Aerosol pirfenidone and pyridone analog compounds and uses thereof

Abstract

To provide compositions of pirfenidone or a pyridone analog compound that are suitable for inhalation delivery to the lungs and / or systemic compartment, and to provide methods of using such compositions.SOLUTION: Disclosed herein are formulations of pirfenidone or pyridone analog compounds for aerosolization and use of such formulations for aerosol administration of pirfenidone or pyridone analog compounds for the prevention or treatment of various fibrotic and inflammatory diseases, including disease associated with the lung, heart, kidney, liver, eye and central nervous system. In some embodiments, pirfenidone or pyridone analog compound formulations and delivery options described herein allow for efficacious local delivery of pirfenidone or pyridone analog compound.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] (Priority Claim) This application claims the benefit of U.S. Provisional Patent Application No. 61 / 675,286, filed July 24, 2012, entitled "Aerosol Pirfenidone and Pyridone Analog Compounds and Uses Thereof;" U.S. Provisional Patent Application No. 61 / 756,983, filed January 25, 2013, entitled "Aerosol Pirfenidone and Pyridone Analog Compounds and Uses Thereof;" and U.S. Provisional Patent Application No. 61 / 824,818, filed May 17, 2013, entitled "Aerosol Pirfenidone and Pyridone Analog Compounds and Uses 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 pulmonary 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 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. Compositions of pirfenidone or pyridone analog compounds suitable for inhaled 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] Certain embodiments of the present invention provide pirfenidone or pyridone analog compound formulation compositions for delivery by oral, pulmonary, or intranasal inhalation, 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 aspect, the present disclosure provides a method for treating a pulmonary disease in a mammal, comprising administering a dose of a pirfenidone or pyridone analog compound by inhalation to a mammal in need thereof in a continuous administration schedule. In some embodiments, the continuous administration schedule comprises administering a dose of a pirfenidone or pyridone analog compound daily, every other day, every third day, every fourth day, every fifth day, every sixth day, every week, every other week, every month, or every other month. In some embodiments, the daily or less-than-daily administration schedule comprises administering one, two, or more than three doses of a pirfenidone or pyridone analog compound. In some embodiments, each inhaled dose of a pirfenidone or pyridone analog compound is administered by a nebulizer, a metered-dose inhaler, or a dry powder inhaler. In some embodiments, each inhaled dose comprises an aqueous solution of a pirfenidone or pyridone analog compound. In some embodiments, each inhaled dose comprises about 0.1 mL to about 6 mL of an aqueous solution of the pirfenidone or pyridone analog compound, wherein the concentration of the pirfenidone or 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 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the aqueous solution of each inhaled dose 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. In some embodiments, the aqueous solution of each inhaled dose further comprises a citrate buffer or a phosphate buffer, and one or more salts selected from the group consisting of sodium chloride, magnesium chloride, sodium bromide, magnesium bromide, calcium chloride, and calcium bromide.In some embodiments, the aqueous solution of each inhaled dose comprises water, a pirfenidone or pyridone analog compound at a concentration of about 0.1 mg / mL to about 20 mg / mL, one or more salts (wherein the total amount of the one or more salts is about 0.01% to about 2.0% by weight of the aqueous solution), and optionally a phosphate buffer that maintains the pH of the solution at about pH 5.0 to about pH 8.0, or a citrate buffer that maintains the pH of the solution at about pH 4.0 to about 7.0, and an osmolality of the aqueous solution is about 50 mOsmol / kg to about 2000 mOsmol / kg. In some embodiments, each inhaled dose is administered with a liquid nebulizer. 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 after administration of an inhaled dose; (ii) provides a geometric standard deviation (GSD) of the droplet diameter distribution of the emitted aqueous solution of about 1.0 μm to about 2.5 μm; (iii) provides a) a median aerodynamic diameter (MMAD) of the droplet diameter of the aqueous solution emitted from the high-performance liquid nebulizer of about 1 μm to about 5 μm; b) a volumetric mean diameter (VMD) of about 1 μm to about 5 μm; and / or c) a mass median diameter (MMD) of about 1 μm to about 5 μm; (iv) provides a fine particle fraction (FPF = %≦5 μm) of at least about 30% of the droplets emitted from the liquid nebulizer; (v) provides a consumption 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, a) the lung tissue Cmax of the pirfenidone or pyridone analog compound from each inhaled dose is at least equal to or greater than the lung tissue Cmax of up to 801 mg of an oral dose of the pirfenidone or pyridone analog compound; and / or b) the blood AUC of the pirfenidone or pyridone analog compound from each inhaled dose administered directly to the lungs of a mammal. 0-24 The blood AUC of pirfenidone or a pyridone analogue compound was measured at an oral dose of 801 mg. 0-24In some embodiments, the blood AUC of the pirfenidone or pyridone analog compound from each inhaled dose is less than or equal to 0-24 The blood AUC of pirfenidone or a pyridone analogue compound was measured at an oral dose of 801 mg. 0-24 In some embodiments, the blood AUC of the pirfenidone or pyridone analog compound from each inhaled dose is less than 0-24 The blood AUC of pirfenidone or a pyridone analogue compound was measured at an oral dose of 801 mg. 0-24 In some embodiments, the blood AUC of the pirfenidone or pyridone analog compound from each inhaled dose is less than 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 2.5%, 1.0%, 0.5%, 0.25%, 0.1%, 0.05%, 0.025%, or 0.01%. 0-24 The blood AUC of pirfenidone or a pyridone analogue compound was measured at an oral dose of 801 mg. 0-24Between 0.01-90%, 0.01-80%, 0.01-70%, 0.01-60%, 0.01-50%, 0.01-40%, 0.01-30%, 0.01-20%, 0.01-10%, 0.01-5%, 0.01-2.5%, 0.01-1%, 0.01-0.1%, between 5-90%, between 5-80%, 5- In some embodiments, the inhaled dose is between 70%, between 5-60%, between 5-50%, between 5-40%, between 5-30%, between 5-20%, between 5-10%, between 1-5%, between 1-10%, between 1-20%, between 1-30%, between 1-40%, between 1-50%, between 1-60%, between 1-70%, between 1-80%, or between 1-90%. In some embodiments, each inhaled dose is less than half of an oral dose of up to 801 mg of the pirfenidone or pyridone analog compound. In some embodiments, each inhaled dose is less than 1 / 2, 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 8, 1 / 10, 1 / 20, 1 / 40, 1 / 50, 1 / 75, 1 / 100, 1 / 200, or 1 / 400 of an oral dose of up to 801 mg of the pirfenidone or pyridone analog compound. In some embodiments, the pirfenidone or pyridone analog compound is administered at least once a week. In some embodiments, the pirfenidone or pyridone analog compound is administered on a continuous daily dosing schedule. In some embodiments, the pirfenidone or pyridone analog compound is administered once a day, twice a day, or three times a day. In some embodiments, the pulmonary disease is idiopathic pulmonary fibrosis, lung cancer, or pulmonary hypertension. In some embodiments, the pulmonary disease is idiopathic pulmonary fibrosis. In some embodiments, the pulmonary disease is pulmonary hypertension. In some embodiments, the pulmonary disease is secondary pulmonary hypertension to interstitial lung disease. In some embodiments, the pulmonary disease is cancer. In some embodiments, the pulmonary disease is lung cancer. In some embodiments, the pulmonary disease is lung cancer, where the therapeutic target is tumor stroma. In some embodiments, the pulmonary disease is lung cancer, and the treatment comprises inhibiting, reducing, or slowing the growth of lung tumor stroma. In some embodiments, the method further comprises administering one or more additional therapeutic agents to the mammal.

[0006] In another aspect, described herein is a method for treating a pulmonary disease in a mammal, the method comprising: administering a dose of a pirfenidone or pyridone analog compound by inhalation to a mammal in need thereof, wherein the blood AUC of the pirfenidone or pyridone analog compound from the inhaled dose is 0-24 The blood AUC of pirfenidone or a pyridone analogue compound was measured at an oral dose of 801 mg. 0-24 In some embodiments, the blood AUC of the pirfenidone or pyridone analog compound from each inhaled dose is less than 0-24 The blood AUC of pirfenidone or a pyridone analogue compound was measured at an oral dose of 801 mg. 0-24 In some embodiments, the blood AUC of the pirfenidone or pyridone analog compound from each inhaled dose is less than 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 2.5%, 1.0%, 0.5%, 0.25%, 0.1%, 0.05%, 0.025%, or 0.01%. 0-24 The blood AUC of pirfenidone or a pyridone analogue compound was measured at an oral dose of 801 mg. 0-24Between 0.01-90%, 0.01-80%, 0.01-70%, 0.01-60%, 0.01-50%, 0.01-40%, 0.01-30%, 0.01-20%, 0.01-10%, 0.01-5%, 0.01-2.5%, 0.01-1%, 0.01-0.1%, between 5-90%, between 5-80%, 5- The inhaled dose of the pirfenidone or pyridone analog compound may be between 70%, 5-60%, 5-50%, 5-40%, 5-30%, 5-20%, 5-10%, 1-5%, 1-10%, 1-20%, 1-30%, 1-40%, 1-50%, 1-60%, 1-70%, 1-80%, or 1-90%. In some embodiments, the inhaled dose of the pirfenidone or pyridone analog compound is administered using a nebulizer, metered dose inhaler, or dry powder inhaler. In some embodiments, the inhaled dose comprises an aqueous solution of the pirfenidone or pyridone analog compound, and the dose is administered using a liquid nebulizer. In some embodiments, each inhaled dose administered directly to the lungs of a mammal comprises about 0.1 mL to about 6 mL of an aqueous solution of the pirfenidone or pyridone analog compound, wherein the concentration of the pirfenidone or 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 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the aqueous solution of each inhaled dose 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. In some embodiments, the aqueous solution of each inhaled dose further comprises a citrate buffer or a phosphate buffer, and one or more salts selected from the group consisting of sodium chloride, magnesium chloride, sodium bromide, magnesium bromide, calcium chloride, and calcium bromide.In some embodiments, each inhaled dose of the aqueous solution comprises: water; a pirfenidone or pyridone analog compound at a concentration of about 0.1 mg / mL to about 20 mg / mL; one or more salts (wherein the total amount of the one or more salts is about 0.01% to about 2.0% by weight of the aqueous solution); and, optionally, a phosphate buffer that maintains the pH of the solution at about pH 5.0 to about pH 8.0, or a citrate buffer that maintains the pH of the solution at about pH 4.0 to about 7.0. In some embodiments, the inhaled doses of the pirfenidone or pyridone analog compound are administered on a continuous dosing schedule. In some embodiments, the pulmonary disease is idiopathic pulmonary fibrosis, lung cancer, or pulmonary hypertension. In some embodiments, the pulmonary disease is idiopathic pulmonary fibrosis. In some embodiments, the pulmonary disease is pulmonary hypertension. In some embodiments, the pulmonary disease is secondary pulmonary hypertension to interstitial lung disease. In some embodiments, the pulmonary disease is cancer. In some embodiments, the pulmonary disease is lung cancer. In some embodiments, the pulmonary disease is lung cancer, where the therapeutic target is the tumor stroma. In some embodiments, the pulmonary disease is lung cancer, and the treatment comprises inhibiting, reducing, or slowing the growth of lung tumor stroma. In some embodiments, the method further comprises administering one or more additional therapeutic agents to the mammal.

[0007] In one aspect, the present specification describes an aqueous solution for nebulized inhalation administration, the aqueous solution comprising: water; a pirfenidone or pyridone analog compound at a concentration of about 0.1 mg / mL to about 20 mg / mL; wherein the osmolality of the aqueous solution is about 50 mOsmol / kg to about 2000 mOsmol / kg. In some embodiments, the aqueous solution does not contain any cosolvents and / or surfactants. In some embodiments, the solution further comprises one or more additional components selected from a buffer and a salt. In some embodiments, the buffer is a citrate buffer or a phosphate buffer; and the salt is sodium chloride or magnesium chloride, or sodium bromide or magnesium bromide, calcium chloride or calcium bromide. In some embodiments, the aqueous solution comprises water, a pirfenidone or pyridone analog compound at a concentration of about 1 mg / mL to about 20 mg / mL, wherein the total amount of one or more salts is about 0.01% to about 2.0% v / v, and optionally a phosphate buffer that maintains the pH of the solution at about pH 6.0 to about pH 8.0 or a citrate buffer that maintains the pH of the solution at about pH 4.0 to about 7.0. In some embodiments, the aqueous solution comprises water, a pirfenidone or pyridone analog compound at a concentration of about 5 mg / mL to about 18 mg / mL, wherein the total amount of one or more salts is about 0.01% to about 2.0% v / v, and optionally a phosphate buffer that maintains the pH of the solution at about pH 6.0 to about pH 8.0 or a citrate buffer that maintains the pH of the solution at about pH 4.0 to about 7.0, wherein the osmolality of the aqueous solution is about 50 mOsmol / kg to about 2000 mOsmol / kg.

[0008] In embodiments described herein, the inhaled dose is delivered <5, <4, <3, <2, <1 per day, or less than daily. In some embodiments, the inhaled dose is delivered by nebulization using standard Cheyne-Stokes (tidal) breathing of a continuous-flow aerosol or a breath-activated aerosol. In such embodiments of nebulized delivery, the delivery frequency can be <20, <15, <10, <8, <6, <4, <2, and <1 minute. In some embodiments, the inhaled dose is delivered by inhalation of a dispersed dry powder aerosol using <10, <8, <6, <5, <4, <3, <2, or 1 breath from either a passive dispersed dry powder inhaler or an active dispersed dry powder inhaler. In some embodiments, the inhaled dose is delivered by inhalation of an aerosol using <10, <8, <6, <5, <4, <3, <2, or 1 breath of a compressed gas metered dose inhaler, with or without a spacer.

[0009] 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 at a concentration of about 30 mg / mL to about 50 mg / mL. In some embodiments, the osmolality of the aqueous solution is about 50 mOsmol / kg to about 6000 mOsmol / kg. In some embodiments, the osmolality of the aqueous solution is 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 contains both ethanol and propylene glycol. In some embodiments, the aqueous solution further comprises 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 comprises 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 contains one or more buffers selected from a citrate buffer and a phosphate buffer. In some embodiments, the aqueous solution contains a phosphate buffer. In some embodiments, the aqueous solution contains a citrate buffer. In some embodiments, provided herein is from about 0.5 mL to about 6 mL of an aqueous solution described herein.

[0010] 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.

[0011] 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 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.

[0012] 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.

