sweetener, and a salt. In some embodiments, the taste-making agent / sweetener is saccharin or a salt thereof. In some embodiments, the aqueous solution further includes one or more additional ingredients selected from a surfactant and a salt. 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 includes one or more buffers selected from a citrate buffer and a phosphate buffer. In some embodiments, the aqueous solution includes a phosphate buffer. In some embodiments, the aqueous solution includes a citrate buffer. In some embodiments, provided herein is from about 0.5 mL to about 6 mL of an aqueous solution described herein.

[0006] In some embodiments, the aqueous solution further comprises one or more additional components selected from a surfactant, a buffer, and a salt, hi 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 pirfenidone or pyridone analog compound at a concentration of about 10 mg / mL to about 60 mg / mL, one or more cosolvents, wherein the total concentration of the one or more cosolvents is about 1% v / v to about 40% v / v, and the one or more cosolvents are about 1% v / v to about 25% v / v ethanol, about 1% v / v to about 25% v / v propylene glycol, and about 1% v / v to about 25% v / v glycerol, and optionally, a phosphate buffer that maintains the pH of the solution at about pH 6.0 to about pH 8.0.

[0008] In some embodiments, the aqueous solution comprises water, a pirfenidone or pyridone analog compound at a concentration of about 15 mg / mL to about 50 mg / mL, and one or more cosolvents, wherein the total amount of the one or more cosolvents is about 1% v / v to about 30% v / v, and the one or more cosolvents are selected from about 1% v / v to about 10% v / v ethanol and about 1% v / v to about 20% v / v propylene glycol, and optionally a phosphate buffer that maintains the pH of the solution at about pH 6.0 to about pH 8.0, and wherein the osmolality of the aqueous solution is 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 pirfenidone or pyridone analog compound at a concentration of about 10 mg / mL to about 50 mg / mL, optionally a phosphate buffer solution that maintains the pH of the solution at about pH 6.0 to about pH 8.0, one or more cosolvents selected from about 1% v / v to about 25% v / v ethanol, and about 1% v / v to about 25% v / v propylene glycol, the total amount of cosolvents being 1% v / v to 25% v / v. In some embodiments, the aqueous solution for nebulized inhalation administration described herein comprises water, a pirfenidone or pyridone analog compound at a concentration of about 10 mg / mL to about 50 mg / mL, optionally a phosphate buffer solution that maintains the pH of the solution at about pH 6.0 to about pH 8.0, about 8% v / v ethanol, and about 16% v / v propylene glycol. In some embodiments, the nebulized aqueous solution for inhalation administration described herein consists essentially of water, a pirfenidone or pyridone analog compound at a concentration of about 10 mg / mL to about 50 mg / mL, optionally a phosphate buffer solution that maintains the pH of the solution at about pH 6.0 to about pH 8.0, one or more cosolvents selected from about 1% v / v to about 25% v / v ethanol, and about 1% v / v to about 25% v / v propylene glycol, the total amount of cosolvents being 1% v / v to 25% v / v. In some embodiments, the nebulized aqueous solution for inhalation administration described herein consists essentially of water, a pirfenidone or pyridone analog compound at a concentration of about 10 mg / mL to about 50 mg / mL, optionally a phosphate buffer solution that maintains the pH of the solution at about pH 6.0 to about pH 8.0, about 8% v / v ethanol, and about 16% v / v propylene glycol. In some embodiments, from about 0.5 mL to about 6 mL of the aqueous solutions described herein.

[0010] In some embodiments, a unit dosage suitable for use in a liquid nebulizer is described, comprising about 0.5 mL to about 6 mL of an aqueous solution of pirfenidone or a pyridone analog compound, wherein the concentration of the pirfenidone or a pyridone analog compound in the aqueous solution is 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 a cosolvent, a tonicity agent, a sweetener, a surfactant, a humectant, a chelating agent, an antioxidant, a salt, and a buffer, and the osmolality of the aqueous solution is about 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the aqueous solution further comprises one or more cosolvents selected from ethanol, propylene glycol, and glycerol, and one or both of a citrate buffer and a phosphate buffer. In some embodiments, the aqueous solution comprises a pirfenidone or pyridone analog compound dissolved in water at a concentration of about 15 mg / mL to about 50 mg / mL, optionally a phosphate buffer that maintains the pH of the solution between about pH 6.0 and about pH 8.0, and one or more cosolvents, wherein the total amount of the one or more cosolvents is about 1% v / v to about 30% v / v, and the one or more cosolvents are selected from about 1% v / v to about 10% v / v ethanol and about 1% v / v to about 20% v / v propylene glycol, and wherein the osmolality of the aqueous solution is about 400 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the aqueous solution is as described herein.

[0011] In some embodiments, kits are described herein that include a unit dose of an aqueous solution of pirfenidone or a pyridone analog as described herein in a container suitable for use in a liquid nebulizer.

[0012] In some embodiments, provided herein are aqueous droplets of a pirfenidone or pyridone analog compound, wherein the droplets have a diameter of less than about 5.0 μm. In some embodiments, the aqueous droplets are generated from a liquid nebulizer and an aqueous solution of a pirfenidone or pyridone analog compound. In some embodiments, the aqueous solution of a pirfenidone or pyridone analog compound is as described herein. In some embodiments, the aqueous solution has a pirfenidone or pyridone analog compound concentration of about 0.1 mg / mL to about 60 mg / mL and an osmolality of about 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the aqueous droplets are generated by spraying an aqueous solution of a pirfenidone or pyridone analog compound 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 droplets of a pirfenidone or pyridone analog compound is provided herein. In some embodiments, an aqueous aerosol comprising a plurality of droplets of a pirfenidone or pyridone analog compound is provided herein, wherein the plurality of droplets has a volumetric mean diameter (VMD), mass median aerodynamic diameter (MMAD), and / or mass median diameter (MMD) of less than about 5.0 μm. In some embodiments, the plurality of droplets is generated from a liquid nebulizer and an aqueous solution of a pirfenidone or pyridone analog compound. In some embodiments, the aqueous solution has a concentration of a pirfenidone or pyridone analog compound of about 10 mg / mL to about 60 mg / mL and an osmolality of about 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, at least 30% of the droplets in the aerosol have a diameter of less than about 5 μm. In some embodiments, the aqueous aerosol is generated by using a nebulizer to nebulize an aqueous solution of the pirfenidone or pyridone analog compound described herein. 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 lung deposition of at least 7% of the pirfenidone or pyridone analog compound administered to the mammal, (ii) provides a geometric standard deviation (GSD) of the particle size distribution of emitted droplets of the aqueous solution of about 1.0 μm to about 2.5 μm, (iii) provides a) a mass median aerodynamic diameter (MMAD) of droplets of the aqueous solution emitted using a high-efficiency liquid nebulizer of about 1 μm to about 5 μm, b) a volume mean diameter (VMD) of about 1 μm to about 5 μm, and / or c) a mass median diameter (MMD) of about 1 μm to about 5 μm, (iv) provides at least about 30% of the droplets emitted from the liquid nebulizer with fine particle fraction (FPF = %≦5 microns), (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 the 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), and (vi). In some embodiments, the aqueous solution (i) achieves lung deposition of 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% of the pirfenidone or pyridone analog compound administered to a mammal. In some embodiments, the aqueous solution (ii) provides a geometric standard deviation (GSD) of the emitted droplet size distribution of the aqueous solution of about 1.0 μm to about 2.5 μm, about 1.2 μm to about 2.3 μm, about 1.4 μm to about 2.1 μm, or about 1.5 μm to about 2.0 μm. In some embodiments, the liquid atomizer (iii) provides a) a mass median aerodynamic diameter (MMAD) of droplets of the aqueous solution emitted by the high-efficiency liquid atomizer of less than about 5 μm or about 1 μm to about 5 μm, b) a volume mean diameter (VMD) of less than about 5 μm or about 1 μm to about 5 μm, and / or c) a mass median diameter (MMD) of less than about 5 μm or about 1 μm to about 5 μm. In some embodiments, the liquid atomizer 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% of the droplets emitted from the liquid atomizer with a fine particle fraction (FPF=%≦5 microns).In some embodiments, the liquid nebulizer (v) 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 (vi) 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 the aqueous solution to the mammal. In some embodiments, the liquid nebulizer provides a respirable delivered dose (RDD) of 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%.

[0016] In some embodiments, methods for treating pulmonary diseases in a mammal are described herein, the methods comprising administering an aqueous solution comprising a pirfenidone or pyridone analog compound to the mammal using a liquid nebulizer. In some embodiments, methods for treating pulmonary diseases in a mammal are described herein, the methods comprising administering an aqueous solution comprising a pirfenidone or pyridone analog compound to the mammal using a liquid nebulizer, wherein the aqueous solution comprises water, a pirfenidone or pyridone analog compound at a concentration of from about 0.1 mg / mL to about 60 mg / mL, and one or more cosolvents, and the osmolality of the aqueous solution is from about 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the aqueous solution comprises water, a pirfenidone or pyridone analog compound at a concentration of about 10 mg / mL to about 60 mg / mL, and one or more cosolvents, wherein the total amount of the one or more cosolvents is about 1% v / v to about 40% v / v, and the one or more cosolvents 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 optionally, a phosphate buffer that maintains the pH of the aqueous solution at about pH 6.0 to about pH 8.0. In some embodiments, the aqueous solution comprises water, a pirfenidone or pyridone analog compound at a concentration of about 15 mg / mL to about 50 mg / mL, and one or more cosolvents, wherein the total amount of the one or more cosolvents is about 1% v / v to about 30% v / v, and the one or more cosolvents 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 optionally a phosphate buffer solution that maintains the pH of the aqueous solution at about pH 6.0 to about pH 8.0, and wherein the osmolality of the aqueous solution is 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 (i) achieves lung deposition of at least 7% of the pirfenidone or pyridone analog compound administered to the mammal, (ii) provides a geometric standard deviation (GSD) of the emitted droplet size distribution of the aqueous solution of about 1.0 μm to about 2.5 μm, (iii) provides a) a mass median aerodynamic diameter (MMAD) of about 1 μm to about 5 μm, b) a volume mean diameter (VMD) of about 1 μm to about 5 μm, and / or c) a mass median diameter (MMD) of about 1 μm to about 5 μm for droplets of the aqueous solution emitted by the high-efficiency liquid nebulizer, (iv) provides at least about 30% of the droplets emitted from the liquid nebulizer with fine particle fraction (FPF=%≦5 microns), (v) provides an output rate of at least 0.1 mL / min, and / or (vi) provides at least about 25% of the aqueous solution to the mammal. In some embodiments, the mammal is a human. In some embodiments, the pulmonary disease is pulmonary fibrosis and the mammal is a human. In some embodiments, the pulmonary disease is idiopathic pulmonary fibrosis and the mammal is a human. In some embodiments, the liquid nebulizer delivers about 0.1 mg to about 360 mg of the pirfenidone or pyridone analog compound in a mass median diameter (MMAD) particle size of about 1 micron to about 5 microns to the lungs of the mammal in less than about 20 minutes.

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

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

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

[0020] In some embodiments, methods for reducing the risk of gastrointestinal (GI) adverse events in treating a human with pirfenidone or a pyridone analog compound are described herein, the methods comprising administering to the human an nebulized aqueous solution comprising pirfenidone or a pyridone analog compound using a liquid nebulizer, wherein the aqueous solution comprises water, pirfenidone or a pyridone analog compound at a concentration of from about 0.1 mg / mL to about 60 mg / mL, and one or more cosolvents, and wherein the osmolality of the aqueous solution is from about 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the aqueous solution comprises water, a pirfenidone or pyridone analog compound at a concentration of about 10 mg / mL to about 60 mg / mL, and one or more cosolvents, wherein the total amount of the one or more cosolvents is about 1% v / v to about 40% v / v, and the one or more cosolvents 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 at about pH 6.0 to about pH 8.0.

[0021] In some embodiments, the aqueous solution comprises water, a pirfenidone or pyridone analog compound at a concentration of about 15 mg / mL to about 50 mg / mL, and one or more cosolvents, wherein the total amount of the one or more cosolvents is about 1% v / v to about 30% v / v, and the one or more cosolvents 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 optionally a phosphate buffer that maintains the pH of the aqueous solution at about pH 6.0 to about pH 8.0, wherein the osmolality of the aqueous solution is about 400 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog is administered to treat a pulmonary disease in a human. In some embodiments, the pulmonary disease is idiopathic pulmonary fibrosis.

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

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

[0024] In some embodiments, 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 pirfenidone or a pyridone analog compound from about 0.1 mg / mL to about 60 mg / mL, the osmolality of the aqueous solution is from about 50 mOsmol / kg to about 5000 mOsmol / kg, and the liquid nebulizer is a nebulizer containing a vibrating mesh or plate with many holes.

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

[0026] In some embodiments, an inhalation system for administering pirfenidone or a pyridone analog compound to the human respiratory tract is described herein, the inhalation system comprising: (a) about 0.5 mL to about 6 mL of an aqueous solution of the pirfenidone or a pyridone analog compound; 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 pirfenidone or a pyridone analog compound in the aqueous solution is about 0.1 mg / mL to about 60 mg / mL, and the osmolality of the aqueous solution is about 400 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the aqueous solution comprises water, a pirfenidone or a pyridone analog compound at a concentration of about 10 mg / mL to about 50 mg / mL, optionally a phosphate buffer that maintains the pH of the aqueous solution at about pH 6.0 to about pH 8.0, about 1% to about 8% ethanol, and / or about 2% to about 16% propylene glycol. In some embodiments, the aqueous solution is as described herein.

[0027] In one embodiment, described herein is a method for achieving a lung tissue Cmax of a pirfenidone or pyridone analog compound 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 up to 801 mg of the pirfenidone or pyridone analog compound, the method comprising nebulizing an aqueous solution containing the pirfenidone or pyridone analog compound and administering the nebulized aqueous solution to a human. In some embodiments, methods are described herein for achieving a pulmonary tissue Cmax of a pirfenidone or pyridone analog compound that is at least equal to or greater than the Cmax of an orally administered amount of up to 801 mg of the pirfenidone or pyridone analog compound, the methods comprising nebulizing an aqueous solution containing the pirfenidone or pyridone analog compound and administering the nebulized aqueous solution to a human.

[0028] In one embodiment, the AUC of pirfenidone or a pyridone analog compound at orally administered amounts up to 801 mg 0-24 The lung tissue AUC of pirfenidone or a pyridone analog compound is at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 1.5-fold, at least 1.5-fold, at least 1.5-fold, at least 1.5-fold, at least 1.5-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 1.5-20-fold, at least 1.5-15-fold, at least 1.5-10-fold, at least 1.5-5-fold, or at least 1.5-3-fold. 0-24Described herein are methods for achieving this, comprising nebulizing an aqueous solution containing a pirfenidone or pyridone analog compound and administering the nebulized aqueous solution to a human. In some embodiments, the AUC of an orally administered amount of pirfenidone or a pyridone analog compound of up to 801 mg is 0-24 A lung tissue AUC of pirfenidone or a pyridone analogue compound that is at least equal to or greater than 0-24 Described herein is a method for achieving this, which comprises nebulizing an aqueous solution containing a pirfenidone or pyridone analog compound and administering the nebulized aqueous solution to a human.

[0029] In one embodiment, a method of administering pirfenidone or a pyridone analog compound to a human is described herein, the method comprising administering an nebulized aqueous solution containing the pirfenidone or a pyridone analog compound, wherein the pulmonary tissue Cmax achieved with the nebulized 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 pulmonary tissue Cmax achieved with an orally administered dose of the pirfenidone or a pyridone analog compound that is 80% to 120% of the dose of pirfenidone administered by nebulization.

[0030] In one embodiment, a method for administering a pirfenidone or pyridone analog compound to a human is described herein, the method comprising administering an nebulized aqueous solution containing pirfenidone or a pyridone analog, wherein the pulmonary tissue Cmax achieved with the nebulized 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 pulmonary tissue Cmax achieved with an orally administered dose of the pirfenidone or pyridone analog compound that is 80% to 120% of the dose of the pirfenidone or pyridone analog compound in the nebulized aqueous solution of the pirfenidone or pyridone analog compound. In some embodiments, methods for administering pirfenidone or a pyridone analog compound to a human are described herein, the methods comprising administering an nebulized aqueous solution containing pirfenidone or a pyridone analog, wherein the pulmonary tissue Cmax achieved with the nebulized aqueous solution is at least equal to or greater than the pulmonary tissue Cmax achieved with an orally administered pirfenidone or pyridone analog compound dose that is 80% to 120% of the pirfenidone or pyridone analog compound dose in the nebulized aqueous solution of the administered pirfenidone or pyridone analog compound.

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

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

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

[0034] Described herein are pharmaceutical compositions for pulmonary delivery comprising a solution of pirfenidone or a pyridone analog having a concentration greater than about 34 mcg / mL, an osmolality 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 of 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 of about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of about 50 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the composition 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 composition comprises a mucolytic agent suitable for pulmonary delivery. In some embodiments, the composition comprises a second anti-fibrotic agent suitable for pulmonary delivery. In some embodiments, the composition comprises a second anti-inflammatory agent suitable for pulmonary delivery.

[0035] In some embodiments, pharmaceutical compositions for pulmonary delivery are described herein, comprising a solution of pirfenidone or a pyridone analog and a flavoring agent, wherein the solution has an osmolality greater than about 100 mOsmol / kg and a pH greater than about 4.0. In some embodiments, the concentration of pirfenidone or a pyridone analog is greater than about 34 mcg / mL. In some embodiments, the concentration of pirfenidone or a pyridone analog is greater than about 1.72 mg / mL. In some embodiments, the concentration of pirfenidone or a pyridone analog is greater than about 86 mg / mL. In some embodiments, the pirfenidone or a pyridone analog solution has an osmotic ion concentration of about 30 mM to about 300 mM. In some embodiments, the osmotic ion is chloride or bromide. In some embodiments, the pirfenidone or a pyridone analog solution has a pH of about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of about 50 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the composition 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 composition comprises a mucolytic agent suitable for pulmonary delivery. In some embodiments, the composition comprises a second anti-fibrotic agent suitable for pulmonary delivery. In some embodiments, the composition comprises a second anti-inflammatory agent suitable for pulmonary delivery.

[0036] In some embodiments, described herein are sterile, disposable containers containing from about 0.1 mL to about 20 mL of a pirfenidone or pyridone analog solution having a concentration greater than about 34 mcg / mL, an osmolality 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 of 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 of from about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of from about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of 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, methods for treating pulmonary diseases are described herein, comprising inhaling an aerosol of a pirfenidone or pyridone analog solution having a concentration greater than about 34 mcg / mL, an osmolality 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 of 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 of about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of about 50 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution 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 pulmonary delivery. In some embodiments, the method further comprises administering a second anti-fibrotic agent suitable for pulmonary delivery. In some embodiments, the method further comprises administering a second anti-inflammatory agent suitable for pulmonary delivery. In some embodiments, the pulmonary disease is interstitial lung disease. In some embodiments, the interstitial lung disease is idiopathic pulmonary fibrosis. In some embodiments, the interstitial lung disease is radiation therapy-induced pulmonary fibrosis. In some embodiments, the pulmonary disease is chronic obstructive pulmonary disease. In some embodiments, the pulmonary disease is chronic bronchitis. In some embodiments, the pulmonary disease is asthma. In some embodiments, the aerosol comprises particles having an average aerodynamic diameter of about 1 micron to about 5 microns.In some embodiments, the aerosol has a mean particle size of about 1 micron to about 5 microns in volume mean diameter and a particle size geometric standard deviation of less than or equal to 3 microns. In some embodiments, the inhaling step delivers a minimum dose of 6.8 mcg of pirfenidone or pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 340 mcg of pirfenidone or pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 740 mcg of pirfenidone or pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 1.7 mg of pirfenidone or pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 93 mg of pirfenidone or pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 463 mg of pirfenidone or pyridone analog. In some embodiments, the inhaling step takes less than about 20 minutes. In some embodiments, the inhaling step occurs in less than about 10 minutes. In some embodiments, the inhaling step occurs in less than about 7.5 minutes. In some embodiments, the inhaling step occurs in less than about 5 minutes. In some embodiments, the inhaling step occurs in less than about 2.5 minutes. In some embodiments, the inhaling step occurs in less than about 1.5 minutes. In some embodiments, the inhaling step occurs in less than about 30 seconds. In some embodiments, the inhaling step occurs within less than about 5 breaths. In some embodiments, the inhaling step occurs within less than about 3 breaths.

