(12) Patent Application Publication (10) Pub. No.: US 2015/0196.543 A1 Surber (43) Pub

US 2015O1965.43A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0196.543 A1 Surber (43) Pub. Date: Jul. 16, 2015

(54) AEROSOL PIRFENIDONE AND PYRIDONE A647/22 (2006.01) ANALOG COMPOUNDS AND USES A647/12 (2006.01) THEREOF A647/02 (2006.01) (52) U.S. Cl. (71) Applicant: GENOA PHARMACEUTICALS, CPC ...... A6 IK3I/4418 (2013.01); A61K 47/12 INC., San Diego, CA (US) (2013.01); A61 K47/02 (2013.01); A61K47/22 O O (2013.01); A61 K9/0073 (2013.01); A61 K (72) Inventor: Mark William Surber, San Diego, CA 9/0078 (2013.01) (US) (21) Appl. No.: 14/593,935 (57) ABSTRACT (22) Filed: Jan. 9, 2015 Disclosed herein are formulations of pirfenidone or pyridone analog compounds for aerosolization and use of Such formu Related U.S. Application Data lations for aerosol administration of pirfenidone or pyridone (60) Provisional application No. 62/000,473, filed on May analog compounds for the prevention or treatment of various 19, 2014, provisional application No. 61/977,529, fibrotic and inflammatory diseases, including disease associ filed on Apr. 9, 2014, provisional application No. ated with the lung, heart, kidney, liver, eye and central C 61/951,686, filed on Mar. 12, 2014, provisional appli- Vous system. In some embodiments, pir?enidone O pyridone cation No. 61/925,791 filed on Jan. 10, 2014. analog compound formulations and delivery options s - us s described herein allow for efficacious local delivery of pir Publication Classification fenidone or pyridone analog compound. Compositions include all formulations, kits, and device combinations (51) Int. Cl. described herein. Methods include inhalation procedures, A6 IK3I/448 (2006.01) indications and manufacturing processes for production and A6 IK9/00 (2006.01) use of the compositions described. Patent Application Publication Jul. 16, 2015 Sheet 1 of 5 US 201S/O196543 A1

www.www.www.www.www.www.www.vassy.www.www.www.www.www.www.www.www.www.www.www.www.www.www.www.www.www.www.www.www.www.w Modeled Hurtain Lung Pharmacokinetics: Aerosows. Crai 90 sc W Aesosol. 2 in haiation, 185 g RR 80 cc - - Aesoso; G 3i, iihaiation, 154 g RD - - - Aesosol 138 in it haiation, 1.3 mg RC - - Ojai: 81 mg PC, Fasted State. Rubio et al., 2009 is - - - - - Osai: 81; g PO, Fed State, Rubia et al., 2839 3:.5

FIG. 1. Modeled Nebulized Aerosol Administration to a Human. Patent Application Publication Jul. 16, 2015 Sheet 2 of 5 US 201S/O196543 A1

5 ------Aerosci: 5 min inhalation, 47 mg RDD {t1:2 = 3.5 : ni : A. c a a Crai: 88 nig PC, Fasted State (Rubino et al., 2009 - aOrai: 80 ring PO, Fed State (Rubino et al., 2009 3 .

2 ------

S------FIG. 2. Modeled Nebulized Aerosol Administration to a Human - 50mcg/gram target lung tissue Cmax and correlated lung tissue and plasma pharmacokinetics. Patent Application Publication Jul. 16, 2015 Sheet 3 of 5 US 201S/O196543 A1

s - ?o 2. g E 9 E s

Cmax (gpg) a SO 11.6 33.5 71.5 11.8 AUCo-ahs (ughrig) c 2.6 2.5 7.3 15.5 18.2 <26 26 109 23.3 103 21.7 AUC-2s (ughrimL)

FIG. 3. Hydroxyproline results from bleomycin model of pulmonary fibrosis. Patent Application Publication Jul. 16, 2015 Sheet 4 of 5 US 201S/O196543 A1

-0. 5

Cmax ago) 116 335 715 11.8 33.6 2 AUC (gho) 26 73 15.5 182 344 Cmax gm) 26 109 23.3 103 21.7 AUC (ghtml) 30 77 165 166. 296 FIG. 4. Histopathology results from bleomycin model of pulmonary fibrosis. Patent Application Publication Jul. 16, 2015 Sheet 5 of 5 US 201S/O196543 A1

: so an aeroso: 2 fing R, 5 is initaiatio:

SO ...... k . . . . Aaroso: Sig Ri, 5 in ihaiation

isi N-M N-MN - W - Y - NY N-N-N-N-N-N-M.----- N-N-N-N-N-N-N e s is Aeroso: 2.5 g. Rii, i is irraiatic ---oral: 80 mg Po, Fasted State

3rai: 88 nig O, Fed State

E C. *Airesit....sirc, Ras Na C & 8. 3. Time hrs) Inhaled (mg RDD) Oral (801 mg)

FIG. 5. Modeled human inhaled aerosol pirfenidone pharmacokinetics. US 2015/O 196543 A1 Jul. 16, 2015