[0013] 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 aqueous solution for nebulized inhalation 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, where the total amount of cosolvents is 1% v / v to 25% v / v. In some embodiments, the aqueous solution for nebulized inhalation 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 an aqueous solution described herein.

[0014] 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 between about 1% v / v and 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 between about 400 mOsmol / kg and about 6000 mOsmol / kg. In some embodiments, the aqueous solution is as described herein.

[0015] 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.

[0016] 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 the pirfenidone or pyridone analog compound. In some embodiments, the aqueous solution of the 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 the 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.

[0017] 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 a 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.

[0018] 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 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.

[0019] 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 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% lung deposition 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 (iv) provides 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%.

[0020] In some embodiments, methods for treating pulmonary disease in a mammal are described herein, the methods comprising administering to the mammal an aqueous solution comprising a pirfenidone or pyridone analog compound using a liquid nebulizer. In some embodiments, methods for treating pulmonary disease in a mammal are described herein, the methods comprising administering to the mammal an aqueous solution comprising a pirfenidone or pyridone analog compound using a liquid nebulizer, wherein the aqueous solution comprises water, the 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 pulmonary disease is pulmonary arterial hypertension, and the mammal is a human. In some embodiments, the pulmonary disease is type 1, type 2, type 3, type 4, or type 5 pulmonary arterial hypertension, and the mammal is a human. In some embodiments, the pulmonary disease is cancer, and the mammal is a human. In some embodiments, the lung cancer is small cell lung cancer, and the mammal is a human. In some embodiments, the lung cancer is non-small cell lung cancer, and the mammal is a human. In some embodiments, the lung cancer is large cell carcinoma, and the mammal is a human. In some embodiments, the lung cancer is mesothelioma, and the mammal is a human. In some embodiments, the lung cancer is pulmonary carcinoid tumor or bronchial carcinoid, and the mammal is a human. In some embodiments, the lung cancer is secondary lung cancer resulting from metastatic disease, and the mammal is a human. In some embodiments, the lung cancer is bronchioloalveolar carcinoma and the mammal is a human. In some embodiments, the lung cancer is a sarcoma and the mammal is a human. In some embodiments, the lung cancer is a lymphoma and the mammal is a human.In some embodiments, the liquid nebulizer delivers about 0.1 mg to about 360 mg of pirfenidone or a pyridone analog compound in a mass median diameter (MMAD) particle size of about 1 micron to about 5 microns to the lungs of a mammal in less than about 20 minutes.

[0021] 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 administration of an aqueous solution 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 administration of the pirfenidone or pyridone analog compound at a dose that is about 80% to about 120% of the dose administered using the liquid nebulizer. In some embodiments, the lung tissue 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 the liquid nebulizer is higher than the lung tissue ACU 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 the liquid nebulizer.In some embodiments, the plasma Cmax of the pirfenidone or pyridone analog compound obtained after a single administration of an aqueous solution 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 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 plasma 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 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.

[0022] In some embodiments, the liquid nebulizer delivers about 0.1 mg to about 360 mg of the pirfenidone or pyridone analog compound to the lungs of a mammal in a mass median diameter (MMAD) particle size of about 1 micron to about 5 microns 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, a method for reducing the risk of gastrointestinal (GI) adverse events in treating a human with a pirfenidone or pyridone analog compound is described herein, the method comprising administering to the human using a liquid nebulizer an nebulized aqueous solution comprising pirfenidone or a pyridone analog compound, 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.

[0025] 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, and 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.

[0026] In some embodiments, the liquid nebulizer delivers about 0.1 mg to about 360 mg of the pirfenidone or pyridone analog compound to the lung in a mass median diameter (MMAD) particle size of about 1 micron to about 5 microns in less than about 20 minutes.

[0027] In some embodiments, administration with a liquid nebulizer does not include an initial dose titration period.

[0028] 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 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.

[0029] In some embodiments, the liquid nebulizer delivers about 0.1 mg to about 360 mg of the pirfenidone or 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.

[0030] In some embodiments, an inhalation system for administering a pirfenidone or 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 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 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 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.

[0031] In one aspect, 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 comprising the pirfenidone or pyridone analog compound and administering the nebulized aqueous solution to a human.

[0032] In one embodiment, the AUC of the pirfenidone or 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 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 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. 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 0-24 A lung tissue AUC of pirfenidone or a pyridone analog compound that is at least equal to or greater than 0-24 A method for achieving this is described herein, which comprises nebulizing an aqueous solution containing a pirfenidone or pyridone analog compound and administering the nebulized aqueous solution to a human.

[0033] In one aspect, a method of administering a pirfenidone or pyridone analog compound to a human is described herein, the method comprising administering an nebulized aqueous solution containing the pirfenidone or 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 pyridone analog compound that is 80% to 120% of the dose of pirfenidone administered by nebulization.

[0034] In one aspect, 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 pyridone analog, wherein the pulmonary tissue Cmax achieved with the nebulized aqueous solution is 80% to 120% of the dose of the pirfenidone or pyridone analog compound in the nebulized aqueous solution, and 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 a pirfenidone or pyridone analog compound to a human are described herein, the methods comprising administering an nebulized aqueous solution containing pirfenidone or pyridone analog, wherein the pulmonary tissue Cmax achieved with the nebulized aqueous solution is at least equal to or higher 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.

[0035] 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. 0-24is the plasma AUC achieved at a dose of orally administered 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 administered pirfenidone or pyridone analog compound. 0-24 is at least 10% of or greater than

[0036] 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 measuring the lung tissue AUC 0-24 is the lung tissue 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 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 0-24 is the lung tissue 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 an nebulized aqueous solution of the pirfenidone or pyridone analog compound. 0-24 is at least 1.5 times the

[0037] In one aspect, provided herein are methods 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 for improving the pharmacokinetic profile further includes comparing the pharmacokinetic parameters after inhalation 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 the pulmonary half-life is increased, providing a longer residence time in the lungs. In some embodiments, the improvement in the sustained pharmacokinetic profile is achieved by repeated and frequent administration of an aqueous solution of pirfenidone or a pyridone analog as described herein via inhalation. In some embodiments, continuous administration of pirfenidone or a pyridone analog via inhalation provides more frequent direct pulmonary exposure, benefiting humans through repeated high Cmax levels.In some embodiments, the inhaled pirfenidone or pyridone analog dose is administered once daily, twice daily, three times daily, four times daily, every other day, every second day, every third day, every fourth day, every fifth day, every sixth day, every seventh day, or a combination thereof. In some embodiments, the improved pharmacokinetic profile is similar to that depicted in Figure 2. In some embodiments, the initial improved pharmacokinetic profile is similar to that depicted in Figure 2, but the pulmonary half-life is increased, providing a longer residence time in the lungs. In some embodiments, the sustained improved pharmacokinetic profile is achieved by repeated and frequent administration of an aqueous solution of pirfenidone or pyridone analog as described herein via inhalation. In some embodiments, continuous administration of pirfenidone or pyridone analog via inhalation provides more frequent direct pulmonary exposure, benefiting humans through repeated high Cmax levels. In some embodiments, the inhaled pirfenidone or pyridone analog dose is administered once daily, twice daily, three times daily, four times daily, every other day, every second day, every third day, every fourth day, every fifth day, every sixth day, every seventh day, or a combination thereof. In some embodiments, the improved pharmacokinetic profile is similar to that depicted in Figure 5. In some embodiments, the initial improved pharmacokinetic profile is similar to that depicted in Figure 5, but the pulmonary half-life is increased, providing a longer residence time in the lungs. In some embodiments, the sustained improved pharmacokinetic profile is achieved by repeated and frequent administration of an aqueous solution of pirfenidone or pyridone analog as described herein via inhalation. In some embodiments, continuous administration of pirfenidone or pyridone analog via inhalation provides more frequent direct pulmonary exposure, benefiting humans through repeated high Cmax levels. In some embodiments, the dose of inhaled pirfenidone or pyridone analog is administered once daily, twice daily, three times daily, four times daily, every other day, every third day, every fourth day, every fifth day, every sixth day, every seventh day, or a combination thereof.

[0038] Described herein are pharmaceutical compositions for pulmonary delivery, comprising a solution of pirfenidone or pyridone analogs 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.

[0039] In some embodiments, described herein are pharmaceutical compositions for pulmonary delivery comprising a solution of pirfenidone or pyridone analogs 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 the pirfenidone or pyridone analogs is greater than about 34 mcg / mL. In some embodiments, the concentration of the pirfenidone or pyridone analogs is greater than about 1.72 mg / mL. In some embodiments, the concentration of the pirfenidone or pyridone analogs 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.

[0040] 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 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 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.

[0041] In one aspect, described herein are methods for treating pulmonary diseases, 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 contains 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 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 pirfenidone or pyridone analog dose of at least 6.8 mcg. In some embodiments, the inhaling step delivers a pirfenidone or pyridone analog dose of at least 340 mcg. In some embodiments, the inhaling step delivers a pirfenidone or pyridone analog dose of at least 740 mcg. In some embodiments, the inhaling step delivers a pirfenidone or pyridone analog dose of at least 1.7 mg. In some embodiments, the inhaling 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.

[0042] In some embodiments, described herein are pharmaceutical compositions for pulmonary delivery comprising a solution of pirfenidone or a pyridone analog and a flavoring agent, wherein the solution has an osmolality greater than about 50 mOsmol / kg and a pH greater than about 4.0. In some embodiments, the concentration of the pirfenidone or a pyridone analog is greater than about 34 mcg / mL. In some embodiments, the concentration of the pirfenidone or a pyridone analog is greater than about 1.72 mg / mL. In some embodiments, the concentration of the 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 50 mOsmol / kg to about 2000 mOsmol / kg. In some embodiments, the composition includes a flavoring agent. In some embodiments, the flavoring agent is selected from the group consisting of lactose, sucrose, dextrose, saccharin, aspartame, sucralose, ascorbate, and citrate. In some embodiments, the composition includes a mucolytic agent suitable for pulmonary delivery. In some embodiments, the composition includes a second anti-fibrotic agent suitable for pulmonary delivery. In some embodiments, the composition includes a second anti-inflammatory agent suitable for pulmonary delivery. In some embodiments, the composition includes a second anti-cancer agent suitable for pulmonary delivery. In some embodiments, the composition includes a second anti-pulmonary arterial hypertension agent suitable for pulmonary delivery.

[0043] In one aspect, the present disclosure provides a method for treating a pulmonary disease, comprising inhaling an aerosol of a solution of pirfenidone or a pyridone analog having a concentration greater than about 34 mcg / mL, an osmolality greater than about 50 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 0.1 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 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 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 50 mOsmol / kg to about 2000 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 and the mammal is a human. In some embodiments, the interstitial lung disease is idiopathic pulmonary fibrosis and the mammal is a human. In some embodiments, the interstitial lung disease is radiation therapy-induced pulmonary fibrosis and the mammal is a human. In some embodiments, the pulmonary disease is chronic obstructive pulmonary disease and the mammal is a human. In some embodiments, the pulmonary disease is chronic bronchitis and the mammal is a human. In some embodiments, the pulmonary disease is asthma and the mammal is a human.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 volumetric mean diameter of about 1 micron to about 5 microns and a geometric standard deviation of particle size of 3 microns or less. 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 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.

[0044] In one aspect, the present disclosure provides a method for treating a pulmonary disease, comprising inhaling an aerosol of 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 concentration of pirfenidone or a pyridone analog is greater than about 0.1 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 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 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 50 mOsmol / kg to about 2000 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 an anti-fibrotic or anti-cancer, anti-pulmonary hypertension, or anti-infective 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 composition may be co-administered with an anti-fibrotic or anti-cancer, anti-pulmonary hypertension, or anti-infective agent suitable for pulmonary delivery. In some embodiments, the composition is co-administered with a second anti-inflammatory 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 lung cancer. In some embodiments, the lung cancer is small cell lung cancer.In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the lung cancer is large cell carcinoma. In some embodiments, the lung cancer is mesothelioma. In some embodiments, the lung cancer is pulmonary carcinoid tumor or bronchial carcinoid. In some embodiments, the lung cancer is secondary lung cancer resulting from metastatic disease. In some embodiments, the lung cancer is bronchioloalveolar carcinoma. In some embodiments, the lung cancer can be a sarcoma. In some embodiments, the lung cancer can be a lymphoma. 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 volumetric mean diameter of about 1 micron to about 5 microns and a geometric standard deviation of 3 microns or less. 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 minimum dose of 740 mcg of pirfenidone or a pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 1.7 mg of pirfenidone or a pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 93 mg of pirfenidone or a pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 463 mg of pirfenidone or a 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 takes less than about 1.5 minutes. In some embodiments, the inhaling step takes 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.

[0045] In one aspect, the present disclosure provides a method for treating a pulmonary disease, comprising inhaling an aerosol of 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 concentration of pirfenidone or a pyridone analog is greater than about 0.1 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 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 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 50 mOsmol / kg to about 2000 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 an anti-fibrotic or anti-cancer, anti-pulmonary hypertension, or anti-infective 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 composition may be co-administered with an anti-fibrotic or anti-cancer, anti-pulmonary hypertension, or anti-infective agent suitable for pulmonary delivery. In some embodiments, the composition is co-administered with a second anti-inflammatory 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 lung disease is pulmonary hypertension. In some embodiments, the pulmonary hypertension is type 1.In some embodiments, the pulmonary hypertension is type 2. In some embodiments, the pulmonary hypertension is type 3. In some embodiments, the pulmonary hypertension is type 4. In some embodiments, the pulmonary hypertension is type 5. In some embodiments, the pulmonary hypertension is associated with pulmonary fibrosis. 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 volumetric mean diameter of about 1 micron to about 5 microns and a geometric standard deviation of 3 microns or less. 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 a pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 93 mg of pirfenidone or a pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 463 mg of pirfenidone or a 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.

[0046] In one aspect, a method of 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 of 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.

[0047] 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.

[0048] In any of the methods described herein using an aerosol or nebulizer to deliver a pirfenidone or pyridone analog compound to the lung, 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 inhaling step delivers a minimum dose of 93 mg of pirfenidone or a pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 463 mg of pirfenidone or a 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.

[0049] 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 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 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, hi 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 minimum 6.8 mcg dose of pirfenidone or a pyridone analog. In some embodiments, the inhaling step delivers a minimum 340 mcg dose of pirfenidone or a pyridone analog. In some embodiments, the inhaling step delivers a minimum 740 mcg dose of pirfenidone or a pyridone analog. In some embodiments, the inhaling step delivers a minimum 1.7 mg dose of pirfenidone or a pyridone analog. In some embodiments, the inhaling step delivers a minimum 93 mg dose of pirfenidone or a pyridone analog. In some embodiments, the inhaling step delivers a minimum 463 mg dose of pirfenidone or a 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 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.