[0038] In one aspect, a method for administering an anti-fibrotic agent to a patient's lungs is described herein, comprising introducing into a nebulizer a pirfenidone or pyridone analog solution having a concentration greater than about 34 mcg / mL, an osmolality greater than about 100 mOsmol / kg, and a pH greater than about 4.0. In another aspect, a method for administering an anti-inflammatory agent to a patient's lungs is described herein, comprising introducing into a nebulizer a pirfenidone or pyridone analog solution having a concentration greater than about 34 mcg / mL, an osmolality 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 ion concentration of about 30 mM to about 300 mM. In some embodiments, the permeant ion is chloride or bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH of about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of about 50 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution 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 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 anti-fibrotic 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, described herein are methods for treating extrapulmonary disease targets, comprising inhaling an aerosol of a pirfenidone or pyridone analog solution having a concentration greater than about 34 mcg / mL, an osmolality 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 downstream disease targets 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 a permeant ion concentration of about 30 mM to about 300 mM. In some embodiments, the permeant ion is chloride or bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH of about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of about 50 mOsmol / kg to about 5000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution 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 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 anti-fibrotic agent suitable for pulmonary delivery. In some embodiments, the method further comprises 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 using an aerosol or nebulizer to deliver pirfenidone or pyridone analog compounds to the lungs, the aerosol comprises particles having a mean aerodynamic diameter of about 1 micron to about 5 microns. In some embodiments, the aerosol has a mean particle size of about 1 micron to about 5 microns in volume mean diameter and a particle size geometric standard deviation of less than or equal to 3 microns. In some embodiments, the inhalation step delivers a pirfenidone or pyridone analog dose of at least 6.8 mcg. In some embodiments, the inhalation step delivers a pirfenidone or pyridone analog dose of at least 340 mcg. In some embodiments, the inhalation step delivers a pirfenidone or pyridone analog dose of at least 740 mcg. In some embodiments, the inhalation step delivers a pirfenidone or pyridone analog dose of at least 17 mg. In some embodiments, the inhalation step delivers a pirfenidone or pyridone analog dose of at least 93 mg. In some embodiments, the inhaling step delivers a minimum dose of 463 mg of pirfenidone or pyridone analog. In some embodiments, the inhaling step occurs in less than about 20 minutes. In some embodiments, the inhaling step occurs in less than about 10 minutes. In some embodiments, the inhaling step occurs in less than about 7.5 minutes. In some embodiments, the inhaling step occurs in less than about 5 minutes. In some embodiments, the inhaling step occurs in less than about 2.5 minutes. In some embodiments, the inhaling step occurs in less than about 1.5 minutes. In some embodiments, the inhaling step occurs in less than about 30 seconds. In some embodiments, the inhaling step occurs within less than about 5 breaths. In some embodiments, the inhaling step occurs within less than about 3 breaths.

[0041] In one aspect, described herein are methods for treating neurological disorders, comprising intranasal inhalation of an aerosol of a pirfenidone or pyridone analog solution having a concentration greater than about 34 mcg / mL, an osmolality 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 of 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 of about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of 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 disease is multiple sclerosis. In some embodiments, the aerosol comprises particles having an average aerodynamic diameter of about 1 micron to about 20 microns. In some embodiments, the aerosol has a mean particle size of about 1 micron to about 20 microns by volume mean diameter and a particle size geometric standard deviation of less than or equal to 3 microns. In some embodiments, the inhaling step delivers a dose of at least 6.8 mcg of pirfenidone or a pyridone analog.In some embodiments, the inhaling step delivers a minimum dose of 340 mcg of pirfenidone or pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 740 mcg of pirfenidone or pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 1.7 mg of pirfenidone or pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 93 mg of pirfenidone or pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 463 mg of pirfenidone or pyridone analog. In some embodiments, the inhaling step takes less than about 20 minutes. In some embodiments, the inhaling step takes less than about 10 minutes. In some embodiments, the inhaling step takes less than about 7.5 minutes. In some embodiments, the inhaling step takes less than about 5 minutes. In some embodiments, the inhaling step takes less than about 2.5 minutes. In some embodiments, the inhaling step occurs within less than about 1.5 minutes. In some embodiments, the inhaling step occurs within less than about 30 seconds. In some embodiments, the inhaling step occurs within less than about 5 breaths. In some embodiments, the inhaling step occurs within less than about 3 breaths.

[0042] In some embodiments, methods for administering an anti-demylination agent to the nasal passages of a patient are described herein, comprising introducing into a nebulizer a pirfenidone or pyridone analog solution having a concentration greater than about 34 mcg / mL, an osmolality 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 a permeant ion concentration of about 30 mM to about 300 mM. In some embodiments, the permeant ion is chloride or bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH of about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of 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 a step of introducing pirfenidone or a pyridone analog solution into a nebulizer, the method includes a step of opening a sterile, disposable container containing about 0.5 mL to about 10 mL of pirfenidone or a pyridone analog solution for introduction into the nebulizer.

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

[0045] In one embodiment, provided herein is a kit comprising a pharmaceutical composition comprising a pirfenidone or pyridone analog solution in a sterile container, the pirfenidone or pyridone analog solution having a concentration greater than about 34 mcg / mL, an osmolality greater than about 100 mOsmol / kg, and a pH greater than about 4.0; and a nebulizer suitable for aerosolizing the pirfenidone or pyridone analog solution for delivery to the central to lower respiratory tract via 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 pirfenidone or pyridone analog solution has a permeant ion concentration of about 30 mM to about 300 mM. In some embodiments, the permeant ion is chloride or bromide. In some embodiments, the pirfenidone or pyridone analog solution has a pH of about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of 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 pulmonary delivery. In some embodiments, the kit further comprises a second anti-fibrotic agent suitable for pulmonary delivery. In some embodiments, the kit further comprises a second anti-inflammatory agent suitable for pulmonary delivery.

[0046] In another aspect, provided herein is a kit comprising a pharmaceutical composition comprising a pirfenidone or pyridone analog solution in a sterile container, wherein the pirfenidone or pyridone analog solution has a concentration greater than about 34 mcg / mL, an osmolality greater than about 100 mOsmol / kg, and a pH greater than about 4.0, and a nebulizer suitable for aerosolizing the pirfenidone or pyridone analog solution for delivery to the nasal cavity via intranasal 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 pirfenidone or pyridone analog solution has an osmotic ion concentration of 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 of about 4.0 to about 8.0. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of about 100 mOsmol / kg to about 1000 mOsmol / kg. In some embodiments, the pirfenidone or pyridone analog solution has an osmolality of 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 intranasal delivery. In some embodiments, the kit further comprises a second anti-fibrotic agent suitable for intranasal delivery. In some embodiments, the kit further comprises a second anti-inflammatory agent suitable for intranasal delivery.

[0048] In one aspect, a method for treating a pulmonary disease is described herein, the method comprising administering pirfenidone or a pyridone analog via oral inhalation of an aerosol comprising pirfenidone or a pyridone analog to the central to lower respiratory tract of a subject having or suspected of having interstitial lung disease, wherein the disease is selected from interstitial lung disease, including idiopathic pulmonary fibrosis and radiation therapy-induced fibrosis, chronic obstructive pulmonary disease, and asthma. In some embodiments, the subject is identified as having interstitial lung disease. In some embodiments, the subject is identified as having idiopathic pulmonary fibrosis. In some embodiments, the subject is identified as having radiation therapy-induced fibrosis. In some embodiments, the subject is identified as having chronic obstructive pulmonary disease. In some embodiments, the subject is identified as having chronic bronchitis. In some embodiments, the subject is identified as having 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 via oral inhalation of an aerosol comprising pirfenidone or a pyridone analog to the central to lower respiratory tract of a subject having or suspected of having a disease associated with extrapulmonary fibrosis, inflammation, and / or toxicity, for pulmonary vascular absorption and delivery to the extrapulmonary diseased tissue, wherein the disease is selected from cardiac fibrosis, renal fibrosis, hepatic fibrosis, nephrotoxicity, and cardiac toxicity. In some embodiments, the subject is identified as having cardiac fibrosis. In some embodiments, the subject is identified as having renal fibrosis. In some embodiments, the subject is identified as having hepatic fibrosis. In some embodiments, the subject is identified as having nephrotoxicity. In some embodiments, the subject is identified as having cardiac toxicity. In some embodiments, the subject is a mechanically ventilated subject.

[0050] In one embodiment, a method for treating a neurological disease is described herein, comprising administering pirfenidone or a pyridone analog to the nasal passages of a subject suspected of having or suffering from a neurological disease via intranasal inhalation of an aerosol comprising pirfenidone or a pyridone analog for nasal vascular absorption and delivery to the central nervous system, wherein the disease is multiple sclerosis. In some embodiments, the subject is confirmed to have multiple sclerosis. In some embodiments, the subject is a mechanically ventilated subject.

[0051] In one aspect, a pharmaceutical composition for pulmonary delivery is described herein, comprising a dry powder containing pirfenidone or a pyridone analog having a dosage content of 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 comprises a blending agent. In some embodiments, the blending agent is selected from the group consisting of lactose.

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

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

[0054] In one embodiment, described herein is a kit comprising a pharmaceutical composition comprising a dry powder pirfenidone or pyridone analog formulation in a container, wherein the pharmaceutical composition has a pirfenidone or pyridone analog dosage content of greater than about 1%, and a dry powder inhaler suitable for aerosolizing the dry powder formulation of pirfenidone or pyridone analog for delivery to the central to lower respiratory tract via oral inhalation.In another embodiment, described herein is a kit comprising a pharmaceutical composition comprising a dry powder pirfenidone or pyridone analog formulation in a container, wherein the pharmaceutical composition has a pirfenidone or pyridone analog dosage content of greater than about 1%, and a dry powder inhaler suitable for aerosolizing the dry powder formulation of pirfenidone or pyridone analog for delivery to the nasal cavity via intranasal inhalation.In some embodiments, the pirfenidone or pyridone analog dosage content is greater than about 6.8mcg.In some embodiments, the pirfenidone or pyridone analog content is greater than about 340mcg.In some embodiments, the pirfenidone or pyridone analog content is greater than about 17mg. In some embodiments, the pirfenidone or pyridone analog content is greater than about 463 mg. In some embodiments, the dry powder further comprises a blending agent. In some embodiments, the blending agent is lactose.

[0055] In one aspect, a method for treating a pulmonary disease is described herein, the method comprising administering pirfenidone or a pyridone analog via oral inhalation of an aerosol comprising pirfenidone or a pyridone analog to the central to lower respiratory tract of a subject having or suspected of having interstitial lung disease, wherein the disease is selected from interstitial lung disease, including idiopathic pulmonary fibrosis and radiation therapy-induced fibrosis, chronic obstructive pulmonary disease, and asthma. In some embodiments, the subject is identified as having interstitial lung disease. In some embodiments, the subject is identified as having idiopathic pulmonary fibrosis. In some embodiments, the subject is identified as having radiation therapy-induced pulmonary fibrosis. In some embodiments, the subject is identified as having chronic obstructive pulmonary disease. In some embodiments, the subject is identified as having chronic bronchitis. In some embodiments, the subject is identified as having asthma. In some embodiments, the subject is a mechanically ventilated subject.

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

[0057] In some embodiments, the subject is identified to have cardiac fibrosis. In some embodiments, the subject is identified to have renal fibrosis. In some embodiments, the subject is identified to have liver fibrosis. In some embodiments, the subject is identified to have nephrotoxicity. In some embodiments, the subject is identified to have cardiac toxicity. In some embodiments, the subject is a mechanically ventilated subject.

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

[0059] In one embodiment, 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, as indicated by Grade 2 or higher abnormalities after oral administration of one or more biomarkers of liver function, following administration of pirfenidone or a pyridone analog, the method comprising 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 elevations of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), or gamma-glutamyltransferase (GGT) greater than 2.5 times but not greater than 5 times the upper limit of normal (ULN). Grade 2 liver function abnormalities also include elevations of bilirubin levels greater than 1.5 times but not greater than 3 times the ULN. In some embodiments, the pirfenidone or pyridone analog is delivered to the patient by oral 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 the pirfenidone or pyridone analog is less than 10 mcg / mL. In some embodiments, the blood Cmax after administration of the pirfenidone or pyridone analog is greater than 10 mcg / mL.

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

[0061] In one embodiment, a method for administering pirfenidone or pyridone analogues to treat patients with idiopathic pulmonary fibrosis (IPF) is described herein, and the patient avoids the occurrence of phototoxicity after oral administration, the method comprising administering pirfenidone or pyridone analogues to the patient at a dosage of less than 360 mg per day.In some embodiments, pirfenidone or pyridone analogues are delivered to patients 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 pyridone analogues is less than 10 mcg / mL.In some embodiments, the blood Cmax after administration of pirfenidone or pyridone analogues is greater than 10 mcg / mL.

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

[0064] In one embodiment, a pharmaceutical composition is described herein comprising a therapeutically effective amount of an inhaled drug, wherein the drug is pirfenidone or a pyridone analog, the drug is in particles having a mass mean aerodynamic diameter of less than 5 microns or a volume mean diameter of less than 10 microns, and the composition delivers a dose of the pirfenidone or pyridone analog compound to the lungs after inhalation in excess of 1 mcg per gram of lung tissue in an adult human.

[0065] In one aspect, described herein is a pharmaceutical composition for pulmonary aerosol delivery, comprising a solution of 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 a pyridone analog to the divalent cation is within a molar range of about 1:0.1 to 1:10 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, or 1:about 0.1. In some embodiments, the active pharmaceutical ingredient is pirfenidone or a pyridone analog, and the concentration is between 0.1 mg / mL and 50 mg / mL in 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 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 active pharmaceutical 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 osmolality is greater than about 50 mOsmol / kg of the composition by an increment of about 1 mOsmol / kg.For example, 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 In some embodiments, the pH is greater than about 3.0, in increments of about 0.1 pH units. For example, about pH 3, about pH 3.5, about pH 4, about pH 4.5, about pH 5, about pH 5.5, about pH 6, about pH 6.5, about pH 7, about pH 7.5, about pH 8, about pH 8.5, about pH 9, about pH 9.5, about pH 10, about pH 10.5, and about pH 11. 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, pyrophosphate, phosphoric acid, phosphate, PIPES, ACES, MES, cacodylic acid, carbonic acid, carbonate, and ADA (N-(2-acetamido)-2-iminodiacetic acid). In some embodiments, the pirfenidone or pyridone analog solution comprises an osmotic ion concentration. In some embodiments, the permeant ion is selected from the group consisting of bromine, chloride, and lithium. In some embodiments, the permeant ion concentration is from about 30 mM to about 300 mM in increments of about 0.1 mM.For example, 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, 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 packaged in a primary package. In some embodiments, the primary packaging material is selected 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 comprises a vial, syringe, or ampoule. In some embodiments, the composition is protected from light.

[0067] In some embodiments, the compositions described herein are formulated under or will be subjected to hypoxic conditions. In some embodiments, oxygen is reduced by injecting a formulation diluent prior to the addition of the active pharmaceutical ingredient. The insufflation 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 the addition of the active pharmaceutical ingredient. The insufflation 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 of the formulation container with an inert gas, which may be selected from the group consisting of argon or nitrogen.

[0069] In some embodiments, oxygen exposure is reduced by replacing the ambient gas in the headspace of the primary packaging container with an inert gas, which 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 packaging container.

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

[0072] In some embodiments, the aerosols described herein for delivery to the lungs of a mammal contain between 10 and 100% granule particles in 1% increments, e.g., 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 granule dosage 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 present 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 incorporated herein by reference in their entirety, as if each were individually incorporated. Aspects of the present invention can be modified, as necessary, to employ concepts from the various patents, applications, and publications to provide further embodiments of the present invention. [Brief explanation of the drawings]

[0075] [Figure 1]1 shows modeled nebulized aerosol administration of pirfenidone and oral administration of pirfenidone to human subjects. DETAILED DESCRIPTION OF THE INVENTION

[0076] Many undesirable lung diseases, such as interstitial lung disease (ILD and its subtypes), chronic obstructive pulmonary disease (COPD and its subtypes), asthma, and fibrotic manifestations of the lung, kidney, heart, and eye, are initiated by external insults. By way of non-limiting example, these effectors may include infection, smoking, environmental exposure, radiation exposure, surgical procedures, and transplant rejection. However, other causes related to genetics and the effects of aging may also be attributable.

[0077] In epithelia, scarring plays a valuable healing role after injury. However, epithelial tissues can become increasingly scarred after chronic and / or repeated injury, resulting in functional abnormalities. In idiopathic pulmonary fibrosis (IPF and other subtypes of ILD), scarring of a significant proportion of the lung can lead to respiratory failure. In either case, progressive scarring can result from a series of recurrent insults to different regions of the organ or from an inability to halt the repair process after injury has healed. In such cases, the scarring process becomes uncontrolled and unregulated. In some forms of fibrosis, scarring can remain localized to a limited area, but it can affect more diffuse and widespread areas, resulting in direct or associated organ failure.

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

[0079] Epithelial injury induces the release of multiple profibrotic mediators, including the potent fibroblast growth factor transforming growth factor beta (TGF-beta), tumor necrosis factor (TNF), endothelin, cytokines, metalloproteinases, and the coagulation mediator tissue factor. Importantly, these releases render epithelial cells vulnerable to apoptosis, which, combined with a likely inability to restore the epithelial cell layer, is a fundamental abnormality in fibrotic diseases. In the case of demyelination, aberrant TNF expression or activity is thought to be an underlying cause of other neurological disorders, such as multiple sclerosis and rheumatic diseases.

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

[0081] TNF-alpha is expressed in asthmatic airways and may play an important role in amplifying asthmatic inflammation through activation of NF-kappaB, AP-1, and other transcription factors. Activation of IgE receptors triggers the release of TNF-alpha from human lung tissue and upregulates TNF mRNA levels in eosinophils. TNF-alpha induces transient bronchial hyperresponsiveness, possibly 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 contact with various pollutants, including cigarette smoke. TNF-alpha has been shown to induce pathological features associated with COPD in animal models, such as inflammatory cell infiltration into the lungs, pulmonary fibrosis, and emphysema. Interestingly, TNF-alpha levels in sputum are significantly increased during acute 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, reducing the accumulation of inflammatory cells in response to various stimuli. Pirfenidone also attenuates fibroblast proliferation, the production of proteins and cytokines associated with fibrosis, and the increased synthesis and accumulation of extracellular matrix in response to cytokine growth factors such as transforming growth factor beta (TGF) and platelet-derived growth factor (PDGF).

[0084] In in vitro cell-based assays, pirfenidone inhibited fibroblast proliferation, inhibited lipopolysaccharide (LPS)-stimulated release of PDGF, tumor necrosis factor alpha (TNF-alpha), and TGF-beta1, and inhibited collagen synthesis. Depending on the assay conditions, these in vitro activities were evident at pirfenidone concentrations ranging from approximately 30 μM to approximately 10 mM (approximately 5.5 mcg / mL to approximately 1.85 mg / mL). Given that the oral Cmax of pirfenidone in patients with IPF ranges from the recommended fed state of approximately 42 μM to the fasted state of approximately 84 μM (or approximately 7.9 mcg / mL to approximately 15.7 mcg / mL, respectively), these same activities may be enhanced in vivo, albeit with a narrower range of observed efficacy.

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

[0086] In vitro studies suggest that pirfenidone may also suppress fibrogenesis through selective inhibition of p38 mitogen-activated protein kinase (MAPK). These observations were associated with a decrease in TGF-beta-induced collagen synthesis. Parallel observations that blocking p38 may also restore corticosteroid sensitivity in COPD hold promise for this and other disease populations. Unfortunately, compounds that inhibit p38 MAPK have also proven toxic and have been withdrawn from clinical practice. Each of these compounds is available for oral administration.