AEROSOL PRFENDONE AND PYRIDONE includes administering one, two, three, or more than three ANALOG COMPOUNDS AND USES doses of pirfenidone or a pyridone analog compound on the THEREOF days of dosing. In some embodiments, each inhaled dose of pirfenidone or a pyridone analog compound is administered PRIORITY CLAIM with a nebulizer, a metered dose inhaler, or a dry powder 0001. This application claims benefit of U.S. Provisional inhaler. In some embodiments, each inhaled dose comprises Application No. 61/925,791, entitled “AEROSOL PIRFENI an aqueous solution of pirfenidone or a pyridone analog.com DONE AND PYRIDONE ANALOG COMPOUNDS AND pound. In some embodiments, each inhaled dose comprises USES THEREOF filed on Jan. 10, 2014: U.S. Provisional from about 0.1 mL to about 6 mL of an aqueous solution of Application No. 61/951,686, entitled “AEROSOL PIRFENI pirfenidone or a pyridone analog compound, wherein the DONE AND PYRIDONE ANALOG COMPOUNDS AND concentration of pirfenidone or pyridone analog compound in USES THEREOF filed on Mar. 12, 2014: U.S. Provisional the aqueous solution is from about 0.1 mg/mL and about 60 Application No. 61/977,529, entitled “AEROSOL PIRFENI mg/mL and the osmolality of the of the aqueous solution is DONE AND PYRIDONE ANALOG COMPOUNDS AND from about 50 mOsmol/kg to about 6000 mOsmol/kg. In USES THEREOF filed on Apr. 9, 2014; U.S. Provisional Some embodiments, the aqueous solution of each inhaled Application No. 62/000,473, entitled “AEROSOL PIRFENI dose further comprises one or more additional ingredients DONE AND PYRIDONE ANALOG COMPOUNDS AND selected from co-solvents, tonicity agents, Sweeteners, Sur USES THEREOF filed on May 19, 2014; all of which are factants, wetting agents, chelating agents, anti-oxidants, herein incorporated by reference in their entirety. salts, and buffers. In some embodiments, the aqueous solu tion of each inhaled dose further comprises a citrate buffer or FIELD OF THE INVENTION phosphate buffer, and one or more salts selected from the 0002 The present invention relates in its several embodi group consisting of Sodium chloride, magnesium chloride, ments to liquid, dry powder and metered-dose formulations Sodium bromide, magnesium bromide, calcium chloride and for therapeutic inhaled delivery of pyridone compositions calcium bromide. In some embodiments, the aqueous solu Such as pirfenidone to desired anatomical sites, for treatment tion of each inhaled dose comprises: water, pirfenidone or and/or prophylaxis of a variety of pulmonary, neurologic, pyridone analog compoundata concentration from about 0.1 cardiovascular and Solid organ disease conditions. mg/mL to about 20 mg/mL, one or more salts, wherein the total amount of the one or more salts is from about 0.01% to BACKGROUND OF THE INVENTION about 2.0% by weight of the weight of aqueous solution; and optionally a phosphate buffer that maintains the pH of the 0003) A number of undesirable pulmonary diseases such solution from about pH 5.0 to about pH 8.0, or citrate buffer as interstitial lung disease (ILD; and Sub-class diseases than maintains the pH of the solution from about 4.0 to about therein), chronic obstructive pulmonary disease (COPD; and 7.0; and the osmolality of the of the aqueous solution is from Sub-class diseases therein), asthma, and fibrotic indications of about 50 mOsmol/kg to about 2000 mOsmol/kg. In some the kidney, heart and eye, the diseases are initiated from an embodiments, each inhaled dose is administered with a liquid external challenge. By non-limiting example, these effectors nebulizer. In some embodiments, the liquid nebulizer: (i) after can include infection, cigarette Smoking, environmental administration of the inhaled dose, achieves lung deposition exposure, radiation exposure, Surgical procedures and trans of at least 7% of the pirfenidone or pyridone analog com plant rejection. However, other causes related to genetic dis pound administered to the mammal; (ii) provides a Geometric position and the effects of aging may also be attributed. Standard Deviation (GSD) of emitted droplet size distribution Described herein are compositions of pirfenidone or a pyri of the aqueous solution of about 1.0 um to about 2.5um; (iii) done analog compound that are suitable for inhalation deliv provides: a) a mass median aerodynamic diameter (MMAD) ery to the lungs and/or systemic compartment and methods of of droplet size of the aqueous solution emitted with the high using Such compositions. efficiency liquid nebulizer of about 1 um to about 5um; b) a volumetric mean diameter (VMD) of about 1 um to about 5 SUMMARY um; and/or c) a mass median diameter (MMD) of about 1 um 0004. According to a certain embodiment of the present to about 5um; (iv) provides a fine particle fraction (FPF=%s5 invention, there is provided a pirfenidone or pyridone analog um) of droplets emitted from the liquid nebulizer of at least compound formulation composition for oral pulmonary or about 30%; (v) provides an output rate of at least 0.1 mL/min: intranasal inhalation delivery, comprising formulations for and/or (vi) provides at least about 25% of the aqueous solu aerosol administration of pirfenidone or pyridone analog tion to the mammal. In some embodiments, a) the lung tissue compounds for the prevention or treatment of various fibrotic Cmax of pirfenidone or pyridone analog compound from and inflammatory diseases, including disease associated with each inhaled dose is at least equivalent to or greater than a the lung, heart, kidney, liver, eye and central nervous system. lung tissue Cmax of up to 801 mg of an orally administered 0005. In one aspect, described herein is a method for the dosage of pirfenidone or pyridone analog compound; and/or treatment of lung disease in a mammal comprising adminis b) the blood AUCo. of pirfenidone or pyridone analog com tering a dose of pirfenidone or a pyridone analog compound pound from each inhaled dose that is directly administered to by inhalation to the mammal in need thereof on a continuous the lungs of the mammal is less than or equivalent to the blood dosing schedule. In some embodiments, the continuous dos AUCo. of up to 801 mg of an orally administered dosage of ing schedule includes administering a dose of pirfenidone or pirfenidone or pyridone analog compound. In some embodi a pyridone analog compound daily, every other day, every ments, the blood AUCo. of pirfenidone or pyridone analog third day, every fourth day, every fifth day, every sixth day, compound from each inhaled dose is less than the blood weekly, biweekly, monthly or bimonthly. In some embodi AUCo. of up to 801 mg of an orally administered dosage of ments, the dosing schedule, whether daily or less than daily, pirfenidone or pyridone analog compound. In some embodi US 2015/O 196543 A1 Jul. 16, 2015 ments, the blood AUCo. of pirfenidone or pyridone analog done or pyridone analog compound from each inhaled dose is compound from each inhaled dose is less than 80%, less than between 0.01-90%, 0.01-80%, 0.01-70%, 0.01-60%, 0.01 70%, less than 60%, less than 50%, less