[0050] 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.

[0051] In any of the methods described herein that include a step of introducing a pirfenidone or 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 the pirfenidone or pyridone analog solution for introduction into the nebulizer.

[0052] 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 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 a pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 93 mg of pirfenidone or a pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 463 mg of pirfenidone or a 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.

[0053] In one embodiment, a kit is provided herein, 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 central to lower respiratory tract through oral inhalation. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 1.72 mg / mL. In some embodiments, the pirfenidone or pyridone analog concentration is greater than about 86 mg / mL. In some embodiments, the 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] In one aspect, a method for treating a neurological disease is described herein, 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 aspect, described herein is a pharmaceutical composition for pulmonary delivery 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 a pyridone analog dose content is greater than about 6.8 mcg. In some embodiments, the pirfenidone or a pyridone analog content is greater than about 340 mcg. In some embodiments, the pirfenidone or a pyridone analog content is greater than about 17 mg. In some embodiments, the pirfenidone or a 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.

[0060] In one aspect, described herein is a pharmaceutical composition for pulmonary delivery comprising a dry powder containing a pirfenidone or 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 a pirfenidone or pyridone analog having a dosage content greater than about 1%. In a further aspect, described 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 compounding agent. In some embodiments, the admixture 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 minimum dose of 740 mcg of pirfenidone or a pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 1.7 mg of pirfenidone or a pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 93 mg of pirfenidone or a pyridone analog. In some embodiments, the inhaling step delivers a minimum dose of 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 in a single breath.

[0061] 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 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 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 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 pirfenidone or pyridone analog dose of at least 6.8 mcg. In some embodiments, the inhaling step delivers a pirfenidone or pyridone analog dose of at least 340 mcg. In some embodiments, the inhaling step delivers a pirfenidone or pyridone analog dose of at least 740 mcg. In some embodiments, the inhaling step delivers a pirfenidone or pyridone analog dose of at least 1.7 mg. In some embodiments, the inhaling step delivers a pirfenidone or pyridone analog dose of at least 17 mg. In some embodiments, the inhaling step delivers a dose of pirfenidone or a pyridone analog of at least 93 mg. In some embodiments, the inhaling step delivers a dose of pirfenidone or a pyridone analog of at least 463 mg. 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.

[0062] 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 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.

[0063] 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.

[0064] In one aspect, the present specification describes a method for treating a pulmonary disease, the method comprising administering pirfenidone or a pyridone analog to the middle to lower airways of a subject with or suspected of having a pulmonary disease via oral inhalation of an aerosol containing pirfenidone or a pyridone analog, wherein the pulmonary disease is cancer. In some embodiments, the therapeutic target of the lung cancer is tumor stroma. In some embodiments, the subject is a subject on a ventilator.

[0065] In one aspect, the present specification describes a method for treating a pulmonary disease, the method comprising administering pirfenidone or a pyridone analog to the middle to lower airways of a subject having or suspected of having a pulmonary disease via oral inhalation of an aerosol containing pirfenidone or a pyridone analog, wherein the pulmonary disease is pulmonary hypertension. In some embodiments, the subject is a subject on a mechanical ventilator.

[0066] In one aspect, 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.

[0067] 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.

[0068] 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.

[0069] In one aspect, a method of administering pirfenidone or a pyridone analog to treat a patient with idiopathic pulmonary fibrosis (IPF) is described herein, wherein the patient avoids liver function abnormalities, as indicated by Grade 2 or greater abnormalities after oral administration of one or more biomarkers of liver function, following administration of the pirfenidone or pyridone analog, the method comprising administering the pirfenidone or 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 and less than or equal to 5 times the upper limit of normal (ULN). Grade 2 liver function abnormalities also include elevations of bilirubin levels greater than 1.5 times and less than or equal to 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.

[0070] In one aspect, a method of administering pirfenidone or a pyridone analog to treat a patient with idiopathic pulmonary fibrosis (IPF) is described herein, wherein the patient avoids the occurrence of photosensitivity reactions observed after oral administration, the method comprising administering pirfenidone or a pyridone analog to the patient at a dose of less than 360 mg per day. In some embodiments, the pirfenidone or a pyridone analog is delivered to the patient 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 the pirfenidone or a pyridone analog is less than 10 mcg / mL. In some embodiments, the blood Cmax after administration of the pirfenidone or a pyridone analog is greater than 10 mcg / mL.

[0071] In one aspect, a method for administering pirfenidone or a pyridone analog to treat a patient with idiopathic pulmonary fibrosis (IPF) is described herein, wherein the patient avoids the occurrence of phototoxicity after oral administration, the method comprising administering pirfenidone or a pyridone analog to the patient at a dosage of less than 360 mg per day. In some embodiments, the pirfenidone or a pyridone analog is delivered to the patient by oral inhalation or intranasal inhalation. In some embodiments, the incidence of adverse events of photosensitivity reactions is less than about 12%. In some embodiments, the blood Cmax after administration of the pirfenidone or a pyridone analog is less than 10 mcg / mL. In some embodiments, the blood Cmax after administration of the pirfenidone or a pyridone analog is greater than 10 mcg / mL.

[0072] In one aspect, described herein is a method of administering pirfenidone or a pyridone analog to treat patients with idiopathic pulmonary fibrosis (IPF) by delivering pirfenidone or a pyridone analog directly to the lungs via oral or intranasal inhalation, thereby avoiding the occurrence of gastrointestinal adverse events after oral administration. In some embodiments, gastrointestinal adverse events observed after oral administration of pirfenidone or a pyridone analog include, but are not limited to, any one or more of gastrointestinal disorders, nausea, diarrhea, gastroesophageal reflux disease (GERD), and vomiting. In some embodiments, less than 360 mg of pirfenidone or a pyridone analog is delivered to patients via 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 a pyridone analog is delivered to patients via inhalation per day. In some embodiments, less than 300 mg of pirfenidone or a pyridone analog is delivered to a patient by inhalation per day, hi some embodiments, the pirfenidone or a pyridone analog is delivered by inhalation once a day, twice a day, three times a day, or four times a day.

[0073] 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.

[0074] In one aspect, described herein is a pharmaceutical composition 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 a pyridone analog compound to the lungs after inhalation in excess of 1 mcg per gram of lung tissue in an adult human.

[0075] 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 composition unit increments of about 0.01 mg / mL. 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 in increments 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, In some embodiments, the pH is greater than about 900 mOsmol / kg, about 950 mOsmol / kg, greater than about 1000 mOsmol / kg, about 1500 mOsmol / kg, about 2000 mOsmol / kg, greater than about 2500 mOsmol / kg, greater than about 3000 mOsmol / kg, about 3500 mOsmol / kg, about 4000 mOsmol / kg, greater than about 4500 mOsmol / kg, about 5000 mOsmol / kg, about 5500 mOsmol / kg, about 6000 mOsmol / kg, or greater than about 6000 mOsmol / kg. In some embodiments, the pH is greater than about 3.0 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 0.01mM, about 0.05mM, about 0.1mM, about 0.2mM, about 0.3mM, about 0.4mM, about 0.5mM, about 0.6mM, about 0.7mM, about 0.8mM, about 0.9mM, about 1mM, about 2mM, about 3mM, about 4mM, about 5mM, about 6mM, about 7mM, about 8mM, about 9mM, about 10mM, about 15mM, about 20mM, about 25mM, about 30mM, about 35mM, about 40mM, about 45mM, and about 50mM.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] In some embodiments, oxygen exposure is reduced by replacing the ambient gas in the void space above the perimeter of the primary packaging container with an inert gas.

[0080] In some embodiments, oxygen exposure is reduced by inserting the primary package into a gas-impermeable secondary packaging container. The inert gas may be selected from the group consisting of argon or nitrogen.

[0081] 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.

[0082] 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.

[0083] 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 hereby incorporated 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]

[0084] [Figure 1] 1 shows modeled nebulized aerosol administration of pirfenidone and oral administration of pirfenidone to human subjects. The model incorporates the scaled pharmacokinetics of Example 6. [Figure 2] Modeled nebulized aerosol administration to humans - 50 mcg / gram target lung tissue Cmax and associated lung tissue and plasma pharmacokinetics. The model incorporates the scaled pharmacokinetics of Examples 6 and 7. [Figure 3] Hydroxyproline results from the bleomycin model of pulmonary fibrosis. A U-shaped dose-response of pirfenidone is demonstrated. This study also demonstrates that low-dose, direct pulmonary aerosol delivery of pirfenidone allows for the antifibrotic effects of pirfenidone within the limits of the AUC-dependent U-shaped dose-response. Hydroxyproline delta values ​​were obtained by first subtracting sham results and then subtracting the values ​​from the bleomycin-only control. Obtained p-values: # = 0.012 (same lung Cmax), * = 0.084 (same lung Cmax), and * = 0.075 (same plasma AUC); a. Trivdei et al., Nanotechnology. 23(50):505101, 2012. [Figure 4] Histological examination (fibrosis score) results from the bleomycin model of pulmonary fibrosis demonstrate a U-shaped dose-response of pirfenidone. It also shows that low-dose, direct pulmonary aerosol delivery allows the antifibrotic effect of pirfenidone within the limits of the AUC-dependent U-shaped dose-response. The delta values ​​for fibrosis score were obtained by first subtracting sham results and then subtracting the values ​​from the bleomycin-only control. Obtained p-values: # = 0.007 (same lung Cmax), * = 0.042 (same lung Cmax), and * = 0.143 (same plasma AUC); [Figure 5]Modeling human inhaled aerosol pirfenidone pharmacokinetics. Demonstration that aerosol inhalation allows for a wide therapeutic window for pirfenidone within the limits of pirfenidone's U-shaped dose-response. The model incorporates the scaled pharmacokinetics of Example 8. Inhalation provides a wide therapeutic window within the limits of pirfenidone's U-shaped dose-response. At an 801 mg oral pirfenidone dose (taken with food; Rubino et al., Pulm Pharmacol Ther. 22(4):279-85, 2009), a 120 mg pirfenidone RDD inhaled over 5 minutes resulted in a comparable plasma AUC and a 43-fold greater lung tissue Cmax; a 50 mg pirfenidone RDD inhaled over 5 minutes resulted in a 2.4-fold lower plasma AUC and an 18-fold greater lung tissue Cmax; and a 2.5 mg pirfenidone RDD inhaled over 1 minute resulted in a 50-fold lower plasma AUC and comparable lung tissue Cmax. The inset in the top panel shows pirfenidone pharmacokinetics between 0-10 mcg / gram of human lung tissue and 0-4 hours. DETAILED DESCRIPTION OF THE INVENTION

[0085] 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.

[0086] In epithelia, scarring plays a valuable healing role after injury. However, epithelial tissues can gradually become 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 in a limited area, but can affect more diffuse and widespread areas, resulting in direct or associated organ failure.

[0087] In neurological disorders, 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.

[0088] Epithelial injury induces the release of multiple profibrotic mediators from epithelial cells, 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 the most 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.

[0089] In diseases such as pulmonary fibrosis, renal fibrosis, cardiac fibrosis, and ocular fibrosis, multiple sclerosis, and rheumatic diseases, physiological responses characterized by the regulation 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.

[0090] 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 induces 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.

[0091] 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.

[0092] The mechanism of action of pyridone analogs such as pirfenidone is believed to be anti-inflammatory and anti-fibrotic. Pirfenidone inhibits the synthesis and release of pro-inflammatory cytokines and reduces the accumulation of inflammatory cells in response to various stimuli. Pirfenidone also 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 TGF-beta and platelet-derived growth factor (PDGF).

[0093] 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.

[0094] Oral administration of pirfenidone to LPS-challenged mice resulted in a dose-dependent reduction in mortality and a decrease in the blood levels of the pro-inflammatory cytokines TNF-alpha, interleukin (IL-12), and interferon-gamma, as well as an increase in the blood 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.

[0095] 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.

[0096] 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.

[0097] In rats, pirfenidone reduced collagen synthesis and deposition in liver fibrosis, reversed cardiac and renal fibrosis, and attenuated the increased diastolic stiffness of 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 the increased cardiac stiffness without reducing the increased vascular response to norepinephrine.

[0098] Human studies have demonstrated clinical anti-inflammatory and anti-fibrotic 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 discontinuation of pirfenidone administration.

[0099] In addition to the dose escalation of pirfenidone required to establish gastrointestinal tolerance, dose reduction and the use of food have been employed to enable 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 enable administration tolerance may also be attempted. In both cases, plasma Cmax decreases dose-proportionally. 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.

[0100] 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.

[0101] 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, provided herein are methods 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. Described herein are compositions of pirfenidone or pyridone analog compounds suitable for delivery to mammals by inhalation, and methods of using such compositions.

[0102] 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, low-to-moderate observed clinical efficacy 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.

[0103] 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 analogs 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 analogs. 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).

[0104] 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 benefits to 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 an ELF of about 0.1 mcg / mL to about 5 mcg / mL, or providing an ELF of 0.004 mcg / gram or about 0.7 mcg / gram of pirfenidone or pyridone analog to lung tissue, or providing an ELF of 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 alternatively about 0.004 mcg / gram to about 0.7 mcg / gram of pulmonary tissue pirfenidone or a pyridone analog, 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 may result in effective delivery of the pirfenidone or pyridone analog to the kidney. In some embodiments, the pirfenidone or pyridone analog delivered to the lungs becomes available to the kidney. In some embodiments, providing 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 pirfenidone or pyridone analog, may 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 may result in effective delivery of the pirfenidone or pyridone analog to the central nervous system (CNS). In some embodiments, delivery of pirfenidone or pyridone analogs to the nasal cavity makes them readily available 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 pirfenidone or pyridone analogs in lung tissue, may provide similarly effective administration to the CNS without the increased systemic adverse events or toxicity observed with oral administration.

[0105] 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 pressure sores), 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 pyridone analogs to the eye may prevent the progression of post-operative fibrosis in the conjunctiva and / or episclera following glaucoma surgery.

[0106] In some embodiments, infusion delivery of a liquid pirfenidone or pyridone analog to the desired site of effect, 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.

[0107] 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 result in an AUC that can be mimicked in the lung. In other embodiments, the difference between the lung ELF and tissue AUC may be less.