[0087] In rat, hamster, and mouse models of bleomycin-induced pulmonary fibrosis, prophylactic administration of pirfenidone reduced pulmonary fibrosis as assessed by both histopathological analysis and quantitative determination of collagen content. Treatment with pirfenidone also reduced pulmonary edema and reduced pulmonary levels of TGF-beta, basic fibroblast growth factor (bFGF), and various proinflammatory cytokines.

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

[0089] Human studies have demonstrated clinical anti-inflammatory and antifibrotic benefits of oral pirfenidone. Phototoxicity, gastrointestinal disturbances, and abnormal liver function tests may occur in human populations after oral administration of pirfenidone. As a result, patient dosing must be closely monitored. In phase 3 clinical studies using orally administered pirfenidone, an initial dose escalation was required to establish gastrointestinal tolerance. However, the occurrence of nausea, rash, gastrointestinal disturbances, dizziness, vomiting, photosensitivity reactions, anorexia, and elevated serum AST and ALT transaminases limited dosage levels during and after escalation. In some cases, oral administration of pirfenidone may result in a dose reduction or interruption of pirfenidone administration.

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

[0091] Based on clinical observations and adverse events, as well as observed toxicities, oral pirfenidone therapy is limited to doses of approximately 1800 mg / day to approximately 2400 mg / day (600 mg TID to 801 mg TID, respectively). Thus, while pirfenidone has demonstrated broad non-human efficacy, adverse events and toxicity in humans have limited oral administration to the lower end of this range.

[0092] Regulatory risk-benefit analysis between the observed efficacy and associated adverse events of orally administered pirfenidone has raised concerns that these doses do not provide sufficient efficacy to warrant safety risks, even in end-stage populations with unmet clinical need. In certain embodiments, methods are provided herein for administering equivalent or increased pirfenidone or pyridone analog doses directly to the disease site (e.g., pulmonary inhalation delivery) that would provide equivalent or improved efficacy over the oral route. In certain embodiments, these doses require a lower amount of administered drug. In certain embodiments, this approach to administering pirfenidone by inhalation may benefit from reduced systemic exposure and an increased 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] It is unclear from existing data whether the pirfenidone anti-inflammatory or anti-fibrotic mechanism of action is driven by Cmax or exposure (area under the curve, AUC). In some embodiments, the clinical efficacy observed at low to moderate levels is associated with pirfenidone plasma levels of about 5 mcg / mL or greater than 5 mcg / mL, exposure (AUC) of about 50 mg hr / L or greater than 50 mg hr / L, and / or 0-無限大 ), and / or may be associated with a plasma clearance rate of approximately 2.5 hours.

[0094] In some embodiments, intravenous or oral administration of pirfenidone results in lung epithelial lining fluid (ELF) levels comparable to those observed in plasma; therefore, in some embodiments, a clinically measured plasma Cmax of about 5 mcg / mL or greater than 5 mcg / mL is directly correlated with the observed low-to-moderate clinical pulmonary efficacy. In some embodiments, pirfenidone plasma levels from oral administration are correlated with lower efficacy; therefore, in some embodiments, the resulting ELF and lung tissue levels are also correlated with lower efficacy. In other embodiments, intravenous or oral administration of pirfenidone may result in lung epithelial lining fluid (ELF) levels below the levels observed to be effective from plasma. In some embodiments, orally or intravenously delivered ELF levels consistent with the observed effective levels in plasma may be 0.1 mcg / mL to about 5 mcg / mL. In some embodiments, ELF levels corresponding to the effective levels observed in plasma may be 0.1 mcg / mL to about 1 mcg / mL. In some embodiments, orally or intravenously delivered ELF levels corresponding to the effective levels observed in plasma may be 0.5 mcg / mL to about 5 mcg / mL. In some embodiments, orally or intravenously delivered ELF levels corresponding to the effective levels observed in plasma may be 0.3 mcg / mL to about 3 mcg / mL. In some embodiments, direct administration of pirfenidone to the lungs may result in delivery of about or more than about 5 mcg of pirfenidone per mL of ELF, resulting in comparable pulmonary efficacy without the elevated systemic levels associated with adverse events and toxicity observed with administration.By way of non-limiting example, this is accomplished by delivery of aerosolized pirfenidone or pyridone analog to the lungs via oral or intranasal inhalation, providing the ELF with about 0.1 mcg / mL or greater than about 0.1 mcg / mL, e.g., 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 greater than 10 mcg / mL of pirfenidone or pyridone analog. Once in the ELF, the pirfenidone or pyridone analog, in some embodiments, penetrates lung tissue, resulting in about 0.004 mcg to 0.7 mcg of pirfenidone or pyridone analog per gram of lung tissue (about 0.1 mcg / mL in about 25 mL of ELF to about 5 mcg / mL in about 75 mL of ELF, for about 600 grams of adult lung tissue weight).

[0095] In some embodiments, pirfenidone may readily equilibrate between plasma and the lungs and / or other organs. In some embodiments, organ pirfenidone levels may further mimic plasma levels, such as in the lungs, heart, kidneys, or nervous system. In some embodiments, delivering approximately 0.004 mcg, or 0.004 mcg to 0.7 mcg, of pirfenidone per gram of tissue may provide similar therapeutic effects in other organs. In some embodiments, providing additional pirfenidone or pyridone analogs may provide additional efficacy. In some embodiments, this may be achieved by inhalation (i.e., oral or intranasal) delivery of aerosolized pirfenidone or pyridone analogs to the lungs. In some embodiments, pirfenidone or pyridone analogs delivered to the lungs are readily available to the heart. In some embodiments, providing about 0.1 mcg / mL to about 5 mcg / mL of ELF, or providing 0.004 mcg / gram or about 0.7 mcg / gram of pirfenidone or pyridone analog to lung tissue, or providing 0.2-0.7 mcg / gram of pirfenidone or pyridone analog to lung tissue, may provide similarly effective cardiac administration without the increased systemic adverse events or toxicity observed with oral administration. In some embodiments, delivery of aerosolized pirfenidone or pyridone analog to the lungs via intranasal or oral inhalation may provide effective delivery of pirfenidone or pyridone analog to the liver. In some embodiments, pirfenidone or pyridone analog delivered to the lungs becomes available to the liver. In some embodiments, providing an ELF of about 0.1 mcg / mL to about 5 mcg / mL, or providing lung tissue pirfenidone or a pyridone analog of about 0.004 mcg / gram to about 0.7 mcg / gram, may provide similar effective dosing to the liver without the increased systemic adverse events or toxicity observed with oral dosing.In some embodiments, delivery of aerosolized pirfenidone or pyridone analogs to the lungs via intranasal or oral inhalation can result in effective delivery of pirfenidone or pyridone analogs to the kidney. In some embodiments, pirfenidone or pyridone analogs delivered to the lungs become available to the kidney. In some embodiments, providing an ELF of about 0.1 mcg / mL to about 5 mcg / mL, or providing a lung tissue pirfenidone or pyridone analog of about 0.004 mcg / gram to about 0.7 mcg / gram, can result in similar effective administration to the kidney without the increased systemic adverse events or toxicity observed with oral administration. In some embodiments, delivery of aerosolized pirfenidone or pyridone analogs to the nasal cavity via intranasal inhalation can result in effective delivery of pirfenidone or pyridone analogs to the central nervous system (CNS). In some embodiments, delivery of pirfenidone or pyridone analogs to the nasal cavity can result in readily available pirfenidone or pyridone analogs to the CNS. In some embodiments, a nasally administered dose equivalent to an ELF of about 0.1 mcg / mL to about 5 mcg / mL, or about 0.004 mcg / gram to about 0.7 mcg / gram of pulmonary tissue pirfenidone or pyridone analog, may provide similar effective administration to the CNS without the increased systemic adverse events or toxicity observed with oral administration.

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

[0097] In some embodiments, infusion delivery of a liquid pirfenidone or pyridone analog to the desired effect site, providing about 0.004 mcg / gram to about 0.7 mcg / gram of tissue weight pirfenidone or pyridone analog, results in similarly effective administration without the associated systemic adverse events or toxicity. In some embodiments, infusion delivery of a liquid pirfenidone or pyridone analog to a skeletal joint may prevent scarring, fibrosis, and / or inflammation associated with autoimmune disease, arthritis, rheumatoid arthritis, infection, or other conditions.

[0098] In some embodiments, in addition to Cmax, and in additional embodiments, pirfenidone exposure (AUC) to disease sites may also be essential for efficacy. In some embodiments, a plasma AUC of about 50 mg hr / L or greater than 50 mg hr / L. 0-無限大The difference in AUC between the plasma and lung ELF and between the plasma and lung tissue may also be related to lung efficacy. In some embodiments, partial or complete equilibration of pirfenidone between the plasma and lung ELF and between the plasma and lung tissue may provide an AUC that can be mimicked in the lung. In other embodiments, the difference in AUC between the lung ELF and tissue may be less.

[0099] In some embodiments, Cmax, AUC, and / or half-life, individually or in combination, are required for efficacy; thus, in some embodiments, a conservative model is provided that includes all three parameters (Cmax, AUC, and half-life) required for efficacy. In some embodiments, by non-limiting example, an ELF AUC of about 1.0 mg hr / L or about 50 mg hr / L 0-無限大 Direct inhalation delivery of about 0.1 mcg to about 5 mcg of pirfenidone or a pyridone analog to 1 mL of lung ELF is equally effective, providing a plasma AUC of 0.2004 mcg or 0.2004 mcg to 0.7 mcg of pirfenidone or a pyridone analog in 1 mL of lung ELF and maintaining these values ​​for the same time period as when delivered via the oral route. Similarly, in other embodiments, direct inhalation delivery of about 0.2004 mcg or 0.2004 mcg to 0.7 mcg of pirfenidone or a pyridone analog to 1 gram of lung tissue provides a plasma AUC of 0.2004 mcg or 0.2004 mcg to 0.7 mcg of pirfenidone or a pyridone analog in 1 mL of lung ELF and maintaining these values ​​for the same time period as when delivered via the oral route. 0-無限大 AUC for tissues smaller than 0-無限大 to the AUC of tissues that are equal or nearly equal to it. 0-無限大 and in further embodiments, maintaining these values ​​for the same time period 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 delivered dose (RDD), which is the portion of drug inhaled in aerosol particles less than 5 microns in diameter. 3. The RDD of a typical dry powder, liquid nebulization, or metered dose inhaler device varies from 10% to 70%. In some embodiments, high efficiency or resistivity devices with RDDs greater than 70% and less than 10% are contemplated. 4. The plasma half-life of pirfenidone or a pyridone analog after oral administration is approximately 2.5 hours. In some embodiments, intestinal absorption influences this rule, but for the typical purposes of this model, the pulmonary ELF half-life of pirfenidone after inhalation delivery is assumed to be half that after oral administration (e.g., 2.5 hours / 2 = 1.25 hours). The half-life value may be supported by measurements showing that intravenous administration of pirfenidone results in a pulmonary ELF half-life of approximately half after oral administration. 5. In some embodiments, a lung ELF level of 5 mcg / mL may be the lower limit of efficacy. 6.801 mg of oral pirfenidone results in plasma levels of 5 mcg / mL or greater than 5 mcg / mL (human measurements) over 4 hours. For purposes of comparing pathways, this model assumes that pirfenidone levels at ELF after oral administration remain at 5 mcg / mL or approximately 5 mcg / mL lung ELF for the same duration as plasma.

[0101] Typical ELF calculation: Mcg pirfenidone delivered in 25mL ELF to make 1.5mcg / mL = 125mcg Based on an RDD efficiency of 2.30%, the required unit dose is 416 mcg (125 mcg / 0.3=416 mcg). Based on an RDD efficiency of 3.50%, the required unit dose is 250 mcg (125 mcg / 0.5=250 mcg). Based on an RDD efficiency of 4.70%, the required unit dose is 179 mcg (125 mcg / 0.7 = 179 mcg). Correct to maintain at or above these values ​​for 3.2 half-lives of 1.25 hours each (4 hours at 5 mcg / mL or above 5 mcg / mL with a pulmonary half-life of 1.25 hours = 3.2 half-lives) 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 with a device delivering pirfenidone or a pyridone analog with 30% efficiency may result in a lung ELF level of 5 mcg / mL or greater over the same period as that obtained after oral administration of 801 mg. Furthermore, while the minimum effective pirfenidone dose may be maintained over this duration, local pirfenidone levels may also exhibit significantly higher ELF Cmax levels, providing improved efficacy. In some embodiments, delivery of 4 mg of pirfenidone or a pyridone analog with a 30% efficiency device may result in a lung 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, administration of approximately 66 mg with a device administering pirfenidone or a pyridone analog with 70% efficiency may result in a lung 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, administration of approximately 154 mg with a device administering pirfenidone or a pyridone analog with 30% efficiency may result in a lung 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, administration of approximately 12 mg with a device administering pirfenidone or a pyridone analog with 70% efficiency may result in a lung 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, administration of approximately 28 mg with a device administering pirfenidone or a pyridone analog with 30% efficiency may also result in a lung 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 dose at or above 5 mcg / mL for approximately 6 half-lives or approximately 15 hours. In some embodiments, embodiments described for inhalation therapy provide beneficial efficacy through increased Cmax, maintaining drug exposure at a minimum effective range of 5 mcg / mL or greater for a longer period than is currently limited by oral administration. In some embodiments, extended exposure may allow for a reduction in dosing intervals (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 direct to the lung, these dosages may also result in significantly lower systemic plasma levels (e.g., approximately 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 may result in initially elevated levels in the vasculature and tissues immediately downstream of the lungs (or nasal cavity), resulting in a systemic plasma dilution concentration of 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] Those skilled in the art will recognize from the discussion herein that changes in the actual measured pulmonary ELF half-life of pirfenidone or pyridone analog elimination will alter the dosage calculated by the above model. The shorter the half-life, the more pirfenidone or pyridone analog will need to be administered to maintain a pulmonary ELF concentration above what is considered the minimum effective level. Further increases in the amount of pirfenidone or pyridone analog administered may be desirable to further improve efficacy. Furthermore, in addition to delivering the desired pulmonary tissue Cmax and AUC, delivery of aerosolized pirfenidone or pyridone analogs via oral or intranasal inhalation may also serve as an efficient route for systemic delivery. In some embodiments, administration schemes are contemplated that can achieve the desired pulmonary tissue Cmax and AUC via inhalation delivery of pirfenidone or pyridone analogs, which have a slower plasma half-life than the pulmonary ELF, thereby targeting the delivery of specific plasma concentrations and thereby increasing pulmonary ELF-pirfenidone or pyridone analog exposure.

[0104] Typical lung tissue delivery assumptions: 1. The total wet weight of an adult's lungs is approximately 685 to 1,050 grams (for calculation purposes, we'll use a conservative estimate of approximately 1,000 grams). 2. The pulmonary blood volume of an adult is approximately 450 mL. 3. The lung tissue weight for an adult is conservatively 1,050 grams wet weight minus 450 mL blood weight (assuming a density of 1.0), which equals 600 grams. 4. In some embodiments, mice are injected intravenously with pirfenidone, followed by: -Plasma pirfenidone Tmax is equivalent to pulmonary Tmax. -40 mg / kg intravenous dose results in a plasma Cmax of approximately 55 mcg / mL and a lung Cmax of 30 mcg / gram wet weight. Conservatively, blood accounts for approximately 40% of the wet lung weight. In some embodiments, if the plasma and lung Tmax are equivalent, then most of the 30 mcg / g of pirfenidone measured in the wet lung will be due to the presence of blood. Conservatively, if blood accounts for approximately 40% of the wet lung weight, then 40% of the plasma Cmax of approximately 22 mcg / gram of pirfenidone in the measured lung weight (or 40% of 55 mcg / mL X) will be due to blood. Taking the difference between the wet lung Cmax and this number (or subtracting 22 mcg / g from 30 mcg / g) leaves approximately 8 mcg / g 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 approximately 40% or more of the wet lung pirfenidone is in the blood, the actual lung tissue half-life is 45% longer than in plasma. From the above observations and calculations that a plasma Cmax of 5.55 mcg / mL results in a lung tissue Cmax of approximately 8 mcg / gram, the following comparison can be made to humans. - Based on the initial assumptions, the lower limit of efficacy in humans is 5 mcg / mL of plasma pirfenidone. -Assuming the above ratio (55mcg / mL of plasma results in 8mcg / gram of lung tissue) also applies to humans, 5mcg / mL divided by 55mcg / mL is approximately 9.1%. 9.1% of 8 mcg / gram is approximately 0.7 mcg / gram. -Taken together, 5 mcg / mL of plasma pirfenidone may result in 0.7 mcg / gram of lung tissue pirfenidone. Thus, 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 delivered dose (RDD). The RDD is the portion of drug inhaled in aerosol particles less than 5 microns in diameter. 7. The RDD of a typical dry powder, liquid nebulization, or metered-dose inhaler device varies from 10% to 70%. High-efficiency and low-efficiency devices exist with RDDs greater than 70% and less than 10%. 8. As discussed above, the lung tissue pirfenidone half-life is much longer (2-4 times or more) than the plasma half-life of intravenously delivered pirfenidone. The plasma pirfenidone half-life after oral administration is approximately 2.5 hours. However, continued intestinal absorption affects this number, making it much longer than after intravenous delivery. Therefore, for the purposes of this model, the lung tissue pirfenidone half-life after inhalation 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 efficacy in lung tissue is 8 mcg / gram. Combining that 10.801 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, anything delivered by oral or intranasal inhalation must be 0.7 mcg / gram or greater of lung tissue pirfenidone for at least 4 hours for comparable efficacy against pulmonary fibrosis to 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. Based on an RDD efficiency of 2.30%, the required unit dose is 2,333 mcg (700 mcg / 0.3 = 2,333 mcg). Based on an RDD efficiency of 3.50%, the required unit dose is 1,400 mcg (700 mcg / 0.5 = 1,400 mcg). Based on a 4.70% RDD efficiency, the required unit dose is 1,000 mcg (700 mcg / 0.7 = 1,000 mcg). Correct to maintain at or above these values ​​for 2 half-lives of 2.5 hours each (4 hours in wet lung tissue at 0.7 mcg / gram or greater with a 2.5 hour lung half-life = 1.6 half-lives). For an RDD efficiency of 5.30%, the unit dose required to meet the lower limit of clinically observed efficacy for the oral route (2,333 mcg in this case) for 1.6 half-lives is 3,733 mcg. For an RDD efficiency of 6.50%, the unit dose required to meet the lower limit of clinically observed efficacy for the oral route (1,400 mcg in this case) for 1.6 half-lives is 2,240 mcg. For an RDD efficiency of 7.70%, the unit dose required to meet the lower limit of clinically observed efficacy for the oral route (1,000 mcg in this case) for 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 delivering pirfenidone or a pyridone analog with 30% efficiency may result in wet lung tissue levels of 0.7 mcg / gram or more over the same duration as that achieved after oral administration of 801 mg. Furthermore, while the minimum effective dose of pirfenidone is maintained over this duration, local pirfenidone levels may exhibit significantly higher wet lung tissue Cmax levels, providing improved efficacy. By way of 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 wet lung weight = 1.1 mcg / gram). This number is nearly 1.5 times higher than that delivered after oral delivery. By way of another non-limiting example, based on the above assumptions, a dose of approximately 50 mg in a device 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 wet lung weight = 14.3 mcg / gram), or approximately 20 times higher than when delivered after oral delivery. In this scenario, this dose may result in a minimum effective dose of 0.7 mcg / gram wet lung tissue or more maintained for at least about five half-lives, or about 12.5 hours, compared to 4 hours after administration of an 801 mg oral dose. Similarly, by another limiting example, based on the above assumptions, a dose of approximately 15 mg in a device 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 wet lung weight = 10 mcg / gram), or approximately 14 times higher than when delivered following oral delivery.In this scenario, this dosage may result in a minimum effective dose of 0.7 mcg / gram wet lung tissue or more maintained for approximately 4.5 half-lives, or at least approximately 11 hours, compared to 4 hours after an 801 mg oral dose. Such a duration of more than 0.7 mcg / gram 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 of up to 50 mcg / mL (75 mg x 70% = 52.5 mg; 52.5 mg / 1,050 grams wet lung weight = 50 mcg / gram), or approximately 71-fold higher than when delivered after oral delivery. In this scenario, this dosage may result in the minimum effective dose being maintained at 0.7 mcg / gram wet lung tissue or more for at least about 6 half-lives, or about 15 hours, compared to 4 hours after an 801 mg oral dose. Such a duration of more than 0.7 mcg / gram lung tissue may permit BID administration. 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 of up to 4.3 mcg / mL (15 mg x 30% = 4.5 mg; 4.5 mg / 1,050 grams wet lung weight = 4.3 mcg / gram), or approximately six-fold higher than when delivered after oral delivery. In this scenario, this dosage may result in the minimum effective dose being maintained at 0.7 mcg / gram wet lung tissue or greater for at least about 3 half-lives, or about 7.5 hours, compared to 4 hours after administration of an 801 mg oral dose. Similarly, by another non-limiting example, based on the above assumptions, an approximately 75 mg dose in a device delivering pirfenidone or a pyridone analog with 30% efficiency would result in an elimination efficiency of 21 mcg / mL (75 mg x 30% = 22.5 mg).This dose may result in a wet lung tissue Cmax of up to 22.5 mg / 1,050 grams wet lung weight = 21 mcg / gram, or approximately 31-fold higher when delivered after oral delivery. In this scenario, this dose may result in the minimum effective dose being maintained at 0.7 mcg / gram wet lung tissue or more for at least about 5 half-lives, or about 12.5 hours, compared to 4 hours after an 801 mg oral dose. Such a duration of more than 0.7 mcg / gram lung tissue may permit BID dosing. Similarly, by another non-limiting example, based on the above assumptions, a dose of approximately 15 mg in a device delivering pirfenidone or a pyridone analog with 10% efficiency may result in a wet lung tissue Cmax of up to 1.4 mcg / mL (15 mg x 10% = 1.5 mg; 1.5 mg / 1,050 grams wet lung weight = 1.4 mcg / gram), or approximately twice as high as when delivered after oral delivery. In this scenario, this dose may result in a minimum effective dose of 0.7 mcg / gram wet lung tissue or more maintained for about one half-life, or at least about 2.5 hours, compared to 4 hours after administration of an 801 mg oral dose. Similarly, by another non-limiting example, based on the above assumptions, a dose of approximately 75 mg in a device delivering pirfenidone or a pyridone analog with 10% efficiency may result in a wet lung tissue Cmax of up to 7.1 mcg / mL (75 mg x 10% = 7.5 mg; 7.5 mg / 1,050 grams wet lung weight = 7.1 mcg / gram), or approximately twice as high as when delivered after oral delivery. In this scenario, this dose may result in a minimum effective dose maintained at or above 0.7 mcg / gram wet lung tissue for approximately 3.5 half-lives, or at least about 8.8 hours, compared to 4 hours after administration of an 801 mg oral dose. Such a duration of more than 0.7 mcg / gram of lung tissue may permit TID administration.Such an approach can benefit efficacy by increasing Cmax and maintaining drug exposure at a minimum effective range of 0.7 mcg / gram or more in wet lung tissue for a longer duration than is currently limited by oral administration. Such prolonged exposure may allow for shorter dosing intervals (e.g., once or twice daily compared to the current three times daily oral dosing regimen). Furthermore, while this approach delivers directly to the lung, using the non-limiting examples above, it may also result in reduced systemic plasma levels (e.g., Cmax of less than 0.6 mcg / mL pirfenidone from a 4.5 mg delivered dose to less than 2 mcg / mL pirfenidone from a 15 mg delivered dose, to less than 10 mcg / mL pirfenidone from a 75 mg dose).