than 40%, less than 50%, 0.01-40%, 0.01-30%, 0.01-20%, 0.01-10%, 0.01-5%, 30%, less than 20%, less than 10%, less than 5%, less than 0.01-2.5%, 0.01-1%, 0.01-0.1%, 5-90%, between 5-80%, 2.5%, less than 1.0%, less than 0.5%, less than 0.25%, less between 5-70%, between 5-60%, between 5-50%, between than 0.1%, less than 0.05%, less than 0.025% or less than 5-40%, between 5-30%, between 5-20%, between 5-10%, 0.01% of the blood AUC of up to 801 mg of an orally between 1-5%, between 1-10%, between 1-20%, between administered dosage of pirfenidone or pyridone analog com 1-30%, between 1-40%, between 1-50%, between 1-60%, pound. In some embodiments, the blood AUC of pirfeni between 1-70%, between 1-80%, or between 1-90% of the done or pyridone analog compound from each inhaled dose is blood AUC of up to 801 mg of an orally administered between 0.01-90%, 0.01-80%, 0.01-70%, 0.01-60%, 0.01 dosage of pirfenidone or pyridone analog compound. In some 50%, 0.01-40%, 0.01-30%, 0.01-20%, 0.01-10%, 0.01-5%, embodiments, the inhaled dose of pirfenidone or pyridone 0.01-2.5%, 0.01-1%, 0.01-0.1%, 5-90%, between 5-80%, analog compound is administered with a nebulizer, a metered between 5-70%, between 5-60%, between 5-50%, between dose inhaler, or a dry powder inhaler. In some embodiments, 5-40%, between 5-30%, between 5-20%, between 5-10%, the inhaled dose comprises an aqueous solution of pirfeni between 1-5%, between 1-10%, between 1-20%, between done or a pyridone analog compound and the dose is admin 1-30%, between 1-40%, between 1-50%, between 1-60%, istered with a liquid nebulizer. In some embodiments, each between 1-70%, between 1-80%, or between 1-90% of the inhaled dose that is directly administered to the lungs of the blood AUC of up to 801 mg of an orally administered mammal comprises from about 0.1 mL to about 6 mL of an dosage of pirfenidone or pyridone analog compound. In some aqueous solution of pirfenidone or a pyridone analog com embodiments, wherein each inhaled dose is less than /2 of the pound, wherein the concentration of pirfenidone or pyridone up to 801 mg of an orally administered dosage of pirfenidone analog compound in the aqueous solution is from about 0.1 or pyridone analog compound. In some embodiments, mg/mL and about 60 mg/mL and the osmolality of the of the wherein eachinhaled dose is less than /2, /3, 4, /5, /6, /s, /10, aqueous solution is from about 50 mOsmol/kg to about 6000 /20, 40, /so, /75, /100, /200, /300, or '/400 of the up to 801 mg of mOsmol/kg. In some embodiments, the aqueous solution of an orally administered dosage of pirfenidone or pyridone each inhaled dose further comprises: one or more additional analog compound. In some embodiments, the pirfenidone or ingredients selected from co-solvents, tonicity agents, Sweet a pyridone analog compound is administered at least once a eners, Surfactants, wetting agents, chelating agents, anti-oxi week. In some embodiments, the pirfenidone or a pyridone dants, salts, and buffers. In some embodiments, the aqueous analog compound is administered on a continuous daily dos solution of each inhaled dose further comprises: a citrate ing schedule. In some embodiments, the pirfenidone or a buffer or phosphate buffer, and one or more salts selected pyridone analog compound is administered once a day, twice from the group consisting of sodium chloride, magnesium a day, or three times a day. In some embodiments, the lung chloride, Sodium bromide, magnesium bromide, calcium disease is idiopathic pulmonary fibrosis, lung cancer or pull chloride and calcium bromide. In some embodiments, the monary hypertension. In some embodiments, the lung disease aqueous solution of each inhaled dose comprises: water, pir is idiopathic pulmonary fibrosis. In some embodiments, the fenidone or pyridone analog compound at a concentration lung disease is pulmonary hypertension. In some embodi from about 0.1 mg/mL to about 20 mg/mL, one or more salts, ments, the lung disease is pulmonary hypertension secondary wherein the total amount of the one or more salts is from to interstitial lung disease. In some embodiments, the lung about 0.01% to about 2.0% by weight of the weight of aque disease is cancer. In some embodiments, the lung disease is ous solution; and optionally a phosphate buffer that maintains lung cancer. In some embodiments, the lung disease is lung the pH of the solution from about pH 5.0 to about pH 8.0, or cancer where in the therapeutic target is tumor stroma. In citrate buffer than maintains the pH of the solution from about Some embodiments, the lung disease is lung cancer and the 4.0 to about 7.0. In some embodiments, the inhaled dose of treatment comprises inhibiting, reducing or slowing the pirfenidone or a pyridone analog compound is administered growth of lung tumor stroma. In some embodiments, the on a continuous dosing schedule. In some embodiments, the method further comprises administration of one or more addi lung disease is idiopathic pulmonary fibrosis, lung cancer or tional therapeutic agents to the mammal. pulmonary hypertension. In some embodiments, the lung 0006. In another aspect, described herein is a method for disease is idiopathic pulmonary fibrosis. In some embodi the treatment of lung disease in a mammal comprising: ments, the lung disease is pulmonary hypertension. In some administering a dose of pirfenidone or a pyridone analog embodiments, the lung disease is pulmonary hypertension compound by inhalation to the mammal in need thereof, secondary to interstitial lung disease. In some embodiments, wherein the blood AUCo. of pirfenidone or pyridone analog the lung disease is cancer. In some embodiments, the lung compound from the inhaled dose is less than the blood AUC. disease is lung cancer. In some embodiments, the lung disease 24 of up to 801 mg of an orally administered dosage of pir is lung cancer where in the therapeutic target is tumor stroma. fenidone or pyridone analog compound. In some embodi In Some embodiments, the lung disease is lung cancer and the ments, the blood AUCo. of pirfenidone or pyridone analog treatment comprises inhibiting, reducing or slowing the compound from each inhaled dose is less than 80%, less than growth of lung tumor stroma. In some embodiments, the 70%, less than 60%, less than 50%, less than 40%, less than method further comprises administration of one or more addi 30%, less than 20%, less than 10%, less than 5%, less than tional therapeutic agents to the mammal. 2.5%, less than 1.0%, less than 0.5%, less than 0.25%, less 0007. In one aspect, described herein is an aqueous solu than 0.1%, less than 0.05%, less than 0.025% or less than tion for nebulized inhalation administration comprising: 0.01% of the blood AUC of up to 801 mg of an orally water, pirfenidone, or a pyridone analog compound, at a administered dosage of pirfenidone or pyridone analog com concentration from about 0.1 mg/mL to about 20 mg/mL, pound. In some embodiments, the blood AUCo. of pirfeni Sodium citrate; citric acid; sodium chloride; and sodium sac US 2015/O 196543 A1 Jul. 16, 2015