[0108] 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 about 0.2004 mcg or about 0.2004 mcg to about 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 about 0.2004 mcg to about 0.7 mcg of pirfenidone or a pyridone analog in 1 gram of lung tissue provides a plasma AUC of about 0.2004 mcg or about 0.2004 mcg to about 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:

[0109] 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.

[0110] 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.

[0111] 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, as opposed to 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.

[0112] 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 by 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 by inhalation delivery of pirfenidone or pyridone analogs, which have a plasma half-life slower than the pulmonary ELF, thereby targeting the delivery of specific plasma concentrations and thereby increasing the pulmonary ELF-pirfenidone or pyridone analog exposure.

[0113] 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, after intravenous injection of pirfenidone into mice, -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 comparable, 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 produces human plasma levels of 5 mcg / mL or greater over 4 hours, and that 5 mcg / mL of plasma produces 0.7 mcg / gram of lung tissue pirfenidone, oral or intranasal inhalation delivery must produce 0.7 mcg / gram or more of lung tissue pirfenidone for at least 4 hours for comparable efficacy against pulmonary fibrosis to oral administration.

[0114] 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), corrected 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.

[0115] 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 about 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 rate 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 wet lung tissue of 0.7 mcg / gram or more for a longer duration than is currently limited by oral administration. Such prolonged exposure may allow for shorter dosing intervals (e.g., once daily or twice daily versus 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).

[0116] If the actual measured lung tissue half-life of pirfenidone or pyridone analog elimination changes, the dosage calculated by the above model will change significantly. If the half-life is faster, more inhaled pirfenidone or pyridone analog will be required to maintain a lung tissue concentration higher than what is considered the minimum effective level. Further increases in inhaled pirfenidone or pyridone analog may be desirable to further improve efficacy. Furthermore, in addition to delivering the desired lung tissue Cmax and AUC, inhalation delivery of aerosolized pirfenidone or pyridone analogs may serve as an efficient route for systemic delivery. In some embodiments, an administration scheme is contemplated that allows inhalation delivery of pirfenidone or pyridone analogs 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 analog exposure to the lung tissue.

[0117] 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.

[0118] 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). Esbriet's formulation, threatening this already low efficacy dose, 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).

[0119] For oral administration in the context of treating pulmonary fibrosis, high oral doses are necessary 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, inhaled 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 pyridone analogs serves as an efficient means of delivering pirfenidone or pyridone analogs to systemic compartments. In some embodiments, inhaled delivery of pirfenidone or pyridone analogs provides Cmax and AUC advantages over the oral route. In some embodiments, inhaled delivery of pirfenidone or pyridone analogs provides Cmax and AUC advantages over the oral route, and pirfenidone or pyridone analogs delivered via aerosol with plasma recirculation maintain these beneficial properties. In some embodiments, the methods described herein may be used to treat patients diagnosed with mild to moderate IPF. In some embodiments, the methods described herein may be used to treat patients diagnosed with mild to severe IPF. In some embodiments, the methods described herein may be used to treat patients diagnosed with mild to moderate IPF without the need to first 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 the need to first increase 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 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 treat 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 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 first having to increase the patient's dosage. In some embodiments, the methods described herein may be used to administer prophylactic treatment to patients diagnosed with mild to severe IPF without first having to increase the patient's dosage. In some embodiments, the methods described herein may be used to administer prophylactic treatment to patients diagnosed with mild to moderate IPF without first having 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 administer prophylactic treatment to patients diagnosed with mild to severe IPF without first having to 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 first having to 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), and a reduction in the decline in lung function. CO These include a gradual decrease in serum creatinine, 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.

[0120] [Table 1]

[0121] 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, aqueous solutions of pirfenidone or pyridone analogs described and contemplated herein for administration by inhalation are completely homogeneous and soluble.

[0122] 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 increasing 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.

[0123] Oral administration of pirfenidone is contraindicated in patients receiving concomitant fluvoxamine. Fluvoxamine must be discontinued prior to initiation of 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.

[0124] Similarly, for oral administration, particular caution should be exercised when CYP1A2 inhibitors are used in combination 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).

[0125] 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).

[0126] 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 provides only moderate efficacy), any inhibition of the enzymes described above increases pirfenidone blood concentrations, accelerating 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.

[0127] 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 with a decrease in 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, oral and intranasal delivery of pirfenidone or pyridone analogs can directly achieve effective lung tissue levels, thereby minimizing extrapulmonary metabolism.

[0128] In some embodiments, administration of the pirfenidone or 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 the pirfenidone or pyridone analog compound by inhalation avoids or substantially avoids the gastrointestinal tract, and therefore, the effects observed with oral administration of the pirfenidone or 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.

[0129] 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.

[0130] (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.

[0131] IPF, as used herein, refers to "idiopathic pulmonary fibrosis," a chronic disease that, in some embodiments, 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 can be used in conjunction with the methods described herein, including chest x-rays, pulmonary function tests, exercise tests, bronchoscopy, and lung biopsies.

[0132] 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 pulmonary parenchymal fibrosis. Idiopathic pulmonary fibrosis is a progressive clinical syndrome with unknown etiology and, due to the lack of effective treatment, is often fatal. 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.

[0133] 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.

[0134] 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).

[0135] (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 an overall 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 pyridone analogs 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.

[0136] 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.

[0137] Cardiac and renal toxicity In some embodiments, the compositions and methods described herein can treat, slow the progression of, or prevent cardiac and / or renal toxicity. Chemotherapeutic agents have 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.

[0138] 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.

[0139] 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.

[0140] <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 may selectively reverse existing fibrosis and prevent further fibrosis, thereby improving function even if increased systolic blood pressure remains unchanged.

[0141] 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, but not limited to, viral or bacterial infections, surgery, Duchenne muscular dystrophy, radiation, chemotherapy, and transplant rejection.

[0142] 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.

[0143] <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 primary 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. Furthermore, clinical studies administering oral pirfenidone have shown 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.

[0144] 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.

[0145] <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.

[0146] 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.

[0147] <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 may be an effective means of preventing, managing, or treating COPD or related conditions without exposing the systemic compartment to otherwise toxic drug concentrations associated with oral administration. Furthermore, inhaled delivery of pirfenidone or pyridone analogs may function as conjunctive therapy with corticosteroids to restore their usefulness in this indication.

[0148] 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 pre-existing asthma. COPD refers to a broad spectrum of airway diseases ranging from simple chronic bronchitis (cough due to excessive smoking) to the 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 diseases include, but are not limited to, chronic bronchitis, emphysema, and / or pulmonary hypertension.

[0149] <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. Because pirfenidone has been shown to inhibit TNF-alpha, inhaled delivery of pirfenidone or pyridone analogs may be an effective means of managing or treating asthma or related conditions without exposing the systemic compartment to otherwise toxic drug concentrations associated with oral administration. In some embodiments, inhaled delivery of pirfenidone or pyridone analog compounds is used to treat asthma in humans. Furthermore, inhaled delivery of pirfenidone or pyridone analogs may function as a conjugate therapy with corticosteroids to restore their usefulness in steroid-resistant asthma patients.

[0150] 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.

[0151] <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, which is related to or contributes to the symptoms of bronchitis, asthma, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and interstitial pneumonia.

[0152] <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 pyridone analogs may prove beneficial.

[0153] <Cancer> Lung cancer mortality is high, with annual lung cancer deaths equaling those from prostate, breast, colon, and rectal cancer combined. Despite advances in knowledge of molecular mechanisms and the introduction of numerous new therapeutic lung cancer drugs, the dismal 5-year survival rate (11-15%) remains relatively unchanged. This reflects the limited available knowledge about the factors that promote the neoplastic transformation and proliferation of malignant cells.

[0154] Until recently, the primary focus of cancer research has almost always been the malignant cells themselves. As a result, a significant discrepancy exists today between the vast knowledge about cancer biology generated in experimental settings and the translation of this knowledge into information that can be used in medical decision-making. Understanding the nature of the tumor environment today may be as important to future cancer treatments as understanding cancer genetics itself. Cancers are not simply tumor-cell-autonomous, but are composed of fibroblasts, immune cells, endothelial cells, and specific mesenchymal cells. These different cell types in the stromal environment can be recruited by malignant cells to support tumor growth and promote metastatic dissemination.

[0155] Although the "seed and soil" hypothesis was proposed over a century ago, we are now beginning to grasp the complex crosstalk between tumor cells (the "seed") and the tumor growth microenvironment (the "soil"). We now understand that tumor growth is not solely determined by malignant cells, as interactions between cancer cells and the stromal compartment have a profound impact on cancer growth and progression. Active malignant cells excel at exploiting the intratumoral microenvironment: they (1) establish themselves in and transform the stroma, (2) alter the surrounding connective tissue, and (3) modify the metabolism of resident cells, resulting in a permissive rather than protective stroma.

[0156] Beyond overcoming host microenvironmental control, a key characteristic of cancer cells is their ability to invade tissues and metastasize. For invasion and metastasis, coordinated interactions between fibroblasts, immune cells, and angiogenic cells and factors are essential.

[0157] The tumor stroma essentially consists of (1) non-malignant tumor cells, such as CAFs, specific mesenchymal cell types unique to each tissue environment, innate and adaptive immune cells, and the vasculature with endothelial cells and pericytes; and (2) the extracellular matrix (ECM), which consists of structural proteins (collagen and elastin), specific proteins (fibrillin, fibronectin, and elastin), and proteoglycans. Angiogenesis is central to cancer cell growth and survival and has been the most successful stromal targeting approach in anticancer therapy to date. Initiation of angiogenesis requires the induction of matrix metalloproteinases (MMPs), which lead to basement membrane degradation, endothelial cell sprouting, and regulation of pericyte adhesion. However, CAFs play a key role in orchestrating these events through the expression of numerous ECM molecules and growth factors, including transforming growth factor (TGF)-β, vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF2).

[0158] The stroma of normal tissues is essential for the maintenance and integrity of epithelial tissue and contains numerous cells that cooperate to maintain normal tissue homeostasis. There is continuous, bilateral molecular crosstalk between normal epithelial cells and cells of the stromal compartment, mediated through direct cell-cell adhesion or by secreted molecules. Thus, subtle changes in one compartment can cause dramatic changes in the entire system.

[0159] Similarities exist between stroma from wounds and tumors, as both entities have active angiogenesis and numerous proliferating fibroblasts (all on a background of fibrin deposition) that secrete a complex ECM. Consequently, tumor stroma has commonly been referred to as activated or reactive stroma.

[0160] Genetic alterations during cancer progression that lead to malignant cells result in alterations of the stromal host compartment to establish a permissive and supportive environment for cancer cells. During the early stages of tumor growth and invasion, the basement membrane is degraded, and activated stroma, containing fibroblasts, inflammatory infiltrating cells, and newly formed capillaries, comes into direct contact with tumor cells. The basement membrane matrix also modifies cytokine interactions between cancer cells and fibroblasts. These cancer-induced changes in the stroma contribute to cancer invasion. Animal studies have shown that both injured and activated stroma provide tumorigenic signals that promote tumor formation. While normal stroma in most organs contains a minimal number of fibroblasts relative to physiological ECM, activated stroma is associated with more ECM-producing fibroblasts, enhancing vascularity and increasing ECM production. This formation of specific tumor stroma types at sites of active tumor cell invasion is considered an essential part of tumor invasion and has been termed tumor stromatogenesis.

[0161] The expansion of tumor stroma by fibroblast proliferation and dense deposition of ECM is referred to as the connective tissue formation reaction. It occurs concomitantly with malignant growth and can be isolated from alveolar recesses, which exhibit neither activated fibroblasts nor dense collagen / ECM. Morphologically, this is referred to as connective tissue fibrosis and was initially viewed as a defense mechanism to prevent tumor growth; however, data have shown that in established tumors, this process, quite the opposite, is involved in various aspects of tumor progression, such as angiogenesis, migration, invasion, and metastasis. Subsequent studies have shown that fibroblasts and tumor cells can enhance local tissue growth and cancer progression by secreting ECM and lowering ECM components within the tumor stroma. This is partly related to the release of substances sequestered in the ECM, such as VEGF, and the cleavage of products from ECM proteins in response to the secretion of carcinoma-associated MMPs.

[0162] Profibrotic growth factors released by cancer cells, such as TGF-β, platelet-derived growth factor (PDGF), and FGF2, govern the quantity and composition of tumor stroma because they are all major mediators of fibroblast activation and tissue fibrosis. PDGF and FGF2 play similar significant roles in angiogenesis.

[0163] In tumors, activated fibroblasts are termed peritumoral fibroblasts or carcinoma-associated fibroblasts (CAFs). CAFs, like activated fibroblasts, are highly heterogeneous and are thought to originate from the same source as activated fibroblasts. Their primary ancestor appears to be locally present fibroblasts, but they may also be derived from pericytes and smooth muscle cells from the vasculature, from bone marrow-derived mesenchymal cells, or by epithelial or endothelial mesenchymal transition. Due to the diverse origins from which these cells derive, the term CAF is rather ambiguous, as is the difference between activated fibroblasts and CAFs. There is increasing evidence of epigenetic and possibly genetic differences between CAFs and standard fibroblasts. CAFs can be recognized by their expression of α-smooth muscle actin, but due to their heterogeneity, α-smooth muscle actin expression alone does not necessarily distinguish all CAFs. Therefore, other CAF markers used were fibroblast-specific protein 1, fibroblast activation protein (FAP), and PDGF receptor (PDGFR) α / β.

[0164] In response to tumor growth, fibroblasts are activated primarily by chemokines such as TGF-β, monocyte chemoattractant protein 1, and ECM degraders such as MMPs. Normal fibroblasts in various in vitro studies have demonstrated inhibitory effects on cancer progression, and there is now strong evidence supporting the cancer-promoting role of CAFs. In breast carcinomas, 80% of stromal fibroblasts are thought to possess this activated phenotype (CAFs).

[0165] CAFs promote malignant growth, angiogenesis, invasion, and metastasis. The role of CAFs and their potential as targets for cancer therapy have been investigated in xenograft models, and evidence from translational studies has revealed the prognostic significance of CAFs in various cancer types.

[0166] In the context of tumor growth, CAFs are activated and highly integrated, secreting proteins such as type I and type IV collagen, extra domain A-fibronectin, heparin sulfate proteoglycan, secretory protein acidic and rich in cysteine, tenascin-C, connective tissue growth factor, MMPs, and plasminogen activators. In addition to secreting growth factors and cytokines that affect cell motility, CAFs are also important sources of ECM-degrading proteases, such as MMPs, which play a variety of important roles in tumorigenesis. Through ECM degradation, MMPs can promote tumor growth, invasion, angiogenesis, inflammatory cell recruitment, and metastasis, depending on the substrate. Furthermore, many proinflammatory cytokines appear to be activated by MMPs.