[0107] If the actual measured lung tissue half-life of pirfenidone or pyridone analogue elimination changes, the dosage calculated by the above model will change significantly. If the half-life is faster, more inhaled pirfenidone or pyridone analogue 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 analogue may be desirable to further improve efficacy. Furthermore, in addition to delivering the desired lung tissue Cmax and AUC, inhalation delivery of aerosolized pirfenidone or pyridone analogues may also serve as an efficient route for systemic delivery. In some embodiments, an administration scheme is contemplated that allows inhalation delivery of pirfenidone or pyridone analogues to first achieve the desired lung tissue Cmax and AUC, and because the plasma half-life is expected to be slower than the lung tissue half-life, targeting the delivery of a specific plasma concentration may in turn increase the pirfenidone or pyridone analogue exposure to lung tissue.

[0108] Because scarring is irreversible, the efficacy of IPF depends on protecting native lung tissue from aggressive fibrosis. Therefore, maintaining normal levels of effective drug in unaffected tissues is essential to improving patient survival. Clinical and preclinical studies suggest that pirfenidone's efficacy is dose-responsive, ranging from improvement to amelioration of attenuated disease. Unfortunately, significant gastrointestinal (GI) side effects and systemic toxicity force the approved oral dose to be limited to the lower end of this range. Complicating matters, recommendations for food to absorb the dose and frequent initiation of tapering / discontinuation procedures to address these tissues further reduce the pulmonary dose and interrupt necessary maintenance therapy of this otherwise promising drug. Direct inhalation delivery of aerosolized pirfenidone or pyridone analogs to the lung reduces or eliminates these safety or tolerability limitations associated with oral routes of delivery.

[0109] The efficacy of oral pirfenidone has been demonstrated to some extent in human clinical studies, and data suggest that this effect increases with increasing dose. Unfortunately, serious side effects and toxicity have limited oral dosages to the lower end of this efficacy range (Esbriet has been approved up to 2403 mg / d). Because Esbriet's formulation threatens this already low efficacy dose, it requires an initial dose-titration scheme and recommended administration with food (up to three 267 mg capsules or 801 mg three times daily (TID)) to achieve minimal GI tolerance and an acceptable side effect / toxicity profile. Unfortunately, not all patients achieve this recommended dose, and food reduces bioavailability (food reduces Cmax and AUC by ~50% and ~20%, respectively). Furthermore, increased liver enzyme levels and skin photoreactivity trigger physician-guided dose reduction and discontinuation procedures. This procedure allowed for up to a 50% dose reduction before discontinuation in phase 3 trials (dose reduction occurred in between 48% and 67% of patients in these studies). Because prolonged administration of effective drug concentrations to lung tissue is essential to maintain protection from invasive fibrosis, the prescription and practice of oral pirfenidone likely results in sub-effective administration of this otherwise promising drug (a hypothesis that may partially explain the modest efficacy observed in phase 3 trials).

[0110] For oral administration in the context of pulmonary fibrosis treatment, high oral doses are required to achieve the plasma levels necessary for effective lung tissue exposure. However, gastrointestinal side effects and systemic toxicity have limited approved oral doses to levels confined to efficacy and the lower end of the dose-response curve. In one embodiment, inhaled pirfenidone or pyridone analogs improve the efficacy of pirfenidone treatment by increasing the pulmonary dose 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, minimizing systemic distribution of the delivered dose. In some embodiments, inhalation of pirfenidone reduces or eliminates GI exposure and / or systemic toxicity common with oral administration of pirfenidone or pyridone analogs. In some embodiments, inhalation delivery of pirfenidone or pyridone analogs provided herein provides higher lung tissue levels of pirfenidone than is possible through oral administration. In some embodiments, inhaled delivery of pirfenidone or a pyridone analog serves as an efficient means of delivering pirfenidone or a pyridone analog to systemic compartments. In some embodiments, inhaled delivery of pirfenidone or a pyridone analog provides Cmax and AUC advantages over the oral route. In some embodiments, inhaled delivery of pirfenidone or a pyridone analog provides Cmax and AUC advantages over the oral route, and pirfenidone or a pyridone analog delivered via aerosol with plasma recirculation maintains 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 first having to escalate the patient's dosage. In some embodiments, the methods described herein may be used to treat patients diagnosed with mild to severe IPF without first having to escalate the patient's dosage.In some embodiments, the methods described herein may be used to treat patients diagnosed with mild to moderate IPF without the need to monitor, reduce dosage, or discontinue treatment due to gastrointestinal, phototoxicity, 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, reduce dosage, or discontinue treatment due to gastrointestinal, phototoxicity, or liver enzyme-related adverse events. In some embodiments, the methods described herein may be used to administer prophylactic treatment to patients diagnosed with mild to moderate IPF. In some embodiments, the methods described herein may be used to administer prophylactic treatment to patients diagnosed with mild to severe IPF. In some embodiments, the methods described herein may be used to administer prophylactic treatment to patients with mild to moderate IPF without the need to first increase the patient's dosage. In some embodiments, the methods described herein provide prophylactic treatment to patients diagnosed with mild to severe IPF without the need to first increase the patient's dosage. 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, reduce the dosage, or discontinue treatment due to gastrointestinal, phototoxicity, 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, reduce the dosage, or discontinue treatment due to gastrointestinal, phototoxicity, or liver enzyme-related adverse events. In some embodiments, the methods described herein may be used to slow disease progression in patients diagnosed with mild to moderate IPF without the need to first increase the patient's dosage. In some embodiments, the methods described herein may be used to slow disease progression in patients diagnosed with mild to severe IPF without the need to first increase the patient's dosage.In some embodiments, the methods described herein may be used to slow disease progression in patients diagnosed with mild to moderate IPF without the need to monitor, reduce dosage, or discontinue treatment due to gastrointestinal, phototoxicity, or liver enzyme-related adverse events. In some embodiments, the methods described herein may be used to slow disease progression in patients diagnosed with mild to severe IPF without the need to monitor, reduce dosage, or discontinue treatment due to gastrointestinal, phototoxicity, or liver enzyme-related adverse events. By non-limiting example, clinical endpoints of IPF efficacy include a reduction in the decline in forced vital capacity (FVC), a reduction in the decline in distance walked in a 6-minute interval (6-minute walk test; 6MWT), a reduction in carbon monoxide diffusing capacity (DL). CO These include a gradual decrease in serum creatinine (C1), improved progression-free survival (PFS), reduced mortality, and monitoring changes in biomarkers such as MMP7 and CCL18. In some embodiments, a comparison of oral and inhaled aerosol profiles that may be observed is shown in Table A.

[0111] [Table 1]

[0112] In some embodiments, the methods described herein provide for the delivery of high concentrations of readily bioavailable pirfenidone or pyridone analog compounds, which provide improved efficacy over pirfenidone or pyridone analog compounds administered orally or by inhalation in slowly dissolving or otherwise slowly bioavailable compound formulations. In some embodiments, such slowly dissolving or otherwise slowly bioavailable compound formulations for inhalation include, but are not limited to, dry powder formulations, liposomal formulations, nanosuspension formulations, or microsuspension 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 to patient compliance with oral pirfenidone therapy is GI intolerance. Pirfenidone blood levels can be important because they have been implicated in other observed toxicities. Therefore, factors contributing to increased blood levels must be considered. For the oral route of administration, toxicity and GI intolerance limited the dose to 801 mg three times daily. Elevated liver enzymes, photosensitivity reactions, and phototoxicity occur at this dose, but occur more frequently and with increased severity at higher doses. Second, pirfenidone is primarily metabolized by CYP1A2. In vitro metabolism studies using liver microsomes indicate that approximately 48% of pirfenidone is metabolized by CYP1A2, with other CYP isoenzymes, including CYP2C9, 2C19, 2D6, and 2E1, each contributing less than 13%. Therefore, inhibition of these enzyme systems leads to elevated pirfenidone blood concentrations and increases the incidence and severity of toxicity. To this end, items such as grapefruit juice, fluvoxamine, and other inhibitors of CYP1A2 should be avoided during oral treatment with pirfenidone.

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

[0115] Similarly for oral administration, particular caution should be exercised when CYP1A2 inhibitors are used concomitantly with potent inhibitors 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] The oral product should be used with caution in patients receiving treatment with other moderate or strong inhibitors of CYP1A2 (e.g., ciprofloxacin, amiodarone, propafenone).

[0117] Many products that induce CYP enzymes are useful for fibrosis patients, so allowing their use is beneficial. While the oral route is already at the maximum tolerated dose (which only provides moderate efficacy), any inhibition of the enzymes described above increases pirfenidone blood levels, accelerating the rate and worsening the severity of the toxic events described herein. In some embodiments, delivery of pirfenidone or pyridone analogs by oral and intranasal inhalation can achieve effective tissue levels with much less drug than required by oral drug products, and in some embodiments, results in significantly lower blood concentrations, eliminating the consequences associated with the CYP enzyme inhibitory 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 with pirfenidone or pyridone analogs.

[0118] The primary metabolite of pirfenidone is 5-carboxy-pirfenidone. After oral or intravenous administration, this metabolite quickly reaches high blood concentrations. 5-carboxy-pirfenidone does not appear to have anti-fibrotic or anti-inflammatory effects, and its high blood concentrations occur at reduced pirfenidone blood concentrations. Therefore, while oral products are administered to achieve the highest possible blood concentrations, once pirfenidone enters the blood, it is quickly metabolized to inactive species, further reducing the drug's ability to achieve sufficient lung levels required for significant efficacy. In some embodiments, delivery of pirfenidone or pyridone analogs by oral inhalation and intranasal inhalation can directly achieve effective lung tissue levels, thereby minimizing extrapulmonary metabolism.

[0119] In some embodiments, administration of pirfenidone or a pyridone analog compound by inhalation reduces gastrointestinal side effects compared to oral administration. In some embodiments, the reduced gastrointestinal side effects of inhalation administration eliminate the need for initial dose escalation. In some embodiments, administration of pirfenidone or a pyridone analog by inhalation avoids or substantially avoids the gastrointestinal tract, and therefore the effects observed with oral administration of pirfenidone or a pyridone analog compound are minimized or absent. In some embodiments, the lack of food effect with inhalation administration allows for delivery of the full dose.

[0120] In some embodiments, the pharmaceutical compositions described herein are used to treat pulmonary diseases in a mammal. In some embodiments, the pharmaceutical compositions described herein are administered to a mammal by oral or intranasal inhalation for the purpose of treating pulmonary diseases in a mammal. In some embodiments, the pulmonary disease includes, but is not limited to, asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation-induced fibrosis, silicosis, asbestos-induced pulmonary 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, Kaplan syndrome, coal workers' pneumoconiosis, fibrotic alveolitis of unknown cause, obliterative bronchiolitis, chronic bronchitis, emphysema, interstitial pneumonia, Wegner's granulomatosis, pulmonary scleroderma, silicosis, interstitial lung disease, asbestos-induced pulmonary fibrosis and / or pleural fibrosis. In some embodiments, the pulmonary disease is pulmonary fibrosis (i.e., pulmonary fibrosis). In some embodiments, the pulmonary disease is idiopathic pulmonary fibrosis.

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

[0122] IPF, as used herein, refers to "idiopathic pulmonary fibrosis," a chronic disease that manifests over several years and is characterized by scar tissue within the lungs without a known trigger. Exercise-induced shortness of breath and a chronic, dry cough may be prominent symptoms. IPF belongs to a family of lung disorders known as interstitial lung diseases (ILDs), or more precisely, diffuse parenchymal lung diseases. Within this broad category of diffuse lung diseases, IPF belongs to a subgroup known as idiopathic interstitial pneumonias (IIPs). There are seven distinct 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 a median survival time of approximately three years from the time of diagnosis. There is no single test to diagnose pulmonary fibrosis, and several different tests are used in conjunction with the methods described herein, including chest x-rays, pulmonary function tests, exercise tests, bronchoscopy, and lung biopsies.

[0123] Idiopathic pulmonary fibrosis (also known as fibrosing alveolitis of unknown etiology) is the most common form of interstitial lung disease and can be characterized by chronic, progressive parenchymal fibrosis of the lung. Idiopathic pulmonary fibrosis is a progressive clinical syndrome with unknown etiology, and the lack of effective treatment often results in a fatal prognosis. In some embodiments, pirfenidone inhibits fibroblast proliferation and differentiation 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 platelet-derived growth factor (PDGF) A and B levels in bleomycin-induced pulmonary fibrosis. The pirfenidone methods and compositions described herein may be tolerable and effective in patients with severe idiopathic pulmonary fibrosis and other pulmonary diseases. In some embodiments, the pirfenidone methods and compositions described herein may be tolerable and effective in patients with mild to moderate idiopathic pulmonary fibrosis. In some embodiments, increased patient survival, enhanced lung capacity, fewer acute exacerbation episodes (compared to placebo), and / or slowed disease progression are observed 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 pulmonary fibrosis diseases. The term "pulmonary fibrosis" includes all interstitial lung diseases associated with fibrosis. In some embodiments, pulmonary fibrosis includes the terms "idiopathic pulmonary fibrosis" or "IPF." In some embodiments, pulmonary fibrosis may result from, by non-limiting examples, the inhalation of inorganic and organic dusts, gases, fumes, and vapors; drug use; exposure to radiation or radiotherapy; and the development of disorders such as hypersensitivity pneumonitis, coal workers' pneumoconiosis, radiation, chemotherapy, transplant rejection, silicosis, byssinosis, and genetic factors.

[0125] Exemplary pulmonary 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, fibrosing alveolitis of unknown cause, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), sarcoidosis, scleroderma, chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury and acute respiratory distress syndrome (including bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-pulmonary sepsis-induced, and aspiration-induced).

[0126] (renal fibrosis) In some embodiments, the compositions and methods described herein can treat, slow the progression of, or prevent renal fibrosis. Renal fibrosis can also develop as a result of chronic infection, ureteral obstruction by stones, malignant hypertension, radiation therapy, transplant rejection, severe diabetic conditions, or long-term exposure to heavy metals. Additionally, idiopathic glomerulosclerosis and interstitial renal fibrosis have been reported in children and adults. Renal fibrosis is often associated with a global decline in renal function. Studies have shown that oral pirfenidone provides protection against heavy metal challenge and reversal of fibrosis after diabetes induction in rats. Furthermore, pirfenidone's antifibrotic effects have also been demonstrated in renal fibrosis after partial kidney removal in rats. Additionally, clinical studies using oral pirfenidone have shown a delayed decline in renal function in patients with focal segmental glomerulosclerosis. In some embodiments, because the renal vasculature is immediately downstream of the lungs, delivery of pirfenidone or a pyridone analog by inhalation 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 the otherwise harmful drugs associated with oral administration.

[0127] The term "renal fibrosis" refers to remodeling associated with or resulting from chronic infection, obstruction of the ureter 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, or prevent cardiac and / or renal toxicity. Chemotherapeutic agents have multiple organ toxicity during treatment. By way of non-limiting example, doxorubicin has broad therapeutic activity against a variety of tumors. However, its clinical use is limited by its undesirable systemic toxicity, particularly in the heart and kidney. Treatment with pirfenidone reduced the severity of doxorubicin-induced toxicity as assessed by reduced mortality, reduced the amount of fluid recovered in the peritoneal cavity, and reduced 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 a pyridone analog may be an effective means of preventing, managing, or treating chemotherapy-induced cardiac and / or renal inflammation without exposing systemic compartments to other toxic drug concentrations associated with oral administration. In some embodiments, inhaled delivery of pirfenidone or pyridone analog compounds is used to treat cardiac and / or nephrotoxicity associated with chemotherapeutic or other therapeutic agents in humans.

[0129] By way of non-limiting example, the term "cardiotoxicity" can refer to or be caused by exposure to toxic chemotherapy agents. By way of non-limiting example, doxorubicin has broad therapeutic activity against a variety of tumors. However, its clinical use is limited by its undesirable systemic toxicity, particularly in the heart and kidneys.