charin. In some embodiments, the aqueous solution com embodiments, the aqueous Solution comprises about 3.5 mM prises: water, pirfenidone, or a pyridone analog compound, at sodium citrate and about 1.5 mM citric acid. In some embodi a concentration from about 1 mg/mL to about 20 mg/mL, ments, the osmolality of the aqueous solution is from about 50 Sodium citrate; citric acid; sodium chloride; and Sodium sac mOsmol/kg to about 1000 mOsmol/kg. In some embodi charin. In some embodiments, the aqueous solution com ments, the concentration of Sodium chloride in the aqueous prises about 3.5 mM sodium citrate and about 1.5 mM citric solution is about 150 mM. In some embodiments, the con acid. In some embodiments, the osmolality of the aqueous centration of sodium saccharin in the aqueous solution is solution is from about 50 mOsmol/kg to about 1000 mOsmol/ about 0.1 mM to about 1 mM. In some embodiments, the pH kg. In some embodiments, the osmolality of the aqueous of the aqueous solution is about 5.5; and the osmolality of the solution is from about 50 mOsmol/kg to about 800 mOsmol/ aqueous solution is from about 100 mOsmol/kg to about 500 kg. In some embodiments, the osmolality of the aqueous mOsmol/kg. In some embodiments, the pH of the aqueous solution is from about 50 mOsmol/kg to about 700 mOsmol/ Solution is about 5.5; and the osmolality of the aqueous solu kg. In some embodiments, the osmolality of the aqueous tion is from about 200 mOsmol/kg to about 500 mOsmol/kg. solution is from about 100 mOsmol/kg to about 600 mOsmol/ In some embodiments, the pH of the aqueous solution is about kg. In some embodiments, the aqueous solution comprises 5.5; and the osmolality of the aqueous solution is from about about 150 mM of sodium chloride. In some embodiments, the 250 mOsmol/kg to about 500 mOsmol/kg. aqueous solution comprises about 0.1 mM to about 1 mM of 0010. In another aspect, described herein is a unit dosage Sodium saccharin. adapted for use in a liquid nebulizer comprising from about 0008. In one aspect, described herein is an aqueous solu 0.5 mL to about 6 mL of the aqueous solution described tion for nebulized inhalation administration comprising: herein. In some embodiments, the liquid nebulizer is a jet water, pirfenidone at a concentration from about 0.1 mg/mL nebulizer, an ultrasonic nebulizer, a pulsating membrane to about 20 mg/mL, Sodium citrate; citric acid; sodium chlo nebulizer, a nebulizer comprising a vibrating mesh or plate ride; and sodium saccharin; wherein the pH is about 4.0 to with multiple apertures, a nebulizer comprising a vibration about 7.0. In some embodiments, the aqueous Solution com generator and an aqueous chamber, or a nebulizer that uses prises: water, pirfenidone at a concentration from about 1 controlled device features to assist inspiratory flow of the mg/mL to about 20 mg/mL, Sodium citrate; citric acid; about aerosolized aqueous solution to the lungs of the mammal. In 100-200 mM of sodium chloride; and sodium saccharin. In Some embodiments, the liquid nebulizer: (i) after administra Some embodiments, the Sodium citrate concentration and the tion of the inhaled dose, achieves lung deposition of at least citric acid concentration is in a range of 1-10 mM and the 7% of the pirfenidone administered to the mammal; (ii) pro aqueous solution has a pH of about 5-6, wherein the pH is vides a Geometric Standard Deviation (GSD) of emitted optionally achieved by addition of acid or base. In some droplet size distribution of the aqueous solution of about 1.0 embodiments, the acid is hydrochloric acid. In some embodi um to about 2.5 um; (iii) provides droplets of the aqueous ments, the base is sodium hydroxide. In some embodiments, solution emitted with the high efficiency liquid with: a) a the aqueous Solution comprises about 3.5 mMSodium citrate mass median aerodynamic diameter (MMAD) of about 1 um and about 1.5 mM citric acid. In some embodiments, the to about 5 um; b) a volumetric mean diameter (VMD) of osmolality of the aqueous solution is from about 50 mOsmol/ about 1 um to about 5um; and/or c) a mass median diameter kg to about 1000 mOsmol/kg. In some embodiments, the (MMD) of about 1 um to about 5 um; (iv) provides a fine aqueous solution comprises about 150 mM of sodium chlo particle fraction (FPF=%s5um) of droplets emitted from the ride. In some embodiments, the aqueous solution comprises liquid nebulizer of at least about 30%; (v) provides an output about 0.1 mM to about 1 mM of sodium saccharin. In some rate of at least 0.1 mL/min: and/or (vi) provides at least about embodiments, the pH of the aqueous solution is about 5.5; and 25% of the aqueous solution to the mammal. the osmolality of the aqueous solution is from about 100 0011. In one aspect, described herein is a method of mOsmol/kg to about 500 mOsmol/kg. In some embodiments, decreasing IL-1B levels in the lungs of a mammal diagnosed the pH of the aqueous