[0167] After injection of B16M melanoma cells in mice, the formation of liver metastases was associated with the early activation of stellate cells (fibroblast-like) in the liver, as these cells appear to be important in creating the metastatic niche and promoting angiogenesis. MMPs have also been associated with tumor angiogenesis in various in vivo models. CAFs, when co-injected into mice, promoted the invasion of otherwise non-invasive cancer cells. Furthermore, xenografts containing CAFs apparently grow faster than xenografts injected with standard fibroblasts.

[0168] Upon recruitment and accumulation of CAFs in the tumor stroma, these cells actively communicate with cancer cells, epithelial cells, endothelial cells, pericytes, and inflammatory cells by secreting various growth factors, cytokines, and chemokines. CAFs provide potent tumorigenic molecules such as TGF-β and hepatocyte growth factor (HGF).

[0169] TGF-β is a pleiotropic growth factor expressed by both cancer and stromal cells. TGF-β suppresses tumorigenesis in normal and premalignant cells. However, as cancer cells progress, this antiproliferative effect is lost, and instead, TGF-β promotes tumorigenesis by inducing differentiation toward an invasive phenotype. TGF-β also promotes cancer progression by escaping immune surveillance, and increased TGF-β expression is strongly associated with the accumulation of fibrotic adhesion tissue and cancer progression. Recently, a small molecule inhibitor of the TGF-β type I receptor was reported to inhibit the production of connective tissue growth factor (CTGF) by hepatocellular carcinoma (HCC) cells, resulting in a reduction of the stromal component of HCC. Inhibition of the TGF-β receptor abolished crosstalk between HCC and CAFs, resulting in the prevention of tumor growth, invasion, and metastasis. HGF belongs to the plasminogen family and is restricted to the ECM in its precursor form. It binds to the high affinity receptor c-met, and overexpression or constant oncogenic c-Met signaling leads to proliferation, invasion, and metastasis.

[0170] PDGF is a regulator of fibroblasts and pericytes and plays an important role in tumor progression. It is a chemotactic and growth factor for mesenchymal and endothelial cells. It has a limited autocrine role in tumor cell replication but is a potential player in the paracrine manner and development of tumor stroma. It induces proliferation of activated fibroblasts and recruits CAFs, possibly indirectly by stimulating TGF-β release from macrophages.

[0171] Tumors cannot progress without the parallel expansion of the tumor stroma. Although we still do not understand the precise mechanisms regulating fibroblast activation and their accumulation in cancer, available evidence points to the possibility that the tumor stroma or CAFs may be candidate targets for cancer therapy.

[0172] CAFs and MMPs are thought to be two of the key regulators of epithelial-derived tumors, affecting both transformed and nontransformed components of the tumor environment, representing potential new targets for integrated therapy. As previously noted, experience with MMP inhibitors has been unsuccessful to date. Evidence that CAFs are epigenetically and possibly genetically distinct from standard fibroblasts is beginning to define these cells as potential targets for anticancer therapy. FAP, expressed in more than 90% of epithelial carcinomas, initially emerged as a promising candidate for targeting CAFs, and the potential therapeutic effects of its inhibition have recently been explored. In preclinical studies, silencing FAP reduced tumor growth and significantly enhanced tumor tissue uptake of anticancer drugs. In a phase 1 trial in which patients with FAP-positive advanced carcinomas (colorectal cancer and NSCLC) were treated with an FAP antibody, the antibody clearly bound to the target site, but no objective responses were observed.

[0173] Consistent and repeated findings that cancer cells readily undergo invasion and metastasis in response to TGF-β have pointed to the need for new anticancer agents that target the oncogenic activity of TGF-β. Many anti-TGF-β antibodies and TGF-β receptor I kinases have been tested preclinically over the past decade. Due to a lack of success, targeting the TGF-β signaling system remains elusive. It is noteworthy that both protumoral and antitumor effects are attributed to TGF-β, and the multifunctional nature of TGF-β seemingly represents the greatest obstacle to effectively targeting its ligand, receptor, or downstream effectors.

[0174] <Pulmonary hypertension> Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a significant and sustained elevation of pulmonary arterial pressure. It results in right ventricular failure and death. Current therapeutic approaches for the treatment of chronic pulmonary hypertension primarily provide symptomatic relief, with some improvement in prognosis. Although all treatments have been proposed, evidence demonstrating the direct antiproliferative effects of most approaches is lacking. Additionally, the use of most currently applied drugs is hindered by either unwanted side effects or inconvenient administration routes. Pathological changes in hypertensive pulmonary arteries include endothelial injury, proliferation, and hypercontraction of vascular smooth muscle cells (SMCs).

[0175] The World Health Organization divides pulmonary hypertension (PH) into five groups. These groups are organized based on the cause of the disease and treatment options. In all groups, the mean pulmonary artery pressure is 25 mmHg or higher. Normal pulmonary artery pressure is 8-20 mmHg at rest. (Note that Group 1 is called pulmonary arterial hypertension (PAH), and Groups 2-5 are called pulmonary hypertension. However, all groups are collectively called pulmonary hypertension.) Group 1 pulmonary arterial hypertension includes PAH with no known cause; inherited PAH; PAH caused by drugs or toxins, such as street drugs and certain diet pills; and PAH caused by diseases such as connective tissue disease, HIV infection, liver disease, and congenital heart disease. These include heart disease present at birth, sickle cell disease, and schistosomiasis, an infection caused by a parasitic worm. Schistosomiasis is one of the most common causes of PAH in most parts of the world; and PAH caused by diseases affecting the veins and microvasculature of the lungs. Group 2 pulmonary hypertension includes PH associated with left heart disease. Diseases affecting the left side of the heart, such as mitral valve disease or long-term hypertension, can cause left heart disease and PH. Left heart disease is probably the most common cause of PH. Group 3 pulmonary hypertension includes PH associated with lung diseases such as COPD (chronic obstructive pulmonary disease) and interstitial lung disease. Interstitial lung disease causes scarring of lung tissue. Group 3 also includes PH associated with sleep-related breathing disorders, such as sleep apnea. Group 4 pulmonary hypertension includes PH caused by blood clots or blood clotting disorders in the lungs. Group 5 pulmonary hypertension includes PH caused by various other diseases or disorders. Examples include blood disorders such as polycythemia vera and essential thrombocythemia, and systemic diseases such as sarcoidosis and vasculitis. Systemic diseases involve many of the body's organs, thyroid disease, and metabolic disorders such as glycogen storage diseases. (In glycogen storage diseases, the body's cells do not use forms of glucose properly.) And other diseases such as tumors that affect the lung arteries and kidney disease.

[0176] Various growth factors have been implicated in the abnormal proliferation and migration of SMCs, including PDGF, basic FGF (bFGF), and EGF. In vitro studies have established that PDGF acts as a potent mitogen and chemoattractant for SMCs. Active PDGF is composed of polypeptides (A and B chains) that form homodimers or heterodimers and stimulate α and β cell surface receptors. Recently, two additional PDGF genes have been identified, encoding PDGF-C and PDGF-D polypeptides. PDGF receptors (PDGFRs) belong to the family of transmembrane receptor tyrosine kinases (RTKs) and are presumed to be held together by bivalent PDGF ligands. This complex of dimeric receptor and PDGF results in autophosphorylation of the RTK and increased kinase activity.

[0177] Both receptors activate major signal transduction pathways, including RAS / MAPK, PI3K, and phospholipase Cγ. Recently, upregulation of both PDGFRα and PDGFRβ was demonstrated in sheep with chronic intrauterine pulmonary hypertension. However, pulmonary PDGF-A or PDGF-B mRNA did not differ between pulmonary hypertensive and control animals. PDGF-A chain expression was significantly increased in lung biopsies from patients with severe pulmonary arterial hypertension (PAH).

[0178] PDGF-A and PDGF-B mRNA synthesis, and the steady-state levels of PDGF-A and PDGF-B mRNA and PDGF isoforms are elevated in bleomycin-treated lungs. Pirfenidone suppresses PDGF-A and PDGF-B levels, likely via posttranscriptional or translational mechanisms, resulting in decreased PDGF-A and PDGF-B protein expression. Furthermore, pirfenidone attenuates bleomycin-induced pulmonary fibrosis by downregulating the expression of PDGF-A as well as PDGF-B protein.

[0179] Because altered PDGF signaling plays an important role during PAH, pirfenidone or pyridone analogs also have positive effects on hemodynamics and pulmonary vascular remodeling in PAH and serve as anti-remodeling treatments for this disease.

[0180] 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.

[0181] 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, e.g., via the respiratory tract to the central airways and / or pulmonary beds (e.g., the alveolar-capillary bed) in a human patient. By 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.

[0182] 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.

[0183] 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.

[0184] 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 pyridone analogs are delivered.

[0185] 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.

[0186] 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.

[0187] 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.Chelation of iron(III) 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, formulations of pirfenidone have been found to 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 compartment. 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.

[0188] In certain such embodiments, for example, a pirfenidone or pyridone analog compound formulation comprises at least 0.1 mg to about 100 mg of pirfenidone or pyridone analog, either 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 compartment 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), amount of pirfenidone or pyridone analog, and potential taste-masking agents provides certain therapeutic and other advantages.

[0189] 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 it can be aerosolized into the nasal or pulmonary compartment and injected or inhaled. Thus, and as described in more detail herein, certain therapeutic and other advantages are provided by control of formulation conditions relative to the propellant, suitable pressurized metered-dose inhaler canister, and stability of the pirfenidone or a pyridone analog.

[0190] In certain preferred embodiments, the pirfenidone or pyridone analog compound formulation or salt thereof may function as a prodrug, sustained-release, or active agent in the formulations and compositions disclosed herein and may 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 may 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 so that it may reach the circulatory system following pulmonary delivery of the pirfenidone or pyridone analog compound to the pulmonary vasculature.

[0191] 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. Accordingly, 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 salts thereof, according to particularly preferred embodiments. Other contemplated embodiments may relate to other pyridone analog compounds, such as the pyridone analog compounds disclosed herein.

[0192] By way of non-limiting example, in preferred embodiments, pyridone analog compounds (e.g., pirfenidone) as provided herein are 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 patients with pulmonary fibrosis.

[0193] 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 examples, 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.

[0194] 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.

[0195] 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 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 a human and / or veterinary subject. Such embodiments provide direct and high-concentration delivery of pirfenidone or a pyridone analog compound 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.

[0196] 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 of cardiac fibrosis associated with, by way of non-limiting examples, infection, surgery, radiation therapy, chemotherapy, and transplant rejection.

[0197] 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 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 a pyridone analog compound to the pulmonary vasculature immediately upstream of the left atrium, left ventricle, and thus to the renal vasculature.

[0198] 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.

[0199] 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 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 the pirfenidone or pyridone analog compound to the left atrium, the pulmonary vasculature immediately upstream of the left ventricle, and thus to the cardiac and renal vasculature.

[0200] 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 chemotherapy-related cardiac or renal toxicity, by way of non-limiting example.

[0201] By way of non-limiting example, in a preferred embodiment, a pyridone analog compound (e.g., pirfenidone) as 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, to prevent, manage, or treat liver fibrosis. Such embodiments provide direct and high-concentration delivery of pirfenidone or a pyridone analog compound to the left atrium, the pulmonary vasculature immediately upstream of the left ventricle, and thus to the hepatic vasculature.

[0202] 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.

[0203] By way of non-limiting example, in preferred embodiments, the pyridone analog compounds (e.g., pirfenidone) provided herein are formulated to allow for administration as a mist, gas-liquid suspension or atomized liquid, dry powder, and / or aerosol administered as a metered dose injected or inhaled into the nose, or orally inhaled, to provide an effective concentration or amount that provides the desired anti-inflammatory and / or anti-demyelinating benefit, for example, for preventing, managing, or treating multiple sclerosis. When administered orally, these embodiments provide direct and high-concentration delivery of the pirfenidone or pyridone analog 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 the pirfenidone or pyridone analog compounds to the nasal and sinus vasculature immediately upstream of the central nervous system.

[0204] 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.

[0205] By way of non-limiting example, in preferred embodiments, pyridone analog compounds (e.g., pirfenidone) as provided herein are 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.

[0206] 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.

[0207] By way of non-limiting example, in preferred embodiments, pyridone analog compounds (e.g., pirfenidone) as provided herein are 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.

[0208] 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.

[0209] 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.

[0210] 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 cystic fibrosis.

[0211] 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). bronchodilators (e.g., beta-2 agonists and muscarinic antagonists), corticosteroids (e.g., salmeterol, fluticasone, and budesonide), glucocorticoids (e.g., prednisone), cromolyn, nedocromil, leukotriene modifiers (e.g., benzodiazepines, 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, leukotriene modifiers (e.g., benzodiazepines ... Hyperosmotic solutions (e.g., montelukast, zafirlukast, and zileuton), 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), prostanoids (prostin oids) (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, Nasisterine, Erdosteine), 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), 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.

[0212] Methods of administering pirfenidone or pyridone analogs as a fixed combination, simultaneous administration, sequential administration, or co-formulation (as required by the prescribing physician that the drugs be administered in some sequence as a combination therapy to treat the same disease) with drugs targeting cancer, 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 pyridone analogs are administered in 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, tumor stroma, and / or 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 IW001 (Type V collagen), analogs, or other collagens that target immune tolerogenesis to reduce inflammation, tumor stroma, and / or 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 PRM-151 (recombinant pentraxin-2), analogs, or other molecules that target regulation of the injury response to reduce inflammation, tumor stroma, and / or 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 CC-930 (a Jun kinase inhibitor), analogs, or other Jun kinase inhibitors to reduce inflammatory responses.By way of another non-limiting example, pirfenidone or pyridone analogs may be administered in a fixed combination, simultaneously administered, sequentially administered, or co-formulated with imatinib (also known as Gleeve or Glivec (a tyrosine kinase inhibitor)), analogs, or other tyrosine inhibitors to inhibit lung fibroblast-myofibroblast transformation and proliferation, as well as extracellular matrix production and tumor stroma formation / maintenance through inhibition of PDFG and transforming growth factor (TGF). By way of another non-limiting example, pirfenidone or pyridone analogs may be administered in a fixed combination, simultaneously administered, sequentially administered, or co-formulated with STX-100 (a monoclonal antibody targeting integrin alpha-v beta-6), analogs, or other antibodies targeting integrin alpha-v beta-6 or other integrins to reduce tumor stroma and / or 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 tumor stroma and / or 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 tumor stroma and / or fibrosis. By another non-limiting example, pirfenidone or a piridone analog may be administered in a fixed combination, co-administered, sequentially administered, or co-formulated with CNTO-888 (a monoclonal antibody targeting chemokine [C-C motif] ligand 2 [CCL2]), an analog, or other antibody targeting CCL2 to reduce tumor stroma and / or fibrosis.By way of another non-limiting example, pirfenidone or a pyridone analog may be administered in a fixed combination, simultaneously administered, sequentially administered, or co-formulated with Esbriet, Pirespa, or Pirfenex (trade names for pirfenidone), or an analog that targets inflammation, tumor stroma, and / or fibrosis. By way of another non-limiting example, pirfenidone or a pyridone analog may be administered in a fixed combination, simultaneously 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]), an analog, or another triple kinase inhibitor for reducing fibrosis, tumor stroma, and / or inflammation.