[0130] By way of non-limiting example, the term "nephrotoxicity" can be related to or caused by exposure to toxic chemotherapy agents. By way of non-limiting example, doxorubicin has broad therapeutic activity against a variety of 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, slow, or prevent cardiac fibrosis. Cardiac remodeling, such as that in chronic hypertension, is associated with myocyte hypertrophy and fibrosis, as well as increased and non-uniform deposition of extracellular matrix proteins. The extracellular matrix connects myocytes, aligns contractile elements, prevents myocyte overstretching and rupture, transmits force, and provides tensile strength to prevent rupture. Fibrosis occurs in many models of hypertension, leading to increased diastolic stiffness, impaired cardiac function, and an increased risk of arrhythmias. If fibrosis, rather than myocyte hypertrophy, is a critical factor in impaired cardiovascular function, reversing cardiac fibrosis itself may restore cardiac function to normal. Because collagen deposition is a dynamic process, appropriate drug loading can selectively reverse existing fibrosis and prevent further fibrosis, thereby improving function even if increased systolic blood pressure remains unchanged.

[0132] Treatment of DOCA-salt hypertensive rats with pirfenidone reversed and prevented fibrosis, suggesting that pirfenidone or a pyridone analog may be an effective means of reducing cardiac fibrosis associated with chronic hypertension and cardiac dysfunction in hypertensive humans. Furthermore, reversal of fibrosis following pirfenidone treatment in streptozotocin-induced diabetic rats has also been demonstrated (Miric et al., 2001). In summary, because the cardiac vasculature is immediately downstream of the lungs, inhaled delivery of pirfenidone or a pyridone analog may be an effective means of preventing, managing, or treating cardiac fibrosis resulting from various 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 viral or bacterial infection, surgery, Duchenne muscular dystrophy, radiation therapy, chemotherapy, transplant rejection, and chronic hypertension, which involves myocyte hypertrophy and fibrosis, resulting in increased and non-identical deposition of extracellular matrix proteins. Fibrosis occurs in many models of hypertension, leading to increased diastolic stiffness, decreased cardiac function, increased risk of arrhythmias, and impaired cardiovascular function.

[0134] <Liver fibrosis> In some embodiments, the compositions and methods described herein can treat, slow, or prevent liver fibrosis. Liver fibrosis occurs as a result of severe liver damage in patients with chronic liver disease, including, but not limited to, persistent viral hepatitis, excessive alcohol consumption, and autoimmune diseases. Liver fibrosis is associated with the abnormal accumulation of extracellular matrix components, particularly collagen. Hepatic stellate cells are non-parenchymal hepatocytes present in the perisinusoidal space. These cells have been shown to be the main source of extracellular matrix in liver fibrosis. Studies have shown that oral pirfenidone provides protective effects against dimethylnitrosamine-induced liver fibrosis by preventing weight loss, reducing liver weight loss, inhibiting the induction of liver fibrosis as measured by histological assessment, and reducing hepatic hydroxyproline levels. Pirfenidone treatment also suppressed the expression of mRNA for type I collagen and transforming growth factor beta in the liver. Additionally, clinical studies administering oral pirfenidone have demonstrated reduced fibrosis and improved quality of life in patients with hepatitis C virus-associated liver disease. Collectively, because the hepatic vasculature is immediately downstream of the lungs, these results indicate that inhaled delivery of pirfenidone or pyridone analogs may be an effective means of preventing, managing, or treating liver fibrosis resulting from various conditions or procedures without exposing the systemic compartment to otherwise toxic drug concentrations associated with oral administration.

[0135] By way of non-limiting example, the term "liver fibrosis" can be associated with or caused by severe liver damage in patients with chronic liver disease, such as, but not limited to, persistent viral hepatitis, excessive alcohol consumption, and autoimmune diseases. Liver fibrosis is associated with the abnormal accumulation of extracellular matrix components, particularly collagen. Hepatic stellate cells are non-parenchymal liver cells present in the perisinusoidal space.

[0136] <Multiple sclerosis> In some embodiments, the compositions and methods described herein can treat, slow, or prevent the progression of multiple sclerosis. Multiple sclerosis is a demyelinating disease characterized by neurological deficits due to demyelinating lesions in white matter and progressive axonal loss. Evidence that TNF-alpha plays an important role in the pathogenesis of multiple sclerosis has led to the evaluation of pirfenidone for this indication. In clinical studies, oral pirfenidone improved Scripps Neurological Rating Scale scores more than placebo. Furthermore, pirfenidone reduced relapses and was associated with significant improvement in bladder dysfunction. Taken together, these studies suggest that because the central nervous system vasculature is immediately downstream of the lungs, inhaled delivery of pirfenidone or pyridone analogs may be an effective means of preventing, managing, or treating multiple sclerosis without exposing systemic compartments to other toxic drug concentrations associated with oral administration.

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

[0138] <Chronic obstructive pulmonary disease (COPD)> In some embodiments, the compositions and methods described herein can treat, slow, or prevent the progression of COPD. By way of non-limiting example, oxidants and oxidative stress caused by cigarette smoking promote pulmonary inflammation, mediated at least in part 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 pro-inflammatory cytokines and chemokines, along with IL-1β, potently activate the p38 subgroup of mitogen-activated protein kinases (MAPKs), a family of signaling enzymes that also includes extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK). JNK and p38 members are primarily activated by cytokines involved in inflammation and apoptosis. Within the MAPK family, both the JNK and p38 subgroups are involved in mediating pro-inflammatory responses, 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 p38-gamma MAPK has been demonstrated to have the potential to restore COPD sensitivity to corticosteroids (Mercado et al., 2007). In some embodiments, inhaled delivery of pirfenidone or pyridone analog compounds is used to treat COPD in humans. In some embodiments, inhaled delivery of pirfenidone or pyridone analogs can be an effective means of preventing, managing, or treating COPD or related diseases without exposing the systemic compartment to otherwise toxic drug concentrations associated with oral administration. Furthermore, inhaled delivery of pirfenidone or pyridone analogs can function as conjunctive therapy with corticosteroids to restore their usefulness in this indication.

[0139] By way of non-limiting example, the term "chronic obstructive pulmonary disease" or "COPD" can be related to or caused by exposure to tobacco smoke and existing asthma. COPD refers to a wide range of airway diseases, ranging from simple chronic bronchitis (coughing due to excessive smoking) to more severe chronic obstructive bronchitis. When episodes of airway hyperresponsiveness 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.

[0140] <Asthma> In some embodiments, the compositions and methods described herein can treat, slow, or prevent the progression of asthma. TNF-alpha has been shown to be a highly pro-inflammatory cytokine in asthma because it upregulates adhesion molecules, increases mucin secretion, and promotes airway modeling. TNF-alpha is produced by numerous cells in the airways, including mast cells, smooth muscle cells, epithelial cells, monocytes, and macrophages. This cytokine has been shown to be associated with and elevated in asthma patients. Clinical studies using anti-TNF-alpha therapy have produced promising results. In a series of studies using a soluble form of recombinant human TNF-alpha receptor (etanercept), the drug improved FEV1 and quality of life. Another clinical study administering an anti-TNF-alpha antibody reduced asthma exacerbations (infliximab). However, due to issues related to adverse events, future studies of these therapies in asthma are unlikely. Since pirfenidone has been shown to inhibit TNF-alpha, inhalation delivery 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, inhalation delivery of pirfenidone or pyridone analog compounds is used to treat asthma in humans.In addition, inhalation delivery of pirfenidone or pyridone analogs can function as a conjugate therapy with corticosteroids to restore their usefulness in steroid-resistant asthma patients.

[0141] The term "asthma" refers to a condition related to or caused by environmental and genetic factors. Asthma is a common chronic inflammatory disease of the airways characterized by variable and recurrent symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath. The term asthma may 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, childhood-onset asthma, adult-onset asthma, cough-type asthma, occupational asthma, steroid-resistant asthma, or seasonal asthma.

[0142] <Lung inflammation> In some embodiments, the compositions and methods described herein can treat, slow the progression of, or prevent pulmonary inflammation. Pirfenidone treatment has been shown to have anti-inflammatory effects in addition to anti-fibrotic effects. In some embodiments, pirfenidone or a pyridone analog compound is administered to a human to treat 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. Bleb loss occurs when fibroblasts proliferate and migrate into the wound, ultimately causing scarring and fistula closure. 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 their nonspecific mechanism of action, these agents can cause widespread cell death and apoptosis, resulting in potentially sight-threatening complications such as severe postoperative hypotension, bleb leaks, and endophthalmitis. Therefore, alternative antifibrotic agents are needed. To this end, the antifibrotic agent pirfenidone or a pyridone analog may prove beneficial.

[0144] The present invention, in some embodiments as disclosed herein, provides compositions and methods for compound formulation of pirfenidone and pyridone analogs that offer unprecedented advantages with respect to localized delivery of pirfenidone or pyridone analogs in a manner that allows 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 pirfenidone or pyridone analog compound formulation is delivered to airway tissue in a mammalian subject, for example, via the respiratory tract to the central airways and / or pulmonary beds (e.g., the alveolar-capillary bed) in a human patient. According to certain particularly preferred embodiments, delivery to these regions of the lung can be achieved by inhalation therapy of the pirfenidone or pyridone analog compound formulation, as described herein.

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

[0147] The compositions and methods disclosed herein provide such rapid, sustained, localized delivery of pirfenidone or pyridone analog compounds to a wide variety of tissues. Embodiments are contemplated for the treatment of numerous clinically significant diseases, including pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, cardiac fibrosis, transplants (e.g., lung, liver, kidney, heart, etc.), vascular grafts, and / or other diseases such as multiple sclerosis, for which treatment with rapid, sustained, bioavailable pirfenidone or pyridone analogs may be indicated.

[0148] Thus, 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 of sustained-release active drug to affected tissues). In particular, in certain preferred embodiments, concentrated doses of pirfenidone or a pyridone analog are delivered.

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

[0150] According to certain related embodiments, controlling the total amount of dissolved solutes in a pirfenidone or pyridone analog compound formulation results in an aqueous pirfenidone or pyridone analog compound formulation having therapeutically beneficial properties, including, by non-limiting theory, the properties of atomized droplets formed from an aqueous solution of such a formulation. Furthermore, as disclosed herein, it has been discovered that, within the parameters provided herein for pirfenidone or pyridone analog compound concentration, pH, and total solute concentration, the tolerance of formulations at or near the upper portion of the total solute concentration range can be increased by the inclusion of a taste-masking agent, as provided herein.

[0151] It has been unexpectedly observed that exposure of the lung surface to inhaled pirfenidone results in lung surface cation depletion and an increased tendency toward acute toxicity. The apparent mechanism for this depletion is pirfenidone's ability to chelate ions such as iron(III) at a ratio of three pirfenidone molecules per iron(III) ion. Iron(III) chelation occurs at half the strength of EDTA chelation. One way to prevent lung surface ion depletion is to formulate pirfenidone with polyvalent ions. By way of non-limiting example, such polyvalent cations can include iron(II), iron(III), calcium, magnesium, etc. By way of non-limiting example, it has been found that formulations of pirfenidone chelate magnesium at a ratio of two pirfenidone molecules to one magnesium ion. Thus, a formulation of approximately 2 to 10 pirfenidone molecules with one magnesium molecule results in the chelation capacity of pirfenidone being filled or saturated, reducing the ability of pirfenidone to deplete lung surface cations. Coupled with the need to adjust the osmotic pressure and osmotic ion content of the formulation, salt forms of multivalent ions can also be beneficial. By way of non-limiting example, the use of 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 osmotic ions to the formulation. In certain such embodiments, for example, compound formulations of pirfenidone or pyridone analogs, including those formulated with excipients, are dissolved in a simple aqueous solution that can be aerosolized and injected or inhaled into the nasal or pulmonary compartments. Such formulations may include multivalent cations and / or may be buffered to a pH of from about 4.0 to about 11.0, more preferably from a pH of from about 4.0 to about 8.0, at a concentration of at least 34 mcg / mL to about 463 mg / mL and with a total osmolality of at least 100 mOsmol / kg to about 6000 mOsmol / kg, or from 300 to about 5000 mOsmol / kg.Such simple aqueous formulations may further include flavoring agents, thereby making them acceptable for inhaled administration (i.e., outweighing undesirable taste or irritation characteristics that would otherwise prevent effective therapeutic administration). Thus, and as described in more detail herein, control of formulation conditions with respect to pH, buffer type, pirfenidone or pyridone analog concentration, total osmolality, and potential flavoring agents provides certain therapeutic and other advantages.

[0152] In certain such embodiments, for example, the pirfenidone or pyridone analog compound formulation comprises at least 0.1 mg to about 100 mg of pirfenidone or pyridone analog, alone or formulated with excipients, such as multivalent cations, that provide improved stability and / or dispersibility in a dry powder formulation, such that it can be dispersed into the nasal or pulmonary compartments and insufflated or inhaled. Thus, and as described in more detail herein, control of formulation conditions related to dispersion excipient, pirfenidone or pyridone analog stability (including, by way of non-limiting example, polymorphs, amorphous content, and moisture), pirfenidone or pyridone analog amount, and potential taste-masking agents provides certain therapeutic and other advantages.

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

[0154] In certain preferred embodiments, the pirfenidone or pyridone analog compound formulation or salt thereof can function as a prodrug, sustained-release or active substance in the formulations and compositions disclosed herein and can be delivered under conditions and for a sufficient time to result in a maximum concentration of the sustained-release or active drug to the respiratory tract (including the pulmonary 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 administration of the pirfenidone or pyridone analog compound via oral and / or nasal inhalation to the lower respiratory tract, i.e., the lungs or lung compartments (e.g., respiratory bronchi, alveolar ducts, and / or alveoli), as can be achieved by such "pulmonary delivery," which provides an effective amount of the pirfenidone or pyridone analog compound to the pulmonary compartment and / or other tissues and organs that can reach them via the circulatory system following pulmonary delivery of the pirfenidone or pyridone analog compound to the pulmonary vasculature.

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

[0156] By way of non-limiting example, in preferred embodiments, a pyridone analog compound (e.g., pirfenidone) as provided herein is formulated to allow for administration of a mist, gas-liquid suspension or nebulized liquid, dry powder, and / or metered-dose inhaled aerosol to provide an effective concentration or amount that provides the desired anti-inflammatory, anti-fibrotic, or tissue remodeling benefit, e.g., to prevent, manage, or treat a patient with pulmonary fibrosis.

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

[0158] By way of non-limiting example, in preferred embodiments, the pyridone analog compounds (e.g., pirfenidone) provided herein are formulated to allow for administration of a mist, gas-liquid suspension or atomized liquid, dry powder, and / or metered-dose inhaled aerosol to provide an effective concentration or amount that provides the desired anti-inflammatory, anti-fibrotic, or tissue remodeling benefit, for example, to prevent, manage, or treat cardiac fibrosis in human and / or veterinary subjects. Such embodiments provide direct and high-concentration delivery of pirfenidone or pyridone analog compounds to the pulmonary vasculature immediately upstream of the left atrium and, therefore, to the coronary arterial system with intravenous exposure to the atria and ventricles.

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

[0160] By way of non-limiting example, in preferred embodiments, the pyridone analog compounds (e.g., pirfenidone) provided herein are formulated to allow for administration of a mist, gas-liquid suspension or atomized liquid, dry powder, and / or metered-dose inhaled aerosol to provide an effective concentration or amount that provides the desired anti-inflammatory, anti-fibrotic, or tissue remodeling benefit, for example, to prevent, manage, or treat renal fibrosis. Such embodiments provide direct and high-concentration delivery of pirfenidone or pyridone analog compounds to the pulmonary vasculature immediately upstream of the left atrium, left ventricle, and thus to the renal vasculature.

[0161] While different formulations are known to vary in effectiveness depending on dosage, form, concentration, and delivery characteristics, the embodiments disclosed herein provide specific formulations and delivery parameters that provide protection against and treatment for renal fibrosis associated with, by way of non-limiting examples, infection, ureteral stones, malignant hypertension, radiation therapy, diabetes, exposure to heavy metals, chemotherapy, and transplant rejection.

[0162] By way of non-limiting example, in preferred embodiments, the pyridone analog compounds (e.g., pirfenidone) provided herein are formulated to allow for administration of a mist, gas-liquid suspension or atomized liquid, dry powder, and / or metered-dose inhaled aerosol to provide an effective concentration or amount that provides the desired anti-inflammatory benefit, for example, to prevent, manage, or treat cardiac or renal toxicity. Such embodiments provide direct and high-concentration delivery of pirfenidone or pyridone analog compounds to the left atrium, the pulmonary vasculature immediately upstream of the left ventricle, and thus to the cardiac and renal vasculature.

[0163] While different formulations are known to vary in effectiveness depending on dosage, form, 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 chemotherapy-related cardiac or renal toxicity.

[0164] By way of non-limiting example, in a preferred embodiment, the pyridone analog compound (e.g., pirfenidone) provided herein is formulated to allow for administration of a mist, gas-liquid suspension or atomized liquid, dry powder, and / or metered-dose inhaled aerosol to provide an effective concentration or amount that provides the desired anti-inflammatory, anti-fibrotic, or tissue remodeling benefit, for example, for preventing, managing, or treating liver fibrosis. Such an embodiment provides direct and high-concentration delivery of pirfenidone or the pyridone analog compound to the left atrium, the pulmonary vasculature immediately upstream of the left ventricle, and thus to the hepatic vasculature.

[0165] While different formulations are known to vary in effectiveness depending on dosage, form, concentration, and delivery characteristics, the embodiments disclosed herein provide specific formulations and delivery parameters that provide protection against and treatment for liver fibrosis associated with, by way of non-limiting examples, liver infection, hepatitis, alcohol overdose, autoimmune disease, radiation therapy, chemotherapy, and transplant rejection.

[0166] By way of non-limiting example, in preferred embodiments, the pyridone analogue compound (e.g., pirfenidone) provided herein is formulated to allow administration of a mist, gas-liquid suspension or atomized liquid, dry powder, and / or aerosol administered by nasal injection or inhalation, or orally inhaled, in a metered dose, to provide an effective concentration or amount that provides the desired anti-inflammatory and / or anti-demyelination benefits, for example, for preventing, managing, or treating multiple sclerosis.When administered orally, these embodiments provide direct and high-concentration delivery of pirfenidone or pyridone analogue compounds to the pulmonary vasculature immediately upstream of the left atrium and left ventricle, and thus to the central nervous system.When administered orally, these embodiments provide direct and high-concentration delivery of pirfenidone or pyridone analogue compounds to the nasal and sinus vasculature immediately upstream of the central nervous system.

[0167] While different formulations are known to vary in effectiveness depending on dosage, form, concentration, and delivery characteristics, the embodiments disclosed herein provide specific formulations and delivery parameters that provide protection against and treatment for multiple sclerosis.

[0168] By way of non-limiting example, in preferred embodiments, a pyridone analog compound (e.g., pirfenidone) as provided herein is formulated to allow for administration of a mist, gas-liquid suspension or nebulized liquid, dry powder, and / or metered-dose inhaled aerosol to provide an effective concentration or amount that provides the desired anti-inflammatory, anti-fibrotic, or tissue remodeling benefit for preventing, managing, or treating patients with diseases associated with chronic obstructive pulmonary disease (COPD), including, for example, emphysema and chronic bronchitis.

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

[0170] By way of non-limiting example, in preferred embodiments, a pyridone analog compound (e.g., pirfenidone) as provided herein is formulated to allow for administration of a mist, gas-liquid suspension or nebulized liquid, dry powder, and / or metered-dose inhaled aerosol to provide an effective concentration or amount that provides the desired anti-inflammatory benefit, e.g., to prevent, manage, or treat a patient with asthma.

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

[0172] By way of non-limiting example, in preferred embodiments, a pyridone analog compound (e.g., pirfenidone) as provided herein is formulated to allow for administration of a mist, gas-liquid suspension or nebulized liquid, dry powder, and / or metered-dose inhaled aerosol to provide an effective concentration or amount that provides the desired anti-inflammatory, anti-fibrotic, or tissue remodeling benefit, for example, to prevent, manage, or treat patients with cystic fibrosis. Such embodiments may include co-formulation or co-administration of the pyridone analog compound with antibiotics, steroids, hyperosmotic solutions, DNAse or other mucus-thinning agents, or other agents.