solution is about 5.5; and the osmolality with pulmonary fibrosis comprising administering by inhala of the aqueous solution is from about 200 mOsmol/kg to tion the aqueous solution described herein to the mammal about 500 mOsmol/kg. In some embodiments, the pH of the diagnosed with pulmonary fibrosis, wherein the administra aqueous solution is about 5.5; and the osmolality of the aque tion of the aqueous Solution to the mammal decreases IL-1B ous solution is from about 250 mOsmol/kg to about 500 levels in the bronchial lavage fluid (BAL) of the mammal by mOsmol/kg. at least 10%, 20%, 30%, or 40%. In some embodiments, the 0009. In one aspect, described herein is an aqueous solu IL-1B levels in the bronchial lavage fluid (BAL) of the mam tion for nebulized inhalation administration consisting essen mal are decreased by at least 30%. In some embodiments, the tially of water; pirfenidone at a concentration from about 0.1 pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF) or mg/mL to about 20 mg/mL, Sodium citrate; citric acid; pulmonary fibrosis associated with systemic sclerosis. In Sodium chloride; and Sodium saccharin; wherein the pH is Some embodiments, the aqueous solution is administered by about 4.0 to about 7.0. In some embodiments, the aqueous inhalation to the mammal in need thereof with a liquid nebu Solution consists essentially of water, pirfenidone at a con lizer. In some embodiments, the liquid nebulizer is a jet nebu centration from about 1 mg/mL to about 20 mg/mL, sodium lizer, an ultrasonic nebulizer, a pulsating membrane nebu citrate; citric acid; about 100-200 mM of sodium chloride; lizer, a nebulizer comprising a vibrating mesh or plate with and sodium saccharin. In some embodiments, the Sodium multiple apertures, a nebulizer comprising a vibration gen citrate concentration and the citric acid concentration is in a erator and an aqueous chamber, or a nebulizer that uses con range of 1-10 mM and the aqueous solution has a pH of about trolled device features to assist inspiratory flow of the aero 5-6, wherein the pH is optionally achieved by addition of acid Solized aqueous Solution to the lungs of the mammal. In some or base. In some embodiments, the acid is hydrochloric acid. embodiments, the liquid nebulizer: (i) after administration of In Some embodiments, the base is sodium hydroxide. In some the inhaled dose, achieves lung deposition of at least 7% of US 2015/O 196543 A1 Jul. 16, 2015 the pirfenidone administered to the mammal; (ii) provides a day, three times a day, four times a day, five times a day, or six Geometric Standard Deviation (GSD) of emitted droplet size times a day. In some embodiments, each dose of the aqueous distribution of the aqueous solution of about 1.0 um to about solution of pirfenidone is administered within 20 minutes. In 2.5um; (iii) provides droplets of the aqueous solution emitted Some embodiments, the method further comprises adminis with the high efficiency liquid with: a) a mass median aero tration of one or more additional therapeutic agents to the dynamic diameter (MMAD) of about 1 um to about 5um; b) mammal. a volumetric mean diameter (VMD) of about 1 um to about 5 0013. In one aspect, described herein is an aqueous solu um; and/or c) a mass median diameter (MMD) of about 1 um tion for nebulized inhalation administration comprising: to about 5um; (iv) provides a fine particle fraction (FPF=%55 water, pirfenidone, or a pyridone analog compound, at a um) of droplets emitted from the liquid nebulizer of at least concentration from about 0.1 mg/mL to about 20 mg/mL, about 30%; (v) provides an output rate of at least 0.1 mL/min: wherein the osmolality of the aqueous solution is from about and/or (vi) provides at least about 25% of the aqueous solu 50 mOsmol/kg to about 2000 mOsmol/kg. In some embodi tion to the mammal. In some embodiments, the dose of the ments, the aqueous solution does not include any cosolvents aqueous solution of pirfenidone is administered at least once and/or Surfactants. In some embodiments, the Solution further a week. In some embodiments, the dose of the aqueous solu comprises one or more additional ingredients selected from tion of pirfenidone is administered on a continuous daily buffers and salts. In some embodiments, the buffer is a citrate dosing schedule. In some embodiments, the dose of the aque buffer or phosphate buffer; and the salt is sodium chloride or ous solution of pirfenidone is administered once a day, twice magnesium chloride, or sodium bromide or magnesium bro a day, three times a day, four times a day, five times a day, or mide, calcium chloride or calcium bromide. In some embodi six times a day. In some embodiments, each dose of the ments, the aqueous solution comprises: water, pirfenidone or aqueous solution of pirfenidone is administered within 20 pyridone analog compound at a concentration from about 1 minutes. In some embodiments, the