[0213] Oral and parenteral (by way of example, intravenous and subcutaneous) administration routes of other compounds, molecules, and antibodies targeting the administration of pirfenidone to reduce inflammation, tumor stroma, and / or fibrosis are often associated with adverse reactions, such as, by way of example and not limitation, gastrointestinal side effects, hepatic, renal, dermatological, cardiovascular, or other toxicities. As described herein with respect to 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, tumor stroma, 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 way of another non-limiting example, PRM-151 (recombinant pentraxin-2), analogs, or other molecules that target regulating the injury response to reduce inflammation, tumor stroma, 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 way of another non-limiting example, CC-930 (a Jun kinase inhibitor), analogs, or other Jun kinase inhibitors for reducing tumor stroma and / or 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, imatinib (also known as Gleeve or Glivec (tyrosine kinase inhibitor)), analogs, or other tyrosine inhibitors for inhibiting lung fibroblast-myofibroblast transformation and proliferation, as well as extracellular matrix production and tumor stroma formation / maintenance through inhibition of PDFG and transforming growth factors (TGF), 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 way of 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 to reduce tumor stroma 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 way of another non-limiting example, QAX576 (a monoclonal antibody targeting interleukin-13 [IL-13]), analogs, or other antibodies targeting IL-13 to reduce tumor stroma and / or 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 [C-C motif] ligand 2 [CCL2]), analogs, or other antibodies targeting CCL2 to reduce tumor stroma 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, 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 tumor stroma and / or 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.

[0214] Methods of administering pirfenidone or pyridone analogs simultaneously, sequentially, or co-prescribed with drugs targeting pulmonary hypertension, fibrosis, or inflammatory diseases (as required by the prescribing physician, drugs administered in some order as a combination therapy for treating the same disease) are described to enable "cocktail therapy" or "cocktail prophylaxis" in pulmonary hypertension associated with fibrosis, more specifically type 3 pulmonary hypertension, as shown as a promising method for treating cancer and pulmonary arterial hypertension. By way of non-limiting example, pirfenidone or pyridone analogs are administered in fixed combination, simultaneously, sequentially, or co-prescribed with monoclonal GS-6624 (formerly known as AB0024), an analog, or another antibody targeting the LOXL2 protein associated with connective tissue biogenesis to reduce inflammation, pulmonary hypertension, and / or 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 IW001 (type V collagen), an analog, or another collagen targeting immunogenic resistance to reduce inflammation, pulmonary hypertension, and / or 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 PRM-151 (recombinant pentraxin-2), an analog, or another molecule targeting modulation of the injury response to reduce inflammation, pulmonary hypertension, and / or 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 CC-930 (a Jun kinase inhibitor), an analog, or another Jun kinase inhibitor to reduce inflammatory responses.By way of another non-limiting example, pirfenidone or a pyridone analog may be administered in a fixed combination, simultaneously administered, sequentially administered, or co-formulated with imatinib (also known as Gleeve or Glivec (a tyrosine kinase inhibitor)), analogs, or other tyrosine kinase inhibitors to inhibit pulmonary fibroblast-myofibroblast transformation and proliferation, as well as extracellular matrix production and pulmonary arterial hypertension formation / maintenance through inhibition of PDFG and transforming growth factor (TGF). By way of another non-limiting example, pirfenidone or a pyridone analog may be administered in a fixed combination, simultaneously administered, sequentially administered, or co-formulated with STX-100 (a monoclonal antibody targeting integrin alpha-v beta-6), analogs, or other antibodies targeting integrin alpha-v beta-6 to reduce pulmonary hypertension and / or 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 pulmonary hypertension and / or 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 pulmonary hypertension and / or fibrosis. By another non-limiting example, pirfenidone or a piridone analog is administered in a fixed combination, co-administered, sequentially administered, or co-formulated with CNTO-888 (a monoclonal antibody targeting chemokine [C-C motif] ligand 2 [CCL2]), an analog, or other antibody targeting CCL2 to reduce pulmonary hypertension 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 Esbriet, Pirespa, or Pirfenex (trade names pirfenidone), or an analog targeting inflammation, pulmonary hypertension, 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 BIBF-1120 (also known as Vargatef; a triple kinase inhibitor targeting vascular endothelial growth factor [VEGF], platelet-derived growth factor [PDGF], and fibroblast growth factor [FGF]), an analog, or another triple kinase inhibitor for reducing fibrosis, pulmonary hypertension, and / or 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 an endothelin receptor antagonist (e.g., bosentan or ambrisentan) to treat pulmonary hypertension, tumor stroma, or fibrosis associated with cancer. 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 a PDE5 inhibitor (e.g., sildenafil, vardenafil, and tadalafil) to treat pulmonary hypertension, tumor stroma, or fibrosis associated with cancer. By another non-limiting example, pirfenidone or a pyridone analog is administered in a fixed combination, co-administered, sequentially administered, or co-formulated with a prostanoid (e.g., epoprostenol, iloprost, and treprostinin) to treat pulmonary hypertension, tumor stroma, or fibrosis associated with cancer.By another non-limiting example, pirfenidone or a pyridone analog is administered in a fixed combination, co-administered, sequentially administered, or co-formulated with nitric oxide or a nitric oxide-contributing compound (e.g., a nitrate, nitrite, or inhaled nitrite) to treat cancer-associated pulmonary hypertension, tumor stroma, or fibrosis.

[0215] Similar to the administration of pirfenidone, oral and parenteral routes of administration (including, but not limited to, intravenous and subcutaneous) of other compounds, molecules, and antibodies targeting the reduction of inflammation, pulmonary hypertension, and / or fibrosis are frequently associated with adverse reactions, including, but not limited to, gastrointestinal side effects, hepatic, renal, dermatological, cardiovascular, or other toxicities. As described herein for pirfenidone or pyridone analogs, these compounds also benefit from oral or nasal inhalation directly into the lungs or tissues immediately downstream of the nasal and / or pulmonary compartments. Thus, by way of non-limiting example, monoclonal GS-6624 (formerly known as AB0024), an analog, or another antibody targeting the LOXL2 protein associated with connective tissue biogenesis to reduce inflammation, pulmonary hypertension, and / or fibrosis, is administered by oral or nasal inhalation for direct delivery to the lungs or tissues immediately downstream of the nasal and / or pulmonary compartments. By way of another non-limiting example, PRM-151 (recombinant pentraxin-2), analogs, or other molecules targeted at modulating the injury response to reduce inflammation, pulmonary hypertension, and / or fibrosis can be administered by oral or nasal inhalation for direct delivery to the lungs or tissues immediately downstream of the nasal or pulmonary compartment. By way of another non-limiting example, CC-930 (a Jun kinase inhibitor), analogs, or other Jun kinase inhibitors to reduce inflammatory responses can be administered by oral or nasal inhalation for direct delivery to the lungs or tissues immediately downstream of the nasal or pulmonary compartment. By another non-limiting example, imatinib (also known as Gleeve or Glivec (a tyrosine kinase inhibitor)), analogs, or other tyrosine inhibitors for inhibiting pulmonary fibroblast-myofibroblast transformation and proliferation, as well as extracellular matrix production and pulmonary arterial hypertension through inhibition of PDFG and transforming growth factor (TGF), can be administered by oral or nasal inhalation for delivery directly to the lungs or tissues immediately downstream of the nasal or pulmonary compartment.By way of another non-limiting example, STX-100 (a monoclonal antibody targeting integrin alpha-v beta-6), analogs, or other integrins that target integrin alpha-v beta-6 to reduce pulmonary hypertension and / or fibrosis can be administered by oral or nasal inhalation for direct delivery to the lungs or tissues just downstream of the nasal or pulmonary compartment. By way of another non-limiting example, QAX576 (a monoclonal antibody targeting interleukin-13 [IL-13]), analogs, or other antibodies that target IL-13 to reduce pulmonary hypertension and / or inflammation can be administered by oral or nasal inhalation for direct delivery to the lungs or tissues just 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 pulmonary hypertension and / or fibrosis can be administered by oral or nasal inhalation for direct delivery to the lungs or tissues just downstream of the nasal or pulmonary compartment. By another non-limiting example, CNTO-888 (a monoclonal antibody targeting chemokine [C-C motif] ligand 2 [CCL2]), analogs, or other antibodies targeting CCL2 to reduce pulmonary arterial hypertension and / or fibrosis can be administered by oral or nasal inhalation for direct delivery to the lungs or tissues just downstream of the nasal or pulmonary compartment. By way of 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 pulmonary hypertension and / or fibrosis and / or inflammation can be administered orally or by nasal inhalation for delivery directly to the lungs or tissues immediately downstream of the nasal or pulmonary compartment. By way of another non-limiting example, endothelin receptor antagonists (e.g., bosentan or ambrisentan) treat pulmonary hypertension associated with cancer, tumor stroma, or fibrosis.By way of another non-limiting example, PDE5 inhibitors (e.g., sildenafil, vardenafil, and tadalafil) treat pulmonary hypertension associated with cancer, tumor stroma, or fibrosis. By way of another non-limiting example, prostanoids (e.g., epoprostenol, iloprost, and treprostinil) treat pulmonary hypertension associated with cancer, tumor stroma, or fibrosis. By way of another non-limiting example, nitric oxide or nitric oxide-donating compounds (e.g., nitrates, nitrites, or inhaled nitrites) treat pulmonary hypertension associated with cancer, tumor stroma, or fibrosis.

[0216] As shown as a promising method for treating cancer and pulmonary arterial hypertension, methods are described for administering pirfenidone or a pyridone analog in combination with a cancer-targeting drug, administered simultaneously, sequentially, or simultaneously (as required by the prescribing physician, the drugs are administered in several sequences as a combination therapy for the same disease) to enable "cocktail therapy" or "cocktail prophylaxis" in cancer, more specifically lung cancer. The anticancer drug may include gefitinib (also known as Iressa, ZD1839). Gefitinib is a selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase domain. Target proteins (EGFR) are a family of receptors including Her1 (erb-B1), Her2 (erb-B2), and Her3 (erb-B3). EGFR is overexpressed in cells of certain types of human carcinomas, such as lung and breast cancer. This leads to inappropriate activation of the anti-apoptotic Ras signaling cascade and ultimately to uncontrolled cell proliferation. Studies on gefitinib-sensitive non-small cell lung cancer (NSCLC) have shown that mutations in the EGFR tyrosine kinase domain are responsible for activating the anti-apoptotic pathway. These mutations tend to confer increased sensitivity to tyrosine kinase inhibitors such as gefitinib and erlotinib. Among the histological types of NSCLC, adenocarcinoma is the type that most frequently harbors these mutations. These mutations are more common in Asians, women, and non-smokers (who also tend to have adenocarcinoma more frequently). Gefitinib inhibits EGFR tyrosine kinase by binding to the enzyme's adenosine triphosphate (ATP) binding site. Thus, the function of EGFR tyrosine kinase in activating the anti-apoptotic Ras signaling cascade is inhibited, and malignant cells are inhibited. Although gefitinib must be further proven effective in other cancers, it also has the potential to be used in the treatment of other cancers associated with EGFR overexpression. Because gefitinib is a selective chemotherapeutic agent, its tolerability profile is superior to previous cytotoxic agents. Adverse drug reactions (ADRs) are tolerable with potentially fatal outcomes. Acne-like rashes are very commonly reported.Other common side effects include: diarrhea, nausea, vomiting, loss of appetite, stomatitis, dehydration, skin reactions, paronychia, asymptomatic elevation of liver enzymes, asthenia, conjunctivitis, and blepharitis. Rare side effects include: interstitial lung disease, corneal erosion, and abnormal eyelash and hair growth.