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

[0174] For the applications described herein, the nebulized liquid, dry powder, or metered-dose aerosol of pirfenidone or a pyridone analog compound (or salt thereof) may be co-administered, sequentially administered, or may be administered in combination with an antibacterial agent (e.g., tobramycin and / or other aminoglycosides such as amikacin, aztreonam and / or other beta- or mono-bactams, ciprofloxacin, levofloxacin and / or others, fluoroquinolones, azithromycin and / or other macrolides or ketolides, tetracyclines and / or other tetracyclines). Lacyclines, quinupristin and / or other streptogramins, linezolid and / or other oxazolidinones, vancomycin and / or other glycopeptides, and chloramphenicol and / or other phenicols, and colisitin and / or other polymyxins), bronchodilators (e.g., beta-2 agonists and muscarinic antagonists), corticosteroids (e.g., salmeterol, fluticasone, and budesonide), glucocorticoids (e.g., prednisone), cromolyn, nedocromil, leukotrienes, fluticasone, fluoxetine ... Hypertonic solutions, DNAse or other mucus-thinning agents, interferon gamma, cyclophosphamide, colchicine, N-acetylcysteine, azathioprine, bromhexine, endothelin receptor antagonists (e.g., bosentan and ambrisentan), PDE5 inhibitors (e.g., sildenafil, vardenafil, and tadalafil), PDE4 inhibitors (e.g., roflumilast, cilomilast, oglemilast, tetomilast, and SB256066), prostacyclin, thiazolinone ... prostinoids (e.g. epoprostenol, iloprost and treprostinin), nitric oxide or nitric oxide donating compounds, IL-13 blockers, IL-10 blockers, CTGF specific antibodies, CCN2 inhibitors, angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, PDGF inhibitors, PPAR antagonists, imatinib, CCL2 specific antibodies, CXCR2 antagonists, triple growth factor kinase inhibitors, anticoagulants, TNF blockers, tetracycline or tetracycline derivatives,5-lipoxygenase inhibitors, pituitary hormone inhibitors, TGF-β-neutralizing antibodies, copper chelators, 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-carboxamides), PI3K inhibitors, LTB4 inhibitors, antioxidants (e.g., Mn-pentaazatetracyclohexacosatriene, M40419, N-acetyl-L-cysteine, Mucomyst, Fluimucil, Nacistelin, Erdostein), Ebse Ebeselen, thioredoxin, glutathione peroxidase memetrix, curcumin C3 complex, resveratrol and analogs, tempol, catalytic antioxidants, and OxSODrol), TNF scavengers (e.g., infliximab, ethercept, adalumimab, PEG-sTNFR1, afelimomab, and antisense TNF-alpha oligonucleotides), It may be prepared in fixed combinations with interferon beta-1a (Avonex, Betaseron, or Rebif), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), natalizumab (Tysabri), methotrexate, azathioprine (Imuran), intravenous immunoglobulin (IVIg), cyclophosphamide (Cytoxan), lioresal (baclofen), tizanidine (Zanaflex), benzodiazepines, cholinergic agents, antidepressants, and amantadine.

[0175] Methods of administering pirfenidone or a pyridone analog as a fixed combination, simultaneous administration, sequential administration, or co-formulation (as required by the prescribing physician that the drugs be administered in a sequence as a combination therapy to treat the same disease) with drugs targeting fibrotic or inflammatory diseases are described to enable "cocktail therapy" or "cocktail prophylaxis" in fibrotic diseases, more specifically idiopathic pulmonary fibrosis and other pulmonary fibrotic diseases, as shown as a promising approach for treating cancer and pulmonary arterial hypertension. By way of non-limiting example, pirfenidone or a pyridone analog is administered in a fixed combination, simultaneous administration, sequential administration, or co-formulation with monoclonal GS-6624 (formerly known as AB0024), an analog, or another antibody targeting the LOXL2 protein, which is involved in connective tissue biosynthesis, to reduce inflammation and / or fibrosis. By another non-limiting example, pirfenidone or a pyridone analog may be administered in a fixed combination, co-administered, sequentially administered, or co-formulated with IW001 (Type V collagen), analogs, or other collagens that target immune tolerogenesis to reduce inflammation and / or fibrosis. By another non-limiting example, pirfenidone or a pyridone analog may be administered in a fixed combination, co-administered, sequentially administered, or co-formulated with PRM-151 (recombinant pentraxin-2), analogs, or other molecules that target regulation of the injury response to reduce inflammation and / or fibrosis. By another non-limiting example, pirfenidone or a pyridone analog may be administered in a fixed combination, co-administered, sequentially administered, or co-formulated with CC-903 (Jun kinase inhibitor), analogs, or other Jun kinase inhibitors to reduce inflammatory responses.By way of another non-limiting example, pirfenidone or a pyridone analog may be administered in a fixed combination, co-administered, sequentially administered, or co-formulated with STX-100 (a monoclonal antibody targeting integrin alpha-v beta-6), an analog, or other antibody targeting integrin alpha-v beta-6 or other integrins to reduce fibrosis. By way of another non-limiting example, pirfenidone or a pyridone analog may be administered in a fixed combination, co-administered, sequentially administered, or co-formulated with QAX576 (a monoclonal antibody targeting interleukin-13 [IL-13]), an analog, or other antibody targeting IL-13 to reduce inflammation. By way of another non-limiting example, pirfenidone or a pyridone analog may be administered in a fixed combination, co-administered, sequentially administered, or co-formulated with FG-3019 (a monoclonal antibody targeting connective tissue growth factor [CTGF]), an analog, or other antibody targeting CTGF to reduce fibrosis. By way of another non-limiting example, pirfenidone or a pyridone analog may be administered in a fixed combination, co-administered, sequentially administered, or co-formulated with CNTO-888 (a monoclonal antibody targeting chemokine [CC motif] ligand 2 [CCL2]), an analog, or other antibody targeting CCL2 to reduce fibrosis. By another non-limiting example, pirfenidone or a pyridone analog is administered in a fixed combination, co-administered, sequentially administered, or co-formulated with Esbriet, Pirespa, or Pirfenex (trade names for pirfenidone), or an analog that targets inflammation and fibrosis.By another non-limiting example, pirfenidone or a pyridone analog is administered in a fixed combination, co-administered, sequentially administered, 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]), analogs, or other triple kinase inhibitors to reduce fibrosis and / or inflammation.

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

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

[0178] In addition to the clinical and pharmacological criteria according to which any composition intended for therapeutic administration (such as the pirfenidone or pyridone analog compound formulations described herein) may be characterized, those skilled in the art will recognize many physicochemical factors unique to a given pharmaceutical composition, including, but not limited to, aqueous solubility, viscosity, partitioning coefficient (LogP), predicted stability in various formulations, osmolality, surface tension, pH, pKa, pKb, dissolution rate, sputum permeability, sputum binding / inactivation, taste, throat irritation, and acute tolerance.

[0179] Other factors to consider when selecting a particular product form include the physicochemistry of the formulation (e.g., pirfenidone or pyridone analog compound formulation), the intended disease indication for which the formulation is to be used, clinical acceptability, and patient compliance. By way of non-limiting example, a desired pirfenidone or pyridone analog compound formulation for aerosol delivery (e.g., by oral and / or intranasal inhalation of a mist, such as an atomized suspension of liquid particles, a dry powder formulation generated with a metered dose of propellant, or an aerosol dispersion) can be packaged and administered using an inhalation device, such as a metered dose inhaler, in the form of a simple liquid, such as an aqueous liquid (e.g., a soluble pirfenidone or pyridone analog compound with a non-encapsulated soluble excipient / salt), a complex ... or a complex liquid, such as a soluble pirfenidone or pyridone analog compound with a non-encapsulated soluble excipient / salt, such as a lipid, liposome, cyclodextrin, microencapsulation, and emulsion. The compound may be provided in the form of an excipient-encapsulated or complexed pirfenidone or pyridone analog compound), a complex suspension (e.g., a low-solubility, stable nanosuspension alone, in a co-crystal / co-precipitate complex, and / or in a mixture with a low-solubility lipid such as solid lipid nanoparticles), a dry powder (e.g., a dry powder pirfenidone or pyridone analog compound alone or in a co-crystal / co-precipitate / spray-dried complex or mixture with a low-solubility excipient / salt or a more soluble compound such as lactose), or an organic soluble or organic suspension solution.

[0180] The selection of a particular pirfenidone or pyridone analog compound formulation or composition of a pirfenidone or pyridone analog compound formulation, as provided herein according to certain preferred embodiments, depends on the desired product packaging. Factors to consider when selecting packaging may include, for example, inherent product stability, whether the formulation is susceptible to lyophilization, device selection (e.g., liquid nebulizer, dry powder inhaler, metered dose inhaler), and / or packaging form (e.g., simple liquid, complex liquid formulation), whether provided in a vial as a liquid or lyophilized to be dissolved before insertion into the device, complex suspension formulation, whether provided in a vial as a liquid or lyophilized, and with or without soluble salt / excipient components 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 as a soluble or poorly soluble solid drug in a separate container alone or together with a soluble or poorly soluble solid drug in a separate container.

[0181] The packaged pharmaceutical preparations can be made in a manner to provide compositions of pirfenidone or pyridone analog compound formulations for pulmonary delivery, including solutions provided as aqueous solutions of the pirfenidone or pyridone analog compound at a concentration of at least 0.1 mg / mL to about 50 mg / mL, having a pH of about 3.0 to about 11.0, more preferably about 4 to 8, and having a total osmolality of at least 50 mOsmol / kg to about 1000 mOsmol / kg, more preferably 200 to about 500 mOsmol / kg.

[0182] In some embodiments, the present invention relates to aerosol delivery and / or local delivery of pyridone analog compounds (e.g., pirfenidone). Pirfenidone has favorable solubility, allowing for clinically desirable levels of administration by aerosol (e.g., via liquid atomization, dry powder dispersion, or metered administration) or topically (e.g., as an aqueous suspension, oil formulation, or as a drop, spray, suppository, ointment, or salve), and can be used in methods for acute or preventive treatment of subjects with pulmonary fibrosis or at risk of pulmonary fibrosis. Clinical criteria for determining when pulmonary fibrosis exists or when a subject is at risk of pulmonary fibrosis are known to those skilled in the art. Pulmonary delivery by inhalation allows for direct, targeted, and titrated administration directly to the clinically desired site to reduce systemic exposure.

[0183] In a preferred embodiment, the method treats or serves as a prophylaxis against interstitial lung disease (ILD) by administering a compound formulation of pirfenidone or a pyridone analog as an aerosol (e.g., a suspension of liquid particles in air or another gas) to a subject having or suspected of having ILD. Interstitial lung disease includes those forms of idiopathic interstitial pneumonia, as defined by the American Thoracic Society / European Respiratory Society international multidisciplinary consensus classification of idiopathic interstitial pneumonias, AM. J. Respir. Crit. Care Med. 165, 277-304 (2002). These include ILDs of known cause or related to connective tissue diseases, occupational causes, or adverse drug reactions, idiopathic interstitial pneumonias (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 osteohistiocytosis, eosinophilic pneumonia, and pulmonary alveolar proteinosis).

[0184] Therapeutic methods may also include a diagnostic step, such as identifying a subject with or suspected of having ILD. In some embodiments, the method further subclassifies idiopathic pulmonary fibrosis. In some embodiments, the delivered amount of the aerosol pirfenidone or pyridone analog compound (or salt thereof) formulation is sufficient to provide acute, subacute, or chronic symptom relief, slowing the progression of fibrosis, halting the progression of fibrosis, reversing fibrotic damage, and / or subsequently increasing survival and / or improving quality of life.

[0185] Therapeutic methods may also include a diagnostic step, such as identifying subjects 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 the nebulized liquid, dry powder, or metered-dose aerosol pirfenidone or pyridone analog compound (or salt thereof) formulation is sufficient to provide acute, subacute, or chronic symptom relief, slowing the progression of fibrosis, halting the progression of fibrosis, reversing fibrotic damage, and / or subsequently increasing survival and / or improving quality of life.

[0186] Therapeutic methods 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 the nebulized liquid, dry powder, or metered-dose aerosol pirfenidone or pyridone analog compound (or salt thereof) formulation is sufficient to provide acute, subacute, or chronic symptomatic relief, slowing the progression of demyelination, halting the progression of demyelination, reversing demyelinating damage, and / or subsequently increasing survival and / or improving quality of life.

[0187] In another embodiment, the nebulized liquid, dry powder, or metered-dose aerosol of pirfenidone or a pyridone analog compound (or salt thereof) can be co-administered, sequentially administered, or prepared in a fixed combination with an antibacterial agent to also provide treatment for coexisting bacterial infections. By way of non-limiting example, bacteria can also be present, such as 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 cepacia, 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 haemolyticus), Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, 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 may be a gram-negative bacterium, such as Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides vulgatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides egersii, and Bacteroides plankunnicus. In some embodiments of the methods described above, the bacteria are Gram-negative anaerobic bacteria, including, by non-limiting example, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides vulgatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides egersii, and Bacteroides plancnicus. In some embodiments of the methods described above, the bacteria are Gram-positive bacteria, including, 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. In some embodiments of the methods described above, the bacteria are gram-positive anaerobic bacteria, including, by way of non-limiting example, Clostridium difficile, Clostridium perfringens, Clostridium tetani,tetini, and Clostridium botulinum. In some embodiments of the methods described above, the bacteria is an acid-fast bacterium, including, 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 is an atypical bacterium, including, by way of non-limiting example, Chlamydia pneumoniae and Mycoplasma pneumoniae.

[0188] By way of non-limiting example, in a preferred embodiment, a pyridone analog compound (e.g., pirfenidone) as provided herein is formulated to allow administration of a mist, gas-liquid suspension or nebulized liquid, dry powder, and / or metered-dose inhaled aerosol to provide an effective concentration or amount that achieves and maintains a threshold drug concentration in the lung and / or targeted downstream tissues, as measured by drug concentrations in epithelial lining fluid (ELF), sputum, lung tissue, bronchial lavage fluid (BAL), or by analyzing blood levels via pharmacokinetic analysis. One embodiment includes the use of aerosol administration to provide high or titrated drug exposure directly 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 between 0.1 mg / mL and about 50 mg / mL of pirfenidone or a pyridone analog. In another embodiment, the peak lung wet tissue level achieved after aerosol administration to the lung will be a level of between 0.004 mcg / gram of pirfenidone or pyridone analog and about 500 mcg / gram of lung tissue.

[0189] By way of non-limiting example, in a preferred embodiment, the pyridone analog compound (e.g., pirfenidone) provided herein is formulated to allow administration of a mist, gas-liquid suspension or nebulized liquid, dry powder, and / or metered-dose inhaled aerosol to provide an effective concentration or amount that results in and maintains a threshold drug concentration in the blood and / or lungs, as measured by analyzing blood levels via pharmacokinetic analysis, or absorption into the pulmonary vasculature, resulting in a drug concentration sufficient for extrapulmonary treatment, maintenance, or prevention. One embodiment includes, but is not limited to, the use of aerosol administration, resulting in high drug exposure in the pulmonary vasculature and the following tissues for the treatment, maintenance, and / or prevention of cardiac fibrosis, renal fibrosis, liver fibrosis, cardiac or renal toxicity, or multiple sclerosis. In one such embodiment, the 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 lungs following oral inhalation, or after aerosol administration to the lungs or nasal passages following intranasal administration, are between 0.1 mcg / mL and about 50 mcg / mL of pirfenidone or pyridone analog. In another embodiment, the peak lung wet tissue levels achieved after aerosol administration to the lungs are between 0.004 mcg / gram of pirfenidone or pyridone analog / gamma / gram of lung tissue.

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

[0191] In another embodiment, a method is provided for acute or prophylactic treatment of patients via parenteral or nonnasal topical administration of a compound formulation of pirfenidone or a pyridone analog (or salt thereof) to achieve and maintain a threshold drug concentration at the burn site. One embodiment involves the use of aerosol administration or drops of the formulation to provide high drug exposure directly to affected tissues for the treatment or prevention of scarring after surgical glaucoma surgery (e.g., bleb fibrosis). For example, in these and related embodiments, the term aerosol can include sprays, mists, or other cored liquid or dry powder forms. Drops can be simple liquid or suspension formulations.

[0192] In another embodiment, the pyridone analog compound (e.g., pirfenidone) provided herein is formulated for inhalation, wherein the inhaled liquid aerosol or dry powder aerosol (e.g., after liquid nebulization or metered administration) has a mean aerodynamic mass median particle size of about 1 micron to 10 microns and a geometric standard deviation of about 3 microns or less. In another embodiment, the particle size is a mass aerodynamic mass median particle size of 2 microns to about 5 microns and a geometric standard deviation of about 3 microns or less. In one embodiment, the geometric standard deviation is about 2 microns or less.

[0193] By way of non-limiting example, in preferred embodiments, a pyridone analog compound (e.g., pirfenidone) as provided herein remains at a therapeutically effective concentration at the site of the pulmonary pathology, suspected pulmonary pathology, and / or 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 at least 1 week. An effective pirfenidone or pyridone analog concentration is sufficient to produce a therapeutic effect, which may be localized to the site of the pulmonary pathology or may act broadly from the site of the pulmonary pathology.

[0194] By way of non-limiting example, in preferred embodiments, following inhalation administration, a pyridone analog compound (e.g., pirfenidone or a salt thereof) as provided herein remains at a therapeutically effective concentration at the site of cardiac fibrosis, renal fibrosis, hepatic fibrosis, cardiac or renal toxicity, or multiple sclerosis demyelination 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 at least 1 week. An effective pirfenidone or pyridone analog concentration is sufficient to produce a therapeutic effect, which may be localized to the site of the extrapulmonary pathology or may act broadly from the site of the extrapulmonary pathology.

[0195] In some embodiments, at a delivery site, such as a pulmonary site, a pirfenidone or pyridone analog compound formulation as provided herein is administered in one or more doses to achieve a daily respirable delivered dose of at least about 0.1 mg to about 50 mg of pirfenidone or pyridone analog, 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, the pirfenidone or pyridone analog compound formulation as provided herein is administered in an amount of 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, and administered in one or more administrations to achieve a daily respirable delivered dose of at least about 0.1 mg to about 30 mg of pirfenidone or a pyridone analog, including all integer values ​​such as 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, etc. The pirfenidone or pyridone analog formulation is administered in the respirable delivery dose described 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 inspiration breaths, 8 inspiration breaths, 6 inspiration breaths, 4 inspiration breaths, 3 inspiration breaths, 2 inspiration breaths or 1 inspiration breath. In some embodiments, the pirfenidone or pyridone analog formulation is administered at the respirable delivery dose described using a breathing pattern of 1 second inhalation and 2 seconds exhalation, 2 seconds inhalation and 2 seconds exhalation, 3 seconds inhalation and 2 seconds exhalation, 4 seconds inhalation and 2 seconds exhalation, 5 seconds inhalation and 2 seconds exhalation, 6 seconds inhalation and 2 seconds exhalation, 7 seconds inhalation and 2 seconds exhalation, or 8 seconds inhalation and 2 seconds exhalation.

[0196] In some embodiments, at a delivery site such as the nasal cavity or sinuses, the pirfenidone or pyridone analog (or salt thereof) compound formulation is administered in one or more doses to achieve a daily nasal or sinus deposited dose of at least about 0.1 mg to about 50 mg of pirfenidone or pyridone analog, 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 sinuses, the compound formulation of pirfenidone or a pyridone analog (or salt thereof) is administered at a concentration of 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, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 400, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 48 It is administered in one or more administrations to achieve a daily nasal or sinus deposited dose of at least about 0.1 mg to about 300 mg of pirfenidone or a pyridone analog, including all integer values ​​such as 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, etc. The pirfenidone or pyridone analog formulation is administered at the stated nasal or sinus deposited dose in 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 nasal breaths, 8 nasal breaths, 6 nasal breaths, 4 nasal breaths, 3 nasal breaths, 2 nasal breaths, or 1 nasal breath. In some embodiments, the pirfenidone or pyridone analog formulation is administered at the respirable delivery dose described using a breathing pattern of 1 second inhalation and 2 seconds exhalation, 2 seconds inhalation and 2 seconds exhalation, 3 seconds inhalation and 2 seconds exhalation, 4 seconds inhalation and 2 seconds exhalation, 5 seconds inhalation and 2 seconds exhalation, 6 seconds inhalation and 2 seconds exhalation, 7 seconds inhalation and 2 seconds exhalation, or 8 seconds inhalation and 2 seconds 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 with ILD. In some embodiments, the method further subclassifies idiopathic pulmonary fibrosis. In some embodiments of the methods described above, the human subject may be on a ventilator.