method further com mg/mL to about 20 mg/mL, wherein the total amount of the prises administration of one or more additional therapeutic one or more salts is about 0.01% to about 2.0% w/v.; and agents to the mammal. optionally a phosphate buffer that maintains the pH of the 0012. In another aspect, described herein is a method for solution from about pH 6.0 to about pH 8.0, or citrate buffer the treatment of lung disease in a mammal comprising: than maintains the pH of the solution from about 4.0 to about administering by inhalation a dose of the aqueous solution 7.0. In some embodiments, the aqueous solution comprises: described hereinto the mammal in need thereofon a continu water, pirfenidone or pyridone analog compound at a con ous dosing schedule. In some embodiments, the lung disease centration from about 5 mg/mL to about 18 mg/mL, wherein is idiopathic pulmonary fibrosis, or pulmonary fibrosis asso the total amount of the one or more salts is about 0.01% to ciated with systemic sclerosis, radiation exposure or trans about 2.0% V/vi, and optionally a phosphate buffer that main plant, lung cancer or pulmonary hypertension. In some tains the pH of the solution from about pH 6.0 to about pH 8.0, embodiments, the lung disease is lung cancer and the treat or citrate buffer than maintains the pH of the solution from ment comprises inhibiting, reducing or slowing the growth of about 4.0 to about 7.0; wherein the osmolality of the aqueous lung tumor stroma. In some embodiments, the aqueous solu solution is from about 50 mOsmol/kg to about 2000 mOsmol/ tion is administered by inhalation to the mammal in need kg. thereof with a liquid nebulizer. In some embodiments, the 0014. In the embodiments described herein, the inhaled liquid nebulizer is a jet nebulizer, an ultrasonic nebulizer, a doses are delivered <5, <4,<3, <2, <1 times a day, or less than pulsating membrane nebulizer, a nebulizer comprising a daily. In some embodiments, the inhaled doses are delivered vibrating mesh or plate with multiple apertures, a nebulizer by nebulization using standard tidal breathing of continuous comprising a vibration generator and an aqueous chamber, or flow aerosol or breath actuated aerosol. In such embodiments a nebulizer that uses controlled device features to assist of nebulized delivery, delivery times can be <20, <15, <10, inspiratory flow of the aerosolized aqueous Solution to the <8, <6, <4, <2 or <1 minute. In some embodiments, the lungs of the mammal. In some embodiments, the liquid nebu inhaled doses are delivered by inhalation of a dispersed dry lizer: (i) after administration of the inhaled dose, achieves powder aerosol using <10. <8, <6, <5, <4, <3, <2 or 1 breath lung deposition of at least 7% of the pirfenidone administered of either a passive dispersion dry power inhaler or active to the mammal; (ii) provides a Geometric Standard Deviation dispersion dry powder inhaler. In some embodiments, the (GSD) of emitted droplet size distribution of the aqueous inhaled doses are delivered by inhalation of aerosol using solution of about 1.0 um to about 2.5 um; (iii) provides <10. <8, <6, <5, <4, <3, <2 or 1 breath of a compressed gas droplets of the aqueous solution emitted with the high effi metered dose inhaler with or without a spacer. ciency liquid with: a) a mass median aerodynamic diameter 0015. In one aspect, described herein is an aqueous solu (MMAD) of about 1 um to about 5um; b) a volumetric mean tion for nebulized inhalation administration comprising: diameter (VMD) of about 1 um to about 5 um; and/or c) a water, pirfenidone, or a pyridone analog compound, at a mass median diameter (MMD) of about 1 um to about 5um; concentration from about 10 mg/mL to about 50 mg/mL, and (iv) provides a fine particle fraction (FPF=%s5um) of drop one or more co-solvents. In another aspect, described herein lets emitted from the liquid nebulizer of at least about 30%; is an aqueous solution for nebulized inhalation administration (v) provides an output rate of at least 0.1 mL/min: and/or (vi) comprising: water, pirfenidone, or a pyridone analog com provides at least about 25% of the aqueous solution to the pound, at a concentration from about 10 mg/mL to about 50 mammal. In some embodiments, the dose of the aqueous mg/mL, optionally one or more buffers to maintain the pH Solution of pirfenidone is administered at least once a week. between about pH 4.0 to about pH 8.0; and one or more In some embodiments, the dose of the aqueous solution of co-solvents. In some embodiments, the pH of the aqueous pirfenidone is administered on a continuous daily dosing solution if from about pH 4.0 to about pH 8.0. In some schedule. In some embodiments, the dose of the aqueous embodiments, the pH of the aqueous solution if from about Solution of pirfenidone is administered once a day, twice a pH 6.0 to about pH 8.0. In some embodiments, described US 2015/O 196543 A1 Jul. 16, 2015