[0217] Another anticancer drug is erlotinib (also known as Tarceva). Erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase, which is highly expressed and sometimes mutated in various forms of cancer. It reversibly binds to the adenosine triphosphate (ATP) binding site of the receptor. For a signal to be transmitted, two EGFR molecules must come together to form a homodimer. They then use a molecule of ATP to transphosphorylate each other on tyrosine residues, which generates phosphotyrosine residues and recruits phosphotyrosine-binding proteins to the EGFR to assemble protein complexes that transduce signal cascades to the nucleus or activate other cellular biochemical processes. Inhibition of ATP prevents the formation of phosphotyrosine residues in EGFR, preventing the initiation of signal cascades. Erlotinib has demonstrated survival benefits in the treatment of lung cancer. Erlotinib is approved for the treatment of locally advanced or metastatic non-small cell lung cancer that has failed at least one prior chemotherapy regimen. It is also approved in combination with gemcitabine for the treatment of locally advanced, unresectable, or metastatic pancreatic cancer. In lung cancer, erlotinib has been shown to be effective in patients with and without EGFR mutations, but appears to be more effective in patients with EGFR mutations. The response rate among EGFR mutation-positive patients is approximately 60%. Patients with adenocarcinoma or subtypes such as BAC who are non-smokers and light former smokers are more likely to have EGFR mutations, although mutations can occur in all patient types. EGFR-positive patients are generally KRAS-negative. Erlotinib has recently been shown to be a potent inhibitor of JAK2V617F activity. JAK2V617F is a mutation in the tyrosine kinase JAK2 and is found in most patients with polycythemia vera (PV) and in a significant proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. Studies suggest that erlotinib may be used to treat JAK2V617F-positive PV and other myeloproliferative disorders. A rash occurs in the majority of patients. This resembles acne and primarily involves the face and neck.It is self-limiting and degrades in the majority of cases, even with continued use. Interestingly, several clinical studies have shown a correlation between the severity of skin reactions and increased survival, although this has not been quantitatively assessed. Skin rash may be a surrogate marker of clinical benefit. Other side effects include diarrhea, loss of appetite, fatigue, and, rarely, interstitial pneumonia, characterized by increased cough and dyspnea. This can be severe and must be considered in patients with severe respiratory deterioration. It has also been suggested that erlotinib may cause hearing loss. Rare side effects include severe gastrointestinal, skin, and eye disorders. In addition, some individuals prescribed erlotinib have developed severe or fatal gastrointestinal perforation; bullous, blistering, and peeling skin disease (some fatal); and severe eye disease, including corneal lesions. Some cases, including those resulting in death, have been associated with Stevens-Johnson syndrome / toxic epidermal necrolysis. Erlotinib is primarily metabolized by the hepatic enzyme CYP3A4. Compounds that induce this enzyme (i.e., stimulate its production), such as St. John's wort, can decrease erlotinib concentrations, while inhibitors can increase them. As with other ATP-competitive small-molecule tyrosine kinase inhibitors, such as imatinib in CML, patients rapidly develop resistance. With erlotinib, this typically occurs 8–12 months after the initiation of treatment. More than 50% of resistance is caused by a mutation in the ATP-binding pocket of the EGFR kinase domain involving the replacement of a small, polar threonine residue with a large, nonpolar methionine residue (T790M). Proponents of the "gatekeeper" mutation hypothesis suggest that this mutation prevents erlotinib binding through steric hindrance, but studies suggest that T790M confers increased ATP binding affinity, reducing erlotinib's inhibitory effects. Approximately 20% of drug resistance is caused by amplification of the hepatocyte growth factor receptor, which drives ERBB3-dependent activation of PI3K. Other resistance cases can involve multiple mutations, including recruitment of mutated IGF-1 receptors to homodimerize with EGFR and form heterodimers.This allows activation of downstream effectors of EGFR even in the presence of EGFR inhibitors. Several IGF-1R inhibitors are in various stages of progression (based either around TKIs such as AG1024 or AG538, or pyrrolo[2,3-d]-pyrimidine derivatives such as NVP-AEW541). Figitumumab, a monoclonal antibody targeting IGF-1R, is currently undergoing clinical trials. Another cause of resistance may be inactivating mutations in the PTEN tumor suppressor, which allow increased activation of Akt independent of stimulation by EGFR. Combating resistance is likely to be a combination therapy. Initiating treatment with multiple different therapeutic agents with different modes of action is likely to provide the best defense against the development of resistance to T790M and other resistance-conferring mutations.

[0218] Another anticancer drug is bortezomib (originally codenamed PS-341; sold as Velcade and Bortecad). Bortezomib is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the United States for treating relapsed multiple myeloma and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise resistant or rapidly progressing disease. Bortezomib was originally synthesized as MG-341. After promising preclinical results, the drug (PS-341) was tested in a small Phase I study in patients with multiple myeloma. Bortezomib (Velcade) is approved for use in multiple myeloma. Another commercially available bortezomib product, Bortenat, reportedly contains substantially more active substance than declared and potentially results in even greater toxicity. Furthermore, Bortenat has several other chemical and formulation deviations from its documented ethical product, Velcade, with unclear clinical impact. The boron atom in bortezomib binds with high affinity and specificity to the catalytic site of the 26S proteasome. In normal cells, the proteasome regulates protein expression and function by degrading ubiquitinated proteins and also cleanses cells of abnormal or misfolded proteins. Clinical and preclinical data support a role in maintaining the immortal phenotype of myeloma cells, and cell culture and xenograft data support a similar function in solid tumor cancers. While multiple mechanisms appear to be involved, proteasome inhibition may prevent the degradation of proapoptotic factors and enable the activation of programmed cell death in tumor cells that depend on the suppression of proapoptotic pathways. Recently, bortezomib has been found to induce rapid and dramatic changes in the levels of intracellular peptides delivered by the proteasome. Several intracellular peptides have been shown to be biologically active, and therefore the effect of bortezomib on intracellular peptide levels may contribute to the drug's biological and / or side effects. Bortezomib is rapidly eliminated after intravenous administration; peak concentrations are reached in approximately 30 minutes.Drug concentrations are no longer measurable after 1 hour. Pharmacodynamics are measured by measuring proteasome inhibition in peripheral blood mononuclear cells. The much greater sensitivity of myeloma and mantle cell lines to proteasome inhibition compared with standard peripheral blood mononuclear cells and most other cancer cell lines is less understood. Bortezomib is associated with peripheral neuropathy in 30% of patients; at times, it can be painful. This can be worse than in patients with pre-existing neuropathy. In addition, bone marrow suppression, causing neutropenia and thrombocytopenia, can occur and be dose-limiting. However, these side effects are usually milder for patients with advanced disease who are candidates for bone marrow transplantation and other treatment options. Bortezomib is associated with a high rate of herpes zoster, but prophylactic acyclovir can reduce this risk. Gastrointestinal effects and asthenia are the most common adverse events. The established efficacy of bortezomib is 1.3 mg / m² (with or without dexamethasone) administered by intravenous bolus on days 1, 4, 8, and 11 of a 21-day cycle for up to eight cycles in heavily pretreated patients with relapsed / refractory multiple myeloma. The demonstrated superiority of bortezomib is 1.3 mg / m² over high-dose dexamethasone regimens (by example median TTP 6.2 vs. 3.5 months, and 1-year survival 80% vs. 66%). Laboratory studies and clinical trials are investigating whether it may be possible to further increase the anticancer efficacy of bortezomib by combining it with new types of other pharmacological agents. For example, clinical trials have shown that the addition of thalidomide, lenalidomide, inhibitors of vascular endothelial growth factor (VEGF), or arsenic trioxide may be beneficial. In laboratory studies, it has been found that bortezomib killed multiple myeloma cells more efficiently when combined with, for example, the histone deacetylase inhibitors thapsigargin or celecoxib. There is preclinical evidence that bortezomib is synergistic with Reolysin in pancreatic cancer. However, the therapeutic efficacy and safety of any of these latter combinations have not yet been evaluated in cancer patients.

[0219] Another family of anticancer drugs is Janus kinase inhibitors. Also known as JAK inhibitors, these are a class of drugs that function by inhibiting the activity of one or more members of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2), thereby interfering with the JAK-STAT signaling pathway. These inhibitors have therapeutic applications in the treatment of cancer and inflammatory diseases. Cytokines play an important role in controlling cell proliferation and immune responses. Many cytokines function by binding to and activating type I and type II cytokine receptors. These receptors then depend on the Janus kinase (JAK) family of enzymes for signal transduction. Therefore, drugs that inhibit the activity of these Janus kinases block the cytokine signaling pathway. More specifically, Janus kinases phosphorylate activated cytokine receptors. These phosphorylated receptors then recruit STAT transcription factors, which regulate gene transcription. The first JAK inhibitor to reach clinical trials was tofacitinib. Tofacitinib is a specific inhibitor of JAK3 (IC50=2nM), thereby blocking the activity of IL-2, IL-4, IL15, and IL-21. Thus, Th2 cell differentiation is blocked, and therefore tofacitinib is effective in treating allergic diseases. Tofacitinib also inhibits, to a lesser extent, JAK1 (IC50=100nM) and JAK2 (IC50=20nM), which in turn block IFN-γ and IL-6 signaling and, consequently, Th1 cell differentiation.Examples of JAK inhibitors include: ruxolitinib against JAK1 / JAK2 for psoriasis, myelofibrosis, and rheumatoid arthritis; tofacitinib (tasocitinib; CP-690550) against JAK3 for psoriasis and rheumatoid arthritis; baricitinib (LY3009104, INCB28050) against JAK1 / JAK2 for rheumatoid arthritis; CYT387 against JAK2 for myeloproliferative disorders; lestaurtinib against JAK2 for acute myeloid leukemia (AML); pacritinib (SB1518) against JAK2 for relapsed lymphoma and progressive myeloid malignancies, chronic idiopathic myelofibrosis (CIMF); and TG101348 against JAK2 for myelofibrosis.

[0220] Another family of anticancer drugs is ALK inhibitors. ALK inhibitors are potential anticancer drugs that act against tumors with anaplastic lymphoma kinase (ALK) mutations, such as the EML4-ALK rearrangement. Approximately 7% of non-small cell lung carcinomas (NSCLC) have the EML4-ALK rearrangement. Examples of ALK inhibitors include crizotinib (trade name Xalkori), approved for NSCLC; AP26113, which is in preclinical development; and LDK378, which is being developed by Novartis as a second-generation ALK inhibitor. NPM-ALK is a distinct ALK mutation / fusion that controls anaplastic large cell lymphoma (ALCL) and is the target of other ALK inhibitors. Crizotinib has the structure and function of an aminopyridine, acting as a protein kinase inhibitor by competitively binding within the ATP-binding pocket of the target kinase. Approximately 4% of patients with non-small cell lung cancer (NSLC) have a chromosomal rearrangement that creates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase), resulting in constitutive kinase activity that appears to contribute to carcinogenesis and drive the malignant phenotype. The kinase activity of the fusion protein is inhibited by crizotinib. Patients with this gene fusion are typically younger, non-smokers who do not have mutations in the epidermal growth factor receptor (EGFR) or K-Ras genes. The number of new cases of ALK-fused NSLC is approximately 9,000 per year in the United States and approximately 45,000 worldwide. ALK mutations appear to be important in controlling the malignant phenotype in approximately 15% of neuroblastoma cases, a rare form of peripheral nervous system cancer that occurs almost exclusively in very young children. Crizotinib inhibits the c-Met / hepatocyte growth factor receptor (HGFR) tyrosine kinase, which is involved in the tumorigenesis of many other histological forms of malignant neoplasms. Crizotinib is currently thought to exert its effects by modulating the proliferation, migration, and invasion of malignant cells. Other studies suggest that crizotinib may also act through the inhibition of angiogenesis in malignant tumors.Crizotinib shrank or stabilized tumors in 90% of 82 patients carrying the ALK fusion gene. Tumors shrank by at least 30% in 57% of those treated. Most had adenocarcinoma and were never or former smokers. They had received an average of three other drug treatments before receiving crizotinib, and only 10% were expected to respond to standard therapy. They received 250 mg of crizotinib twice daily for a median duration of 6 months. Approximately 50% of these patients experienced at least one side effect, such as nausea, vomiting, or diarrhea. Some responses to crizotinib lasted up to 15 months. A phase 3 trial (PROFILE 1007) is comparing crizotinib with standard second-line chemotherapy (pemetrexed or taxotere) in the treatment of ALK-positive NSCLC. Additionally, a phase 2 trial (PROFILE 1005) is studying patients who meet similar criteria and have received more than one line of prior chemotherapy. Crizotinib (Xalkori) is approved to treat certain late-stage (locally advanced or metastatic) non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene. Approval required testing of a companion molecule for the EML4-ALK fusion.

[0221] Another anti-cancer drug is crizotinib, which is also being tested in clinical trials for advanced disseminated anaplastic large cell lymphoma and neuroblastoma.

[0222] Anticancer targets include Bcl-2 (B-cell lymphoma 2). Encoded by the BCL2 gene, it is the founding member of the Bcl-2 family of regulatory proteins that regulate cell death (apoptosis). The name Bcl-2 comes from B-cell lymphoma 2, as it is the second member of a family of proteins originally described in a chromosomal translocation involving chromosomes 14 and 18 in follicular lymphoma. Bcl-2 orthologs have been identified in numerous mammalian species for which complete genome data are available. Two isoforms of Bcl-2, isoform 1, also known as 1G5M, and isoform 2, also known as 1G5O / 1GJH, display similar folds. However, the ability of these isoforms to bind BAD and BAK proteins, as well as the resulting structural topology and electrostatic potential of the binding groove, suggest differences in the anti-apoptotic activity of the two isoforms. Damage to the Bcl-2 gene has been identified as a cause of many cancers, including melanoma, breast cancer, prostate cancer, chronic lymphocytic leukemia, and lung cancer, as well as a possible cause of schizophrenia and autoimmune diseases. It also contributes to resistance to cancer treatment. Cancer arises as a result of a disturbance in the homeostatic balance between cell proliferation and cell death. Overexpression of anti-apoptotic genes and underexpression of pro-apoptotic genes can result in the lack of cell death that characterizes cancer. An example can be seen in lymphoma. Overexpression of the anti-apoptotic Bcl-2 protein in lymphocytes alone does not cause cancer. However, simultaneous overexpression of Bcl-2 and the proto-oncogene myc can lead to aggressive B-cell malignancies, including lymphoma. In follicular lymphoma, a chromosomal translocation commonly occurs between chromosomes 14 and 18 (t(14;18)), placing the bcl-2 gene next to the immunoglobulin heavy chain gene locus. This fusion gene is deregulated, leading to excessively high levels of Bcl-2 transcription, which reduces the propensity of these cells to undergo apoptosis. Cell death also plays a vital role in regulating the immune system. When functional, it can cause immune unresponsiveness to self-antigens through both central and peripheral tolerance. Incomplete apoptosis can contribute to the pathogenesis of autoimmune diseases.Autoimmune diseases and type 1 diabetes can be caused by defective apoptosis, leading to abnormal T cell AICD and defective peripheral tolerance. Because dendritic cells are the most important antigen-presenting cells of the immune system, their activity must be tightly regulated by mechanisms such as apoptosis. Researchers have found that mice containing Bim- / - dendritic cells, which are therefore unable to induce effective apoptosis, develop more autoimmune diseases than those with normal dendritic cells. Other studies have shown that dendritic cell lifespan may be partially controlled by an anti-apoptotic Bcl-2-dependent timer. Apoptosis plays a crucial role in regulating various diseases with enormous societal impact. For example, schizophrenia is a neurodegenerative disorder that can result from an abnormal ratio of pro- and anti-apoptotic factors. There is some evidence that this defective apoptosis may result from abnormal expression of Bcl-2 and increased expression of caspase-3. Further research on the Bcl-2 protein family will provide a more complete picture of how these proteins interact to promote and inhibit apoptosis. Understanding the mechanisms involved may also aid in the development of new therapies for treating cancer, autoimmune diseases, and nervous system disorders. Bcl-2 inhibitors include the antisense oligonucleotide drug Genasense (G3139), which targets Bcl-2. The antisense DNA or RNA strand is non-coding and complementary to the coding strand (which is the template for producing the RNA or protein, respectively). Antisense drugs are short sequences of RNA that hybridize with mRNA, inactivating it and preventing the protein from being formed. It has been shown that antisense RNA targeted at the start codon region of Bcl-2 mRNA can inhibit the growth of human lymphoma cells (with the t(14;18) translocation). In vitro studies led to the identification of Genasense, which is complementary to the first six codons of Bcl-2 mRNA. Another Bcl-2 inhibitor is ABT-73.ABT-73, also known as ABT-737, is a novel inhibitor of Bcl-2, Bcl-xL, and Bcl-w. ABT-737 is one of many so-called BH3 mimetic small molecule inhibitors (SMIs) that target Bcl-2 and Bcl-2-related proteins, such as Bcl-xL and Bcl-w, but not A1 and Mcl-1, which may prove beneficial in the treatment of lymphomas and other leukemias. Another inhibitor is ABT-199, a so-called BH3 mimetic drug designed to block the function of the Bcl-2 protein in patients with chronic lymphocytic leukemia. Another Bcl-2 inhibitor is obatoclax (GX15-070) for small cell lung cancer. By inhibiting Bcl-2, obatoclax induces cell death in cancer cells and prevents tumor growth.