[0198] In embodiments where the person is mechanically ventilated, aerosol administration is accomplished using an in-line device (by way of non-limiting example, Nektar Aeroneb Pro) or similar adapter with a device for liquid nebulization. Aerosol administration can also be accomplished using an in-line adapter for the generation and delivery of dry powder or metered dose aerosols.

[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 cardiac fibrosis treatment. In some embodiments of the methods described above, the human subject may be on 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 renal fibrosis treatment. In some embodiments of the methods described above, the human subject may be on 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 liver fibrosis treatment. In some embodiments of the methods described above, the human subject may be on 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 on 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 COPD treatment. In some embodiments of the methods described above, the human subject may be on 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 asthma treatment. In some embodiments of the methods described above, the human subject may be on 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 multiple sclerosis treatment. In some embodiments of the methods described above, the human subject may be on a ventilator.

[0206] In another embodiment, a pharmaceutical composition is provided comprising a simple liquid pirfenidone or pyridone analog (or salt thereof) compound formulation having an unencapsulated water-soluble excipient as described above, with an osmolality of about 50 mOsmol / kg to about 6000 mOsmol / kg. In one embodiment, the osmolality is about 50 mOsmol / kg to about 1000 mOsmol / kg. In one embodiment, the osmolality is about 400 mOsmol / kg to about 5000 mOsmol / kg. In other embodiments, the osmolality 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. In osmolality, and elsewhere in this application, "about" when used to refer to a quantitative value means that the given amount may 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 amount.

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

[0208] In another embodiment, a pharmaceutical composition is provided comprising a complexed liquid pirfenidone or pyridone analog (or salt thereof) compound formulation encapsulated and complexed with a water-soluble excipient, such as a lipid, liposome, cyclodextrin, microencapsulation, or emulsion, as described above, having a solution osmolality of about 50 mOsmol / kg to about 6000 mOsmol / kg. In one embodiment, the osmolality is about 50 mOsmol / kg to about 1000 mOsmol / kg. In one embodiment, the osmolality is about 100 mOsmol / kg to about 500 mOsmol / kg. In one embodiment, the osmolality is about 400 mOsmol / kg to about 5000 mOsmol / kg.

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

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

[0211] In another embodiment, a pharmaceutical composition is provided comprising a simple liquid formulation of a pirfenidone or pyridone analog (or salt thereof) compound formulation having a pirfenidone or pyridone analog to polyvalent cation positive charge molar ratio of between about 2 pirfenidone or pyridone analog compounds to about 0.1 to about 4 positive charges of the polyvalent cation. By way of non-limiting example, two pirfenidone or pyridone analog compounds for one magnesium ion (two cation positive charges), three pirfenidone or pyridone analog compounds for one magnesium ion, four pirfenidone or pyridone analog compounds for one magnesium ion, and two pirfenidone or pyridone analog compounds for two magnesium ions.

[0212] An unexpected discovery was that divalent cations, such as, but not limited to, magnesium, decrease the dissolution time of pirfenidone and increase its aqueous solubility in a molar ratio-dependent manner.This increased saturated solubility allows the expected delivery of sufficient amounts of inhaled nebulized pirfenidone to the lungs.As an example, one pirfenidone molecule per three magnesium molecules exhibits slower dissolution time and reduced saturated solubility than one pirfenidone molecule per one magnesium molecule.Furthermore, one pirfenidone molecule per one magnesium molecule exhibits faster dissolution time and greater aqueous solubility than an equimolar ratio of pirfenidone to sodium.

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

[0214] In another embodiment, a pharmaceutical composition is provided comprising a complex liquid pirfenidone or pyridone analog (or salt thereof) compound formulation as a low-water-soluble stable nanosuspension, either alone or in a co-crystal / co-precipitate complex, or in a mixture with a low-solubility lipid, such as a lipid nanosuspension, as described above, having a solution osmolality of about 50 mOsmol / kg to about 6000 mOsmol / kg. In one embodiment, the osmolality is about 100 mOsmol / kg to about 500 mOsmol / kg. In one embodiment, the osmolality is about 400 mOsmol / kg to about 5000 mOsmol / kg.

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

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

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

[0218] In other embodiments, the pirfenidone or pyridone analog (or salt thereof) compound formulation or pharmaceutical composition as provided herein is provided with 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 the taste, aftertaste, perceived unpleasant saltiness, sourness, or bitterness, or reduce the tendency of an oral or inhaled formulation to irritate the recipient (e.g., by causing coughing or sore throat or other undesirable side effects, which may reduce the delivered dosage or adversely affect patient compliance with a prescribed treatment regimen). Certain flavoring agents may form complexes with the pirfenidone or pyridone analog (or salt thereof) compound.

[0219] In certain preferred embodiments relating to the pirfenidone or pyridone analog (or salt thereof) compound formulations disclosed herein, the formulations comprise a pirfenidone or pyridone analog (or salt thereof) compound and a flavoring agent, and may be optimized for a desired osmolality 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, offers a particular advantage related to its ability to provide a desirable taste effect even when present at very low concentrations, such that it may have little or no effect on the detectable osmolality of the solution, thereby enabling the formulations described herein to be delivered in a well-tolerated manner in aqueous, organic, or dry powder formulations. 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, offers a particular advantage related to its ability to provide a desirable taste effect by masking taste-stimulating chemical moieties on the pirfenidone or pyridone analog. The inclusion of a divalent cation as a flavoring agent can also serve as a substitute for a tonicity adjusting agent, and the pending salt form can also provide an osmotic ion (e.g., magnesium chloride), thereby allowing the formulations described herein to be delivered in a well-tolerated manner in aqueous, organic, or dry powder formulations. Non-limiting examples of these and related embodiments include a pirfenidone or pyridone analog (or salt thereof) compound formulation for pulmonary delivery as described herein, comprising an aqueous solution having a pH of about 4 to about 8 and an osmolality of about 50 to about 1000 mOsmol / kg (e.g., adjusted with sodium chloride), the aqueous solution comprising a pirfenidone or pyridone analog (or salt thereof) compound and sodium saccharin, wherein the aqueous solution contains about 0.1 mM to about 2.0 mM saccharin. A related non-limiting example further comprises a citrate salt (e.g., citric acid) in an aqueous solution containing about 1 mM to about 100 mM citrate salt.A related non-limiting example is an aqueous solution containing about 0.0 mM to about 100 mM phosphate, further including citrate or exchanging citrate for phosphate (e.g., sodium phosphate). Another related non-limiting example is an aqueous solution containing about 0.5 mM to about 100 mM phosphate, further including citrate or exchanging citrate for phosphate (e.g., sodium phosphate). By way of further non-limiting example, these and related embodiments include a pirfenidone or pyridone analog (or salt thereof) compound formulation for pulmonary delivery as described herein, comprising an aqueous solution having a pH of about 4 to about 8 and an osmolality of about 50 to about 5000 mOsmol / kg (e.g., adjusted with magnesium chloride), the aqueous solution comprising the pirfenidone or pyridone analog (or salt thereof) compound, wherein a divalent cation (e.g., beryllium, magnesium, or calcium) adjusts osmolality and functions as a taste masking agent. When included as a taste masking agent, divalent cations (e.g., magnesium) are added stoichiometrically with pirfenidone or pyridone analogs.For example, 1 mol of divalent ion for 2 mol of pirfenidone or pyridone analogs, 1.5 mol of divalent ion for 2 mol of pirfenidone or pyridone analogs, 2 mol of divalent ion for 2 mol of pirfenidone or pyridone analogs, 3 mol of divalent ion for 2 mol of pirfenidone or pyridone analogs, or 4 mol of divalent ion for 2 mol of pirfenidone or pyridone analogs.If it is necessary to further increase the osmotic pressure, sodium chloride or additional divalent salts can be used.A relevant non-limiting example further comprises citrate (e.g., citric acid) in an aqueous solution containing about 1 mM to about 100 mM citrate.A relevant non-limiting example of citrate is exchanged with phosphate (e.g., sodium phosphate) in an aqueous solution containing about 0.0 mM to about 100 mM phosphate. In another related non-limiting example, citrate is exchanged with phosphate (eg, sodium phosphate) in an aqueous solution containing about 0.0 mM to about 100 mM phosphate.

[0220] In another embodiment, including the correct molar ratio of magnesium to pirfenidone reduces dissolution time and increases saturation solubility to the level required for sufficient nebulized liquid delivery to the lungs, but an unexpected discovery was that this formulation also requires a flavoring agent for acute tolerance after inhalation of the nebulized solution. To this end, between 0.1 and 1.0 micromolar saccharin allows for the use of a formulation that allows this solubility.

[0221] In another embodiment, the pharmaceutical composition may be protected from light to avoid photodegradation. By way of non-limiting example, this may occur through the use of a light-protected vial, ampoule, blister, capsule or other colored or light-protected primary packaging. By way of another non-limiting example, this may occur through the use of secondary packaging such as aluminum or other light-protected over-pouch, box or other secondary packaging.

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

[0223] In another embodiment, pirfenidone or a pyridone analog in a pharmaceutical composition can be protected from hydrolysis by including a cationic metal ion. By way of non-limiting example, acid hydrolysis of an amide bond decreases with increasing salt concentration. Specifically, the hydration number is important in this rate reduction, since electrolyte hydration reduces the availability of free water for the reaction. Therefore, the rate decreases as the salt and hydration number increase. The order of increasing hydration number is potassium < sodium < lithium < magnesium. The rate reduction also roughly parallels 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) at a ratio of three pirfenidone molecules to one Fe(III). Therefore, pirfenidone chelates magnesium at two pirfenidone molecules for every magnesium + 2 charge. Therefore, for this purpose, the addition of magnesium or other cationic metal ions can be stoichiometric with the amount of pirfenidone or a pyridone analog.By way of non-limiting example, two pirfenidone molecules for every 0.1 magnesium molecule, two pirfenidone molecules for every 0.25 magnesium molecule, two pirfenidone molecules for every 0.5 magnesium molecule, two pirfenidone molecules for every 0.75 magnesium molecule, two pirfenidone molecules for every 1 magnesium molecule, two pirfenidone molecules for every 1.5 magnesium molecule, two pirfenidone molecules for every 2 magnesium molecules, two pirfenidone molecules for every 3 magnesium molecules, two pirfenidone molecules for every 4 magnesium molecules, two pirfenidone molecules for every 5 magnesium molecules, and the like. The ratio of magnesium to magnesium is preferably 2 pirfenidone molecules, 2 pirfenidone molecules to 6 magnesium molecules, 2 pirfenidone molecules to 7 magnesium molecules, 2 pirfenidone molecules to 8 magnesium molecules, 2 pirfenidone molecules to 9 magnesium molecules, 2 pirfenidone molecules to 10 magnesium molecules, 2 pirfenidone molecules to 12 magnesium molecules, 2 pirfenidone molecules to 14 magnesium molecules, 2 pirfenidone molecules to 16 magnesium molecules, 2 pirfenidone molecules to 18 magnesium molecules, or 2 pirfenidone molecules to 20 magnesium molecules. Potassium, sodium, lithium, or iron can be substituted for magnesium in these ratios and pharmaceutical compositions. The pharmaceutical compositions include maintaining the buffer described herein at a pH of about 4.0 to about 8.0, wherein the buffer contains MgCl or its cation salt at a level that provides an osmolality of 300 mOsmo / kg and 600 mOsmo / kg. Although 300 mOsmol / kg has been discussed in the literature as critical for acute tolerance after inhalation in nebulized solutions, 600 mOsmol / kg has been shown in unpublished studies to be well tolerated with other drug solutions. However, final solution osmolalities of up to 6000 mOsmol / kg are contemplated. Unexpectedly, the formulations described herein demonstrate excellent tolerance at higher osmolalities.

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

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

[0226] In another embodiment, the liquid or dry powder pirfenidone or pyridone analog pharmaceutical composition may contain chelated metal ions to aid in the scavenging of reactive oxygen species. By way of non-limiting example, these may include iron, magnesium, or calcium. For this purpose, the addition of magnesium or other cationic metal ions may be in a stoichiometric ratio to the amount of pirfenidone or pyridone analog. By way of non-limiting example, the ratio may be 2 pirfenidone molecules to 0.1 magnesium molecules, 2 pirfenidone molecules to 0.25 magnesium molecules, 2 pirfenidone molecules to 0.5 magnesium molecules, 2 pirfenidone molecules to 0.75 magnesium molecules, 2 pirfenidone molecules to 1 magnesium molecule, 2 pirfenidone molecules to 1.5 magnesium molecules, 2 pirfenidone molecules to 2 magnesium molecules, 2 pirfenidone molecules to 3 magnesium molecules, 2 pirfenidone molecules to 4 magnesium molecules, 2 pirfenidone molecules to 5 magnesium molecules, or 2 pirfenidone molecules to 5 magnesium molecules. The ratio of magnesium to magnesium is preferably 2 pirfenidone molecules, 2 pirfenidone molecules to 6 magnesium molecules, 2 pirfenidone molecules to 7 magnesium molecules, 2 pirfenidone molecules to 8 magnesium molecules, 2 pirfenidone molecules to 9 magnesium molecules, 2 pirfenidone molecules to 10 magnesium molecules, 2 pirfenidone molecules to 12 magnesium molecules, 2 pirfenidone molecules to 14 magnesium molecules, 2 pirfenidone molecules to 16 magnesium molecules, 2 pirfenidone molecules to 18 magnesium molecules, or 2 pirfenidone molecules to 20 magnesium molecules. Potassium, sodium, lithium, or iron can be substituted for magnesium in these ratios and pharmaceutical compositions. The pharmaceutical compositions include maintaining the buffer described herein at a pH of about 4.0 to about 8.0, wherein the buffer contains MgCl or its cation salt at a level that provides an osmolality of 300 mOsmo / kg and 600 mOsmo / kg.Although 300 mOsmo / kg has been discussed in the literature as critical for acute tolerance after inhalation in nebulized solutions, 600 mOsmo / kg has been shown in unpublished studies to be well tolerated with other drug solutions. However, final solution osmolalities of up to 5000 mOsmo / kg are contemplated.

[0227] In some embodiments, the present disclosure provides pharmaceutical compositions comprising pirfenidone, water, a phosphate buffer or a citrate buffer, and optionally sodium chloride or magnesium chloride. In other embodiments, the present disclosure provides pharmaceutical compositions comprising pirfenidone, water, a buffer, and at least one additional ingredient selected from sodium chloride, magnesium chloride, ethanol, propylene glycol, glycerol, polysorbate 80, and ethylpyridinium chloride bromide (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 contains 1 mg to 500 mg of pirfenidone, for example, 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 osmolality of the pharmaceutical compositions described herein is between about 50 mOsmo / kg and 6000 mOsmo / kg. In some embodiments, the pharmaceutical composition optionally includes saccharin (e.g., the sodium salt). Non-limiting examples of pharmaceutical compositions described herein include any one of the pharmaceutical compositions described in Tables 1-1 to 1-11 in Example 1.

[0228] Solutions of pirfenidone should be kept protected from light due to the susceptibility of the API in solution to degradation.

[0229] In another embodiment, a pharmaceutical composition is provided comprising a simple dry powder pirfenidone or pyridone analog (or salt thereof) compound alone in dry powder form, with or without excipients such as lactose.

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

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

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

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

[0234] In another embodiment, a kit is provided that includes a container containing a pharmaceutical formulation comprising a pirfenidone or pyridone analog (or salt thereof) compound, 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, e.g., pulmonary compartments such as the alveoli, alveolar ducts, and / or bronchioles, after oral administration. The formulation can also be delivered as a dry powder or via a metered-dose inhaler.

[0235] In another embodiment, a kit is provided that includes a container containing a pharmaceutical formulation comprising a pirfenidone or pyridone analog (or salt thereof) compound, 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 intranasal administration. The formulation can also be delivered as a dry powder or via a metered-dose inhaler.

[0236] It will be appreciated that many carriers and excipients may serve several functions, even within the same formulation.

[0237] Contemplated pharmaceutical compositions provide a therapeutically effective amount of the pirfenidone or pyridone analog compound, allowing for administration, for example, once daily, twice daily, three times daily, etc. In some embodiments, pharmaceutical compositions for delivery by inhalation provide an effective amount of the pirfenidone or pyridone analog compound, allowing for once-daily administration. In some embodiments, pharmaceutical compositions for delivery by inhalation provide an effective amount of the pirfenidone or pyridone analog compound, allowing for twice-daily administration. In some embodiments, pharmaceutical compositions for delivery by inhalation provide an effective amount of the pirfenidone or pyridone analog compound, allowing for three-times-daily administration.

[0238] It is to 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 terminology> The term "mg" refers to milligrams.

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

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

[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 dosing.

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

[0246] As used herein, the term "about" is used synonymously with the term "approximately." Explaining this, the use of the term "about" in reference to a particular therapeutically effective dose indicates that value may vary slightly from the cited value, e.g., ±0.1% to ±10%, which is both effective and safe.

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

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

[0249] The terms "pulmonary administration," "inhalation," or "pulmonary delivery," or "oral inhalation," or "intranasal inhalation," and other related terms, refer to a method of administering a dose of a therapeutic or prophylactic formulation, such as a pirfenidone or pyridone analog (or salt thereof) compound formulation described herein, to a mammal by a route that delivers the desired therapeutic or prophylactic agent to the lungs of the mammal. Such delivery to the lungs can occur by intranasal administration or 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 passive delivery of an aerosol described herein by a ventilator.

[0250] The terms "intranasal inhalation administration" and "intranasal inhalation delivery" refer to a method of administering a dose of a therapeutic or prophylactic formulation, such as a pirfenidone or pyridone analog (or salt thereof) compound formulation described herein, to a mammal by a route in which the formulation targets delivery and absorption of the therapeutic formulation directly to the mammal's lungs 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 dose of a therapeutic or prophylactic formulation, such as a pirfenidone or pyridone analog (or salt thereof) compound formulation described herein, to a mammal by a route such that the desired therapeutic or prophylactic agent is delivered to the nasal cavity or downstream diseased organs (e.g., aerosol delivery to the nasal cavity for absorption and secondary delivery to the central nervous system or other diseased site). Such delivery to the nasal cavity can occur by intranasal administration, where the administration route can occur as inhalation of an aerosol of a formulation described herein, injection of an aerosol of a formulation described herein, tube feeding of a formulation described herein, or passive delivery via a ventilator.

[0252] The terms "intraocular administration" and "intraocular delivery" refer to a method of administering a dose of a therapeutic or prophylactic formulation, such as a pirfenidone or pyridone analog (or salt thereof) compound formulation described herein, to a mammal by a route that delivers the desired therapeutic or prophylactic agent to the eye. Such delivery to the eye can occur by direct administration to the eye. This administration route can occur as a spray of an aerosol of a formulation described herein, an injection of an aerosol of a formulation described herein, or drops of a formulation described herein.

[0253] "Oral administration" or "orally" or "oral" is a route of administration in which a substance (e.g., a pharmaceutical composition) is obtained through the oral cavity. In some embodiments, when used without any further description, it refers to the administration of a substance directly through the oral cavity to the digestive 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 dose of a therapeutic or prophylactic formulation, such as a pirfenidone or pyridone analog (or salt thereof) compound formulation described herein, to a mammal through the oral cavity for delivery and absorption of the formulation directly into the mammal's lungs. In some embodiments, oral inhalation administration is performed by use of a nebulizer.