herein is an aqueous solution for nebulized inhalation admin 0017. In some embodiments, the aqueous solution com istration comprising: water, pirfenidone, or a pyridone analog prises: water, pirfenidone or pyridone analog compound at a compound, at a concentration from about 0.1 mg/mL to about concentration from about 10 mg/mL to about 60 mg/mL, one 60 mg/mL, and one or more co-solvents, wherein the osmo or more co-solvents, wherein the total amount of the one or lality of the aqueous solution is from about 50 mOsmol/kg to more co-solvents is about 1% to about 40% V/V, where the one about 6000 mOsmol/kg. In some embodiments, pirfenidone, or more co-solvents are selected from about 1% to about 25% or a pyridone analog compound, is at a concentration from V/v of ethanol, about 1% to about 25% V/v of propylene about 10 mg/mL to about 60 mg/mL. In some embodiments, glycol, and about 1% to about 25% V/v of glycerol; and pirfenidone, or a pyridone analog compound, is at a concen optionally a phosphate buffer that maintains the pH of the tration from about 10 mg/mL to about 50 mg/mL. In some solution from about pH 6.0 to about pH 8.0. embodiments, pirfenidone, or a pyridone analog compound, 0018. In some embodiments, the aqueous solution com is at a concentration from about 15 mg/mL to about 50 prises: water, pirfenidone or pyridone analog compound at a mg/mL. In some embodiments, pirfenidone, or a pyridone concentration from about 15 mg/mL to about 50 mg/mL, one or more co-solvents, wherein the total amount of the one or analog compound, is at a concentration from about 20 mg/mL more co-solvents if about 1 to about 30% V/V, where the one to about 50 mg/mL. In some embodiments, pirfenidone, or a or more co-solvents are selected from about 1% to about 10% pyridone analog compound, is at a concentration from about V/v of ethanol, and about 1% to about 20% v/v of propylene 25 mg/mL to about 50 mg/mL. In some embodiments, pir glycol; and optionally a phosphate buffer that maintains the fenidone, or a pyridone analog compound, is at a concentra pH of the solution from about pH 6.0 to about pH 8.0: wherein tion from about 30 mg/mL to about 50 mg/mL. In some the osmolality of the aqueous solution is from about 400 embodiments, the osmolality of the aqueous Solution is from mOsmol/kg to about 6000 mOsmol/kg. about 50 mOsmol/kg to about 6000 mOsmol/kg. In some 0019. In some embodiments, the aqueous solution for embodiments, the osmolality of the aqueous Solution is from nebulized inhalation administration described herein com about 50 mOsmol/kg to about 5000 mOsmol/kg. In some prises: water, pirfenidone or pyridone analog compound at a embodiments, the osmolality of the aqueous Solution is from concentration from about 10 mg/mL to about 50 mg/mL.; about 100 mOsmol/kg to about 5000 mOsmol/kg, from about optionally a phosphate buffer that maintains the pH of the 300 mOsmol/kg to about 5000 mOsmol/kg, from about 400 solution from about pH 6.0 to about pH 8.0; one or more mOsmol/kg to about 5000 mOsmol/kg, from about 600 mOs co-solvents selected from about 1% to about 25% V/v of mol/kg to about 5000 mOsmol/kg, from about 1000 mOsmol/ ethanol and about 1% to about 25% V/v of propylene glycol, kg to about 5000 mOsmol/kg, or from about 2000 mOsmol/ where the total amount of co-solvents is from 1% to 25% V/v. kg to about 5000 mOsmol/kg. In some embodiments, the total In some embodiments, the aqueous solution for nebulized concentration of co-solvents is from about 1% to about 40% inhalation administration described herein comprises: water; V/v. In some embodiments, the total concentration of co pirfenidone or pyridone analog compound at a concentration solvents is from about 1% to about 30% w/v. In some embodi from about 10 mg/mL to about 50 mg/mL, optionally a phos ments, the total concentration of co-solvents is from about 1% phate buffer that maintains the pH of the solution from about to about 25% V/v. In some embodiments, the one or more pH 6.0 to about pH 8.0; about 8% V/v of ethanol; and about co-solvents are selected from ethanol, propylene glycol, and 16% V/v of propylene glycol. In some embodiments, the glycerol. In some embodiments, the one or more co-solvents aqueous solution for nebulized inhalation administration are selected from ethanol, and propylene glycol. In some described herein consists essentially of water; pirfenidone or embodiments, the aqueous solution includes both ethanol and pyridone analog compound at a concentration from about 10 propylene glycol. In some embodiments, the Solution further mg/mL to about 50 mg/mL, optionally a phosphate buffer that comprises one or more additional ingredients selected from maintains the pH of the solution from about pH 6.0 to about Surfactants, taste masking agents/sweeteners and salts. In pH 8.0; one or more co-solvents selected from about 1% to Some embodiments, the tastemaking agent/sweetener is sac about 25% v/v of ethanol and about 1% to about 25% v/v of charin, or salt thereof. In some embodiments, the Solution propylene glycol, where the total amount of co-solvents is further comprises one or more additional ingredients selected from 1% to 25% V/v. In some embodiments, the aqueous from Surfactants and salts. In some embodiments, the Surfac solution for nebulized inhalation administration described tant is polysorbate 80 or cetylpyridinium bromide. In some herein consists essentially of water, pirfenidone or pyridone embodiments, the salt is sodium chloride or magnesium chlo analog compoundata concentration from about 10 mg/mL to ride. In some embodiments, the surfactant is polysorbate 80 about 50 mg/mL, optionally a phosphate buffer that maintains or cetylpyridinium bromide, and the salt is sodium chloride or the pH of the solution from about pH 6.0 to about pH 8.0: magnesium chloride. In some embodiments, the aqueous about 8% V/v of ethanol; and about 16% V/v of propylene solution includes one more buffers selected from a citrate glycol. In some embodiments, described herein is from about buffer and a phosphate buffer. In some embodiments, the 0.5 mL to about 6 mL of the aqueous solution described aqueous Solution includes a phosphate buffer. In some herein. embodiments, the aqueous Solution includes a citrate buffer. 0020. In some embodiments, described herein is a unit In some embodiments, described herein is from about 0.5 mL dosage adapted for use in a liquid nebulizer comprising from to about 6 mL of the aqueous solution described herein. about 0.5 mL to about 6 mL of an aqueous solution of pir 0016. In some embodiments, the solution further com fenidone or a pyridone analog compound, wherein the con prises one or more additional ingredients selected from Sur centration of pirfenidone or pyridone analog compound in the factants, buffers and salts. In some embodiments, the Surfac aqueous solution is from about 0.1 mg/mL to about 60 tant is polysorbate 80 or cetylpyridinium bromide; the buffer mg/mL. In some embodiments, the aqueous solution further is a citrate buffer or phosphate buffer; and the salt is sodium comprises one or more additional ingredients selected from chloride or magnesium chloride. co-solvents, tonicity agents, Sweeteners, Surfactants, wetting US 2015/O 196543 A1 Jul. 16, 2015