[0223] Another family of anticancer drugs is PARP inhibitors. PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP-ribose polymerase (PARP). They are being developed for a number of indications; the most important is the treatment of cancer. Various forms of cancer depend more on PARP than normal cells, making PARP an attractive target for cancer therapy. In addition to their use in cancer therapy, PARP inhibitors are considered potential treatments for acute, life-threatening diseases such as stroke and myocardial infarction, as well as long-term neurodegenerative diseases. DNA is damaged thousands of times during each cell cycle, and this damage must be repaired. BRCA1, BRCA2, and PALB2 are proteins critical for the repair of double-stranded DNA breaks by error-free homologous recombination repair, or HRR, pathway. When the gene for any of these proteins is mutated, the change can lead to errors in DNA repair, which can ultimately cause breast cancer. When exposed to sufficient damage at once, the altered gene can cause cell death. PARP1 is a protein important for the repair of single-strand breaks ("nicks" in DNA). If such breaks remain unrepaired until DNA is replicated (which must precede cell division), the repair itself can then lead to the formation of double-strand breaks. Drugs that inhibit PARP1 cause numerous double-strand breaks to form in this manner, and in tumors with BRCA1, BRCA2, or PALB2 mutations, these double-strand breaks are not repaired efficiently, leading to cell death. Normal cells, which do not repair DNA as frequently as cancer cells and lack any mutated BRCA1 or BRCA2, still possess homologous repair mechanisms, allowing them to survive PARP inhibition. Some cancer cells lacking the tumor suppressor PTEN may be sensitive to PARP inhibitors due to downregulation of Rad51 (a critical homologous recombination component), but other data suggest that PTEN may not regulate Rad51. Thus, PARP inhibitors may be effective against many PTEN-deficient tumors (e.g., some aggressive prostate cancers). Cancer cells that are low in oxygen (eg, in fast-growing tumors) are sensitive to PARP inhibitors.PARP inhibitors were originally thought to work primarily by blocking PARP enzyme activity, thereby preventing DNA damage repair and ultimately causing cell death. PARP inhibitors have an additional mode of action: localization of PARP proteins at sites of DNA damage, which is associated with antitumor activity. Trapped PARP protein-DNA complexes are highly toxic to cells because they block DNA replication. When researchers tested three PARP inhibitors for their differential ability to trap PARP proteins on damaged DNA, they found that the trapping properties of the inhibitors varied widely. The human PARP family of proteins includes PARP1 and PARP2, which are DNA-binding and repair proteins. When activated by DNA damage, these proteins recruit other proteins that perform the actual work of DNA repair. Under standard conditions, PARP1 and PARP2 are released from DNA once the repair process is underway. However, as this study shows, upon their binding to a PARP inhibitor, PARP1 and PARP2 become trapped on DNA. Researchers have shown that trapped PARP-DNA complexes are more toxic to cells than unrepaired single-strand DNA breaks that accumulate in the absence of PARP activity, indicating that PARP inhibitors act as PARP poisons. These results suggest that there are two types of PARP inhibitors: catalytic inhibitors, which act primarily to inhibit PARP enzymatic activity and do not trap PARP protein on DNA, and dual inhibitors, which block PARP enzymatic activity and act as PARP poisons. The primary function of radiation therapy is to induce DNA strand breaks, causing severe DNA damage and leading to cell death. Although radiation therapy has the potential to kill 100% of any target cell, the doses required to do so cause unacceptable side effects in healthy tissue. Therefore, radiation therapy can only be administered up to a certain level of radiation exposure. Combining PARP inhibitors with radiation therapy offers the potential for success, as the inhibitors lead to the formation of double-strand breaks from single-strand breaks induced by radiation therapy in tumor tissue with BRCA1 / BRCA2 mutations.This combination therefore leads to more effective treatment than with the same radiation dose, or similarly effective treatment with a lower radiation dose. Examples of PARP inhibitors include: iniparib (BSI 201) for breast cancer and squamous cell lung cancer; olaparib (AZD-2281) for breast, ovarian, and colorectal cancer; rucaparib (AG014699, PF-01367338) for metastatic breast and ovarian cancer; veliparib (ABT-888) for metastatic melanoma and breast cancer; CEP 9722 for non-small cell lung cancer (NSCLC); MK 4827, which inhibits both PARP1 and PARP2; BMN-673 for advanced hematological malignancies and advanced or recurrent solid tumors; and 3-aminobenzamide.

[0224] Another family of anti-cancer targets is the PI3K / AKT / mTOR pathway. This pathway is a signaling pathway important for many cellular functions, such as growth regulation, metabolism, and translation initiation. Many valuable anti-cancer drug treatment targets exist within this pathway, and for this reason, it has received much research in recent years. Phosphoinositide 3-kinase inhibitors (PI3K inhibitors) are potential therapeutic agents that function by inhibiting the phosphoinositide 3-kinase enzyme, which is part of this pathway and therefore frequently results in tumor suppression through inhibition. Many different types and isoforms of PI3K exist. Type 1 PI3K has a catalytic subunit known as p110, with four types (isoforms): p110 alpha, p110 beta, p110 gamma, and p110 delta. Researched inhibitors inhibit one or more isoforms of type 1 PI3K. They are being actively investigated for the treatment of various cancers. Examples include: wortmannin, an irreversible inhibitor of PI3K; demethoxyviridine, a derivative of wortmannin; and LY294002, a reversible inhibitor of PI3K.Other PI3K inhibitors include: perifosine for colorectal cancer and multiple myeloma; CAL101, an oral PI3K delta for certain late-stage leukemias; IAPL-866; IPI-145, a novel inhibitor of PI3K delta and gamma, particularly for hematologic malignancies; BAY 80-6946, which predominantly inhibits the PI3K alpha and delta isoforms; BEZ235, a dual PI3K / mTOR inhibitor; RP6503, a dual PI3K delta / gamma inhibitor for the treatment of asthma and COPD; TGR 1202, an oral PI3K delta inhibitor (also known as RP5264); SF1126, the first PI3K inhibitor for B-cell chronic lymphocytic leukemia (CLL); INK1117, a PI3K-alpha inhibitor; and 3 nM GDC-0941. IC50; BKM120; XL147 (also known as SAR245408); XL765 (also known as SAR245409); Palomid 529; GSK1059615 (in which clinical trials were terminated due to lack of sufficient exposure after single or repeated dosing); ZSTK474, a potent inhibitor of p110a; PWT33597 - a dual PI3K alpha / mTOR inhibitor for advanced solid tumors; IC87114, a selective inhibitor of p110δ. It has an IC50 of 100 nM for inhibition of p110-δ; TG100-115, which inhibits all four isoforms but is 5-10-fold more potent against p110-γ and p110-δ; CAL263; RP6530, a dual PI3K delta / gamma inhibitor for T-cell lymphoma; PI-103, a dual PI3K-mTOR inhibitor; GNE-477, a PI3K-alpha and mTOR inhibitor with IC50 values ​​of 4 nM and 21 nM; CUDC-907, which is also an HDAC inhibitor; and AEZS-136, which also inhibits Erk1 / 2.

[0225] Another anticancer drug is apatinib. Also known as YN968D1, apatinib is a tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor-2 (VEGFR2, also known as KDR). It is an orally bioavailable small molecule drug that appears to inhibit angiogenesis in cancer cells; specifically, apatinib inhibits VEGF-mediated endothelial cell migration and proliferation, thereby blocking new blood vessel formation in tumor tissue. The drug also mildly inhibits c-Kit and c-SRC tyrosine kinases. Apatinib is an investigational cancer drug currently undergoing clinical trials as a potential targeted treatment for metastatic gastric cancer, metastatic breast cancer, and advanced hepatocellular carcinoma. Cancer patients received various doses of apatinib daily for 28 days. Apatinib is well tolerated at doses below 750 mg / day, with three dose-limiting toxicities reported at 1000 mg / day, and the maximum tolerated dose measured at 850 mg / day. Researchers also reported on 65 cancer patients treated in Phase I / II, with 1.54% experiencing a complete response, 12.31% experiencing a partial response, 66.15% experiencing stable disease, and 20% experiencing progressive disease. Separate published reports on the safety and pharmacokinetics of apatinib in human clinical studies concluded that it has promising antitumor activity across a wide range of cancer types. Some cancer cells have the ability to develop resistance to the cytotoxicity of certain anticancer drugs (called multidrug resistance). Studies have concluded that apatinib may help circumvent multidrug resistance in cancer cells to certain conventional anticancer drugs. Studies have shown that apatinib reverses ABCB1- and ABCG2-mediated multidrug resistance by inhibiting their function a...

Claims

1. A unit dose of an aqueous solution for the daily treatment of interstitial lung disease in an adult delivered by a liquid nebulizer, said unit dose comprising one or more daily respirable delivered doses of an aqueous solution having an osmolality of about 50 mOsmol / kg to about 2000 mOsmol / kg comprising water and pirfenidone at a concentration of about 5.0 mg / mL to about 20 mg / mL, wherein said one or more daily respirable delivered doses is at least 0.8 mg of pirfenidone, a total daily respirable delivered dose of pirfenidone deliverable by the liquid nebulizer does not exceed 360 mg / day, and said respirable delivered dose is therapeutically effective in treating IPF by reducing the decline in forced vital capacity (FVC) of the adult's lungs.

2. The unit dose of claim 1, wherein the aqueous solution further comprises additional components selected from the group consisting of co-solvents, isotonicity agents, sweeteners, surfactants, humectants, chelating agents, antioxidants, salts, flavoring agents, and buffers, and combinations thereof.

3. The unit dose of claim 1, wherein the aqueous solution of each respirable delivery dose further comprises a buffer selected from a citrate buffer and a phosphate buffer, and one or more salts selected from the group consisting of sodium chloride, magnesium chloride, sodium bromide, magnesium bromide, calcium chloride, and calcium bromide, and combinations thereof.

4. The unit dose of claim 1, wherein each respirable delivery dose of the aqueous solution comprises water, one or more salts, wherein the total amount of the one or more salts is from about 0.01% to about 2.0% by weight of the aqueous solution, optionally a phosphate buffer or a citrate buffer that maintains the pH of the solution below about pH 8, and wherein the osmolality of the aqueous solution is from about 50 mOsmol / kg to about 2000 mOsmol / kg.

5. The liquid sprayer comprises: (i) achieving lung deposition of at least 5% of the pirfenidone administered to humans; (ii) a) a mass median aerodynamic diameter (MMAD) of droplets of an aqueous solution emitted by a high performance liquid atomizer of about 0.5 μm to about 5 μm; and / or b) a volume mean diameter (VMD) of about 0.5 μm to about 5 μm Provide (iii) providing a geometric standard deviation (GSD) of the aqueous solution emitted droplet size distribution of from about 1.0 μm to about 3.4 μm; (iv) providing a fine particle fraction of droplets emitted from the liquid atomizer of at least about 30%; (v) providing a consumption rate of at least 0.1 mL / min; and / or (vi) The unit dose of claim 1, wherein at least about 25% of the aqueous solution is administered to a human.

6. The unit dose of claim 1, wherein the blood AUC 0-24 of pirfenidone achieved after administration of each respirable delivered dose to the lungs of the adult is less than or equal to the blood AUC 0-24 achieved after administration of an 801 mg oral dose of pirfenidone to the adult.

7. The unit dose of claim 1, wherein the unit dose is formulated to be administered on a continuous daily dosing schedule.

8. The unit dose of claim 1, wherein the unit dose is formulated to be administered once daily, twice daily, three times daily, or four times daily.

9. The unit dose of claim 1, further comprising one or more additional therapeutic agents. [0023] Claim 10: a) the pulmonary tissue Cmax of pirfenidone obtained in humans after administration of each respirable delivered dose is at least equal to or greater than the pulmonary Cmax achievable after administration of an 801 mg oral dose of pirfenidone to humans; and / or b) the blood AUC 0-24 of pirfenidone obtained in humans after administration of each respirable delivered dose is less than the blood AUC 0-24 achievable after administration of an 801 mg oral dose of pirfenidone to adults; 2. The unit dose of claim 1.

11. The unit dose of claim 1, wherein each respirable delivered dose from the liquid nebulizer is formulated to be delivered in less than about 30 minutes with a particle size of about 1 micron to about 5 microns mass median diameter (MMAD).

12. The unit dose of claim 1, formulated to deliver one or more respirable delivery doses within 20 minutes.

13. The additional therapeutic agent is 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 an integrin alpha-v beta-6, an antibody targeting a CTGF ligand or receptor, or a CCL 10. The unit dose of claim 9, wherein the therapeutic agent is selected from the group consisting of an antibody targeting a vascular endothelial growth factor (VEGF) ligand or receptor, a small molecule targeting a platelet derived growth factor (PDGF) ligand or receptor, a small molecule targeting a fibroblast growth factor (FGF) ligand or receptor, an antibody targeting LOXL2, a small molecule targeting Jun kinase, and a small molecule targeting TGF beta, and combinations thereof.

14. The unit dose of claim 1, wherein the capacity is between about 0.5 mg and about 10 mg of aqueous solution filled into the liquid sprayer, the aqueous solution containing pirfenidone at a concentration of about 5.0 mg / mL to about 20 mg / mL.

15. The unit dose of claim 1, wherein the pirfenidone is deuterated.

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