[0255] The term "abnormal liver function" may be manifested as abnormalities in the levels of biomarkers of liver function, including alanine transaminase, aspartate transaminase, bilirubin, and / or alkaline phosphatase, and may be indicative 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) above 2.5 and below 5 times the upper limit of normal (ULN). Grade 2 liver function abnormalities also include elevations of bilirubin levels above 1.5 and below 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 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, saline, buffers, nonionic surfactants, and edible oils, such as peanut and sesame oils. In addition, various adjuvants commonly used in the art may be included. These and other such compounds are described in the literature, for example, in Merck Index, Merck & Company, Rahway, NJ. Discussions of the inclusion of various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.

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

[0260] "Patient" or "subject" are used interchangeably and refer 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 experiments or procedures performed in or on living tissue in an artificial environment other than that of an organism.

[0263] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and bactericidal 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 the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0264] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compounds of the present invention, which is not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which 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, 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, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. Organic bases from which 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, especially isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, histidine, arginine, lysine, benethamine, N-methyl-glucamine, and ethanolamine, etc. 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 effectiveness and properties of the compounds of the present invention, without being biologically or otherwise undesirable. Pharmaceutically acceptable pH-reducing acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. By way of non-limiting example, pH-reducing acids can 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, and the like.

[0266] According to certain embodiments disclosed herein, pirfenidone or pyridone analog compound formulations may include an "acidic excipient," typically present as an aqueous acidic excipient solution. Examples include acid salts such as phosphate, sulfate, nitrate, acetate, formate, citrate, tartrate, propionate, and sorbate; organic acids such as carboxylic acids, sulfonic acids, phosphonic acids, phosphinic acids, phosphoric acid monoesters, and phosphoric acid diesters; and / or other organic acids containing 1 to 12 carbon atoms, including 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" refers to a compound that functions to regulate pH. In certain related embodiments, the pH buffer is present under conditions and in sufficient amount to maintain a pH "about" a specified pH value. Such a pH "about" refers to the functional existence of the buffer, which may be the result of 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 equilibrium between the protonated and deprotonated forms (typically the center of the effective buffering range of pH values)), and other factors, as known in the art.

[0268] Thus, "about" in the context of pH can be understood to represent a quantitative variation in pH that can be greater or less than the recited value by no more than 0.5 pH units, more preferably no more than 0.4 pH units, more preferably no more than 0.3 pH units, even more preferably no more than 0.2 pH units, and most preferably no more than 0.1-0.15 pH units. As indicated above, in certain embodiments, a substantially constant pH (e.g., a pH maintained within a recited range for an extended period of time) can be about pH 4.0 to about pH 8.0, about pH 4.0 to about pH 7.0, or about pH 4.0 to about pH 6.8, or any other pH or pH range as described herein, which in preferred embodiments can be about pH 4.0 to about pH 8.0 for pirfenidone or pyridone analog compound formulations and greater than pH 8.0 for aqueous solutions of pirfenidone or pyridone analog compounds.

[0269] Thus, pH buffers typically include compositions that, when present under appropriate conditions and in sufficient amounts, can maintain a desired pH level as selected by one skilled in the art, such as buffers containing citrate, formate, malate, formate, pyridine, piperazine, succinate, histidine, maleate, bis-tris, pyrophosphate, PIPES, ACES, histidine, MES, cacodylic acid, H2CO3 / NaHCO3, and N-(2-acetamido)-2-iminodiacetic acid (ADA), or other buffers to maintain, preserve, enhance, protect, or promote the desired biological or pharmacological activity of pirfenidone or a pyridone analog compound based on the disclosure herein. Suitable buffers may include those in Table 1 or known in the art (see, e.g., Calbiochem® Biochemicals & Immunochemicals Catalog 2004 / 2005, pp. 68-69 and catalog pages cited therein, EMD Biosciences, La Jolla, CA).

[0270] Non-limiting examples of buffers that may 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), cacodylate (pKa 6.27), H2CO3 / NaHCO3 (pKa 1) (6.37), ADA (N-(2-acetamido)-2-iminodiacetic 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 pirfenidone or pyridone analog compound, metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates, including hydrates.

[0272] By "therapeutically effective amount" or "pharmaceutically effective amount" is meant a pirfenidone or pyridone analog compound as disclosed herein that has a therapeutic effect. The amount of pirfenidone or pyridone analog compound that is useful for treatment is a therapeutically effective amount. Thus, as used herein, a therapeutically effective amount refers to that amount of pirfenidone or pyridone analog compound that produces the desired therapeutic effect as determined by clinical trial results and / or animal models of pulmonary fibrosis, cardiac fibrosis, renal fibrosis, liver fibrosis, cardiac or renal toxicity, multiple sclerosis, COPD, or asthma. In a specific embodiment, the pirfenidone or pyridone analog compound is administered at a predetermined dosage, and therefore the therapeutically effective amount is the amount of the administered dosage. This amount and the amount of pirfenidone or pyridone analog compound can be routinely determined by those skilled in the art and will vary depending on various factors, such as whether a therapeutic or preventive effect against fibrotic, inflammatory, or demyelinating damage is produced, and how far the disease site is from the first breath receiving the initial inhaled aerosol dose. This amount will also depend on the patient's height, weight, sex, age, and medical history. For preventive treatment, a therapeutically effective amount is an amount that will be effective in preventing fibrotic, inflammatory, or demyelinating damage.

[0273] A "therapeutic benefit" alleviates, to some extent, one or more symptoms related to inflammation, fibrosis, and / or demyelination. This includes slowing the progression of, preventing, or reducing further inflammation, fibrosis, and / or demyelination. With respect to IPF, a "therapeutic benefit" is defined as a patient-reported improvement in quality of life and / or a statistically significant increase or stabilization of exercise testing and associated blood oxygen saturation, a reduction in baseline forced vital capacity decline, a reduction in the occurrence of acute exacerbations, an increase in progression-free survival, an increase in time-to-death or disease improvement, and / or a reduction in pulmonary fibrosis. With respect to cardiac fibrosis, a "therapeutic benefit" is defined as a patient-reported improvement in quality of life and / or a statistically significant improvement in cardiac function, a reduction in fibrosis, a reduction in cardiac stiffness, a reduction or reversal of valvular stenosis, a reduction in the occurrence of arrhythmias, and / or a reduction in atrial or ventricular remodeling. With respect to renal fibrosis, "therapeutic benefit" is defined as a patient-reported improvement in quality of life and / or a statistically significant improvement in glomerular filtration rate and related markers. With respect to hepatic fibrosis, "therapeutic benefit" is defined as a patient-reported improvement in quality of life and / or a statistically significant reduction in elevated aminotransferases (e.g., AST and ALT), alkaline phosphatase, gamma-glutamyltransferase, bilirubin, prothrombin time, and globulin levels, as well as a reversal of thrombocytopenia, leukopenia, and neutropenia and coagulopathy. Additionally, potential reversal of imaging, endoscopic, or other pathological findings. With respect to COPD, "therapeutic benefit" is defined as a patient-reported improvement in quality of life and / or a statistically significant improvement in exercise capacity and related blood oxygen saturation, FEV1 and / or FVC, as well as a delay or halt in progression of progression-free survival, an increase in lifespan or disease improvement, and / or a reduction in the occurrence of acute exacerbations. With respect to asthma, "therapeutic benefit" is defined as a patient-reported improvement in quality of life and / or a statistically significant improvement in exercise capacity, FEV1 and / or FVC, and / or a reduction in the occurrence of acute exacerbations.With respect to multiple sclerosis, "treatment benefit" is defined as a patient-reported improvement in quality of life and / or a statistically significant improvement in Scripps Neurological Rating Scale score, improvement in bladder dysfunction, improvement in Disability Status Scale score, MRI lesion count, and / or slowing or halting 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 alleviating, relieving, or ameliorating at least one symptom of a disease or condition, preventing any further symptoms from occurring, arresting the progression of at least one current symptom of a disease or condition, eliminating at least one symptom of a disease or condition, causing regression of a disease or condition, eliminating illness caused by a disease or condition, or halting the symptoms of a disease or condition. In some embodiments, the compositions described herein are used for prophylactic treatment. The term "prophylactic treatment" refers to treating a patient who is not yet ill, but who is susceptible to or otherwise at risk for a particular disease, or who has the disease, but whose symptoms do not worsen while being treated with a pharmaceutical composition described herein. The term "therapeutic treatment" refers to administering treatment to a patient already suffering from a disease. Thus, in a preferred embodiment, treating is the administration to a mammal (for therapeutic or prophylactic purposes) of a therapeutically effective amount of a pirfenidone or pyridone analog compound.

[0275] "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 is not yet ill, but who is susceptible to or otherwise at risk for a particular disease. The term "therapeutic treatment" refers to administering treatment to a patient who is already suffering from a disease. Thus, in a preferred embodiment, treating is the administration of a therapeutically effective amount of a pirfenidone or pyridone analog compound to a mammal (for therapeutic or prophylactic purposes).

[0276] The term "dosing interval" refers to the time between administration of two consecutive doses of a pharmaceutical agent in a multiple dosing regimen.

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

[0278] "Pulmonary deposition" as used herein refers to a small nominal dose of active pharmaceutical ingredient (API) that is deposited on the interior surfaces of the lungs.

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

[0280] "Enhanced pharmacokinetic properties" refers to the improvement of some pharmacokinetic parameters. Pharmacokinetic parameters that may be improved include AUC last , AUC (0-∞)、 T max , and optionally C maxIn some embodiments, the enhanced pharmacokinetic properties may be quantitatively measured by comparing the pharmacokinetic parameters obtained for a nominal dose of an active pharmaceutical ingredient (API) administered by one type of inhalation 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 illness that is physically manifested in the respiratory tract, 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 medicines, compositions, formulations, suspensions, mixtures, etc. into a fine mist or aerosol for delivery to the lungs. A nebulizer may also be called an atomizer.

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

[0285] <Pirfenidone and pyridone analogue compounds> As noted elsewhere herein, in a preferred embodiment, the pyridone compound for use in the formulation of pyridone compounds as described herein comprises pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) or a salt thereof. While various embodiments are described with the use of pirfenidone, it is noted that other pyridone analog compounds, or salts thereof, may 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] [ka]

[0288] "Pyridone analog" or "pyridone compound" refers to a compound that has the same type of biological activity and efficacy 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, pyridone analogs are compounds having a substituted 2-(1H)pyridone or 3-(1H)pyridone core structure. In some embodiments, pyridone analogs are compounds having a substituted 2-(2h)pyridone core structure.

[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(1H)pyridone 1-(4'-nitrophenyl)-2-(1H)pyridone, 1-(2'-furyl)-5-methyl-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 have been replaced with deuterium.

[0292] According to certain other different embodiments of the compositions and methods described herein, the pyridone compound is bis(2-hydroxyethyl)azanium; 2-(3,5-diiodo-4-oxopyridin-1-yl)acetate, 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-anilino-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-(3-chlorophenyl)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-Diiodo-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 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-( 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-amido]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-dihydro-pyridine-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-morpholine-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-carboxamide, 1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 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 So-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}- 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 (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-dihydropyridin-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-dihydropyridin-3-yl methanesulfonic acid, 5-ethoxy-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-(2-hydroxyethoxy)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-(cyanomethoxy)-6-methyl-N-[ 4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 2-({2-methyl-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydropyridin-3-yl}oxy)ethyl acetate, 5-[2-(dimethylamino)-2-oxoethoxy]-6-methyl-N-[4-(methylsulfonyl)benzyl]amino 5-(2-aminoethoxy)-N-[4-(isopropylsulfonyl)benzyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-(acetylamino)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide N-[4-(isopropylsulfonyl)benzyl]-6-methyl-5-[3-(methylamino)propoxy]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-(1-methoxyethyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide2-Dihydropyridine-3-carboxamide, 5-(2-bromo-1-methoxyethyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-(1-isopropoxyethyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 5-(N, 1 -isobutyryl-hydrazinocarbonyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide, N 5 -Methoxy-6-methyl-N 3 -[4-(Methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 5 -Methoxy-N 5 ,6-dimethyl-N 3 -[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, 5-[(2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 6-methyl-N 3 -[4-(methylsulfonyl)benzyl]-2-oxo-N 5 -pyrrolidin-1-yl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-(piperidin-1-ylcarbonyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 6-methyl-N 3 -[4-(methylsulfonyl)benzyl]-N 5-morpholin-4-yl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, 6-methyl-5-[(4-methylpiperidin-1-yl)carbonyl]-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 6-methyl-N 3 -[4-(methylsulfonyl)benzyl]-2-oxo-N 5 -piperidin-1-yl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 5 -(tert-butyl)-N 5 ,6-dimethyl-N 3 -[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 5 -Butyl-N 5 ,6-dimethyl-N 3 -[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 5 -ethyl-N 5 -isopropyl-6-methyl-N 3 -[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, 5-[N 1 -(Formyl-hydrazinocarbonyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide, N 1-[5-(4-Methanesulfonyl-benzylcarbamoyl)-2-methyl-6-oxo-1-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-3-carbonyl]-hydrazinecarboxylic acid ethyl ester, 5-({2-[(ethylamino)carbonothioyl]hydrazino}carbonyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl) Phenyl]-1,2-dihydropyridine-3-carboxamide, 5-(isoxazolidin-2-ylcarbonyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide, 6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 5-(Methoxy-methyl-amido) 3-[4-(propane-2-sulfonyl)-benzylamide], 6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 3-(4-ethanesulfonyl-benzylamide) 5-(methoxy-methyl-amide), 6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 3-(4-cyclopropanesulfonyl-benzylamide) 5-(methoxy-methyl-amide), 6-methyl- 2-Oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 5-[(2-hydroxy-ethyl)-amido]3-(4-methanesulfonyl-benzylamide, 5-(isoxazolidine-2-carbonyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)1,2-dihydro-pyridine-3-carboxylic acid 4-Ethanesulfonyl-benzylamide, 5-(isoxazolidine-2-carbonyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)1,2-dihydro-pyridine-3-carboxylic acid 4-Cyclopropanesulfonylbenzylamide, 5-(N-hydroxycarbamimidoyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-Methanesulfonyl-benzylamide, N 3 -(cyclohexylmethyl)-N 5 ,N 5 ,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-trimethyl-2-oxo-N 3 -(pyridin-3-ylmethyl)-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-trimethyl-N 3 -(2-morpholin-4-ylethyl)-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-trimethyl-N 3 -(3-morpholin-4-ylpropyl)-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 3 -Benzyl-N 5 ,N 5 ,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydro-pyridine-3,5-dicarboxamide, N 3-[2-(1H-indol-3-yl)ethyl]-N 5 ,N 5 ,6-trimethyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2-dihydro-pyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-trimethyl-2-oxo-N 3 -(1-phenylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-trimethyl-2-oxo-N 3 -(2-phenylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3,5-dicarboxamide, N 5 ,N 5 ,6-trimethyl-2-oxo-N 3 -[(2R)-2-Phenylcyclo...

Claims

1. 1. A dry powder composition delivered to the lungs of an adult human by inhalation for treating interstitial lung disease, comprising pirfenidone, the dry powder composition is maintained in a reservoir of a dry powder inhaler; A dry powder composition characterized in that inhaled pirfenidone is administered at a total daily dose of 120 mg or more but less than 360 mg, which is a dose that treats interstitial lung disease by reducing the decline in forced vital capacity (FVC) of the lungs in adults.

2. 10. The dry powder composition of claim 1, wherein the compound is blended with a carrier or surface modifier.

3. 10. The dry powder composition of claim 1, wherein inhalation of the dry powder delivers about 0.1 mg to about 250 mg of pirfenidone to the lungs of an adult human in less than about 30 minutes.

4. 2. The dry powder composition of claim 1, wherein the pulmonary Cmax and / or AUC of pirfenidone obtained after a single dose of the dry powder administered to a human using the dry powder inhaler is approximately the same as or greater than the pulmonary Cmax and / or AUC of pirfenidone that can be obtained after a single dose of pirfenidone administered orally to a human at a dose of about 80% to about 120% of the dry powder dose.

5. 10. The dry powder composition of claim 1, having one or more additional ingredients selected from bulking agents, carrier agents, surface modifiers, taste masking agents, sweeteners, salts, and combinations thereof.

6. 10. The dry powder composition of claim 1, wherein the dry powder is disposed in a single reservoir of the dry powder inhaler.

7. 10. The dry powder composition of claim 1, wherein the pirfenidone dry powder is co-administered with one or more additional therapeutic agents comprising interferon gamma, interferon beta-1a, pentraxin-2, N-acetyl-L-cysteine, GS-6624, IW001, PRM-151, STX-100, CC-930, QAX576, FG-3019, CNTO-888, BIBF-1120, an antibody targeting an IL-13 ligand or receptor, an antibody targeting integrin alpha-vbeta-6, an antibody targeting a CTGF ligand or receptor, an antibody targeting a CCL2 ligand, an antibody targeting a vascular endothelial growth factor (VEGF) ligand or receptor, an antibody targeting a platelet-derived growth factor (PDGF) ligand or receptor, an antibody targeting a fibroblast growth factor (FGF) ligand or receptor, and combinations thereof.

8. Pirfenidone dry powder is a compound used in combination with corticosteroids, glucocorticoids, prednisone, cromolyn, nedocromil, leukotriene modifiers, interferon gamma, cyclophosphamide, colchicine, N-acetylcysteine, azathioprine, bromhexine, endothelin receptor antagonists, PDE5 inhibitors, PDE4 inhibitors, prostanoids, nitric oxide or nitric oxide donating compounds, IL-13 blockers, IL-10 blockers, CTGF-specific antibodies, CCN2 inhibitors, angiotensin-converting enzyme inhibitors, agents, angiotensin receptor antagonists, PDGF inhibitors, PPAR antagonists, imatinib, CCL2 specific antibodies, CXCR2 antagonists, anticoagulants, TNF blockers, tetracycline or tetracycline derivatives, 5-lipoxygenase inhibitors, pituitary hormone inhibitors, TGF-beta neutralizing antibodies, copper chelators, angiotensin II receptor antagonists, chemokine inhibitors, NF-κB inhibitors, NF-κB antisense oligonucleotides, IKK-1 and IKK-2 inhibitors, JNK2 and / or p38 10. The dry powder composition of claim 1, wherein the composition is co-administered with one or more additional agents comprising a MAPK inhibitor, a PI3K inhibitor, an LTB4 inhibitor, an antioxidant, a TNF scavenger, PEG-sTNFR 1, afelimomab, and antisense TNF-α oligonucleotides, interferon beta-1a, copaxone, mitoxantrone, natalizumab, methotrexate, azathioprine immune globulin, cyclophosphamide, liorezal, tizanidine, benzodiazepines, cholinergic agents, antidepressants, and amantadine, and combinations thereof.

9. 10. The dry powder composition of claim 1, a) the pulmonary Cmax of pirfenidone achieved in the lungs of adult humans upon administration of a therapeutically effective amount to humans is at least equal to or greater than the pulmonary Cmax achievable upon administration of an 801 mg oral dose of pirfenidone to humans; and / or b) the lung tissue AUC0-24h of pirfenidone obtained in the lungs of adult humans upon administration of a therapeutically effective amount is greater than the plasma AUC0-24h achievable upon administration of an 801 mg dose of pirfenidone administered orally to adults; Dry powder composition.

10. 10. The dry powder composition of claim 1, wherein the dry powder is comprised of spherical nanoparticles of pirfenidone.

11. 10. The dry powder composition of claim 1, further comprising a carrier agent selected from the group consisting of lactose, mannitol, starch, lactose, calcium phosphate, sucrose, trehalose, and kaolin.

12. 12. The dry powder composition of claim 11, wherein the carrier agent is magnesium stearate.

13. 12. The dry powder composition of claim 11, wherein the carrier agent is lactose.

14. 10. The dry powder composition of claim 1, wherein the dry powder inhaler delivers a daily dose of pirfenidone dry powder in less than 10 breaths.

15. 10. The dry powder composition of claim 1, further comprising leucine.

16. 10. The dry powder composition of claim 1, wherein the pirfenidone is deuterated.

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