agents, chelating agents, anti-oxidants, salts, and buffers; and embodiments, the nebulizer used in any of the methods the osmolality of the aqueous solution is from about 50 mOs described herein is a jet nebulizer, an ultrasonic nebulizer, a mol/kg to about 6000 mOsmol/kg. In some embodiments, the pulsating membrane nebulizer, a nebulizer comprising a aqueous solution further comprises: one or more co-solvents vibrating mesh or plate with multiple apertures, or a nebulizer selected from ethanol, propylene glycol, and glycerol; and comprising a vibration generator and an aqueous chamber. In one or both of a citrate buffer or a phosphate buffer. In some some embodiments, the nebulizer used in any of the methods embodiments, the aqueous solution comprises: pirfenidone described herein is a nebulizer comprising a vibrating mesh or or pyridone analog compound dissolved in water at a concen plate with multiple apertures. In some embodiments, the liq tration from about 15 mg/mL to about 50 mg/mL, optionally uid nebulizer: (i) achieves lung deposition of at least 7% of the a phosphate buffer that maintains the pH of the solution from pirfenidone or pyridone analog compound administered to about pH 6.0 to about pH 8.0; one or more co-solvents, the mammal; (ii) provides a Geometric Standard Deviation wherein the total amount of the one or more co-solvents if (GSD) of emitted droplet size distribution of the aqueous about 1 to about 30% V/V, where the one or more co-solvents solution of about 1.0 Lum to about 2.5um; (iii) provides: a) a are selected from about 1% to about 10% w/v of ethanol, and mass median aerodynamic diameter (MMAD) of droplet size about 1% to about 20% V/v of propylene glycol; wherein the of the aqueous solution emitted with the high efficiency liquid osmolality of the aqueous solution is from about 400 mOs nebulizer of about 1 um to about 5um; b) a volumetric mean mol/kg to about 6000 mOsmol/kg. In some embodiments, the diameter (VMD) of about 1 um to about 5 um; and/or c) a aqueous solution is as described herein. mass median diameter (MMD) of about 1 um to about 5um; 0021. In some embodiments, described herein is a kitcom (iv) provides a fine particle fraction (FPF=%s5 microns) of prising: a unit dosage of an aqueous solution of pirfenidone or droplets emitted from the liquid nebulizer of at least about pyridone analog as described herein in a container that is 30%; (v) provides an output rate of at least 0.1 mL/min: adapted for use in a liquid nebulizer. and/or (vi) provides at least about 25% of the aqueous solu 0022. In some embodiments, provided herein is an aque tion to the mammal. ous droplet of pirfenidone or pyridone analog compound, 0025. In some embodiments, the liquid nebulizer is char wherein the aqueous droplet has a diameter less than about acterized as having at least two, at least three, at least four, at 5.0 Lum. In some embodiments, the aqueous droplet was pro least five, or all six of (i), (ii), (iii), (iv), (v), (vi). In some duced from a liquid nebulizer and an aqueous solution of embodiments, the liquid nebulizer: (i) achieves lung deposi pirfenidone or pyridone analog compound. In some embodi tion of at least 5%, at least 6%, at least 7%, at least 8%, at least ments, the aqueous solution of pirfenidone or pyridone ana 9%, at least 10%, at least 12%, at least 14%, at least 16%, at log compound is as described herein. In some embodiments, least 18%, at least 20%, at least 25%, at least 30%, at least the aqueous solution has concentration of pirfenidone or pyri 35%, at least 40% at least 45%, at least 50%, at least 55%, at done analog compound from about 0.1 mg/mL and about 60 least 60%, at least 65%, at least 70%, at least 75%, or at least mg/mL and an osmolality from about 50 mOsmol/kg to about 80% of the pirfenidone or pyridone analog compound admin 6000 mOsmol/kg. In some embodiments, the aqueous droplet istered to the mammal. In some embodiments, the liquid is produced by a nebulizing an aqueous Solution of pirfeni nebulizer: (ii) provides a Geometric Standard Deviation done or pyridone analog compound as described herein with (GSD) of emitted droplet size distribution of the aqueous a nebulizer. In some embodiments, the nebulizer is a liquid Solution of about 1.0 um to about 2.5 Lim, about 1.2 um to nebulizer. In some embodiments, the nebulizer is a high effi about 2.3 um, about 1.4 um to about 2.1 um, or about 1.5 um ciency liquid nebulizer. to about 2.0 Lum. In some embodiments, the liquid nebulizer: 0023. In some embodiments, provided herein is an aque (iii) provides a) a mass median aerodynamic diameter ous aerosol comprising a plurality of aqueous droplets of (MMAD) of droplet size of the aqueous solution emitted with pirfenidone or pyridone analog compound. In some embodi the high efficiency liquid nebulizer of about less than 5um or ments, described herein is an aqueous aerosol comprising a about 1 um to about 5 um; b) a Volumetric mean diameter plurality of aqueous droplets of pirfenidone or pyridone ana (VMD) of about less than 5um or about 1 um to about 5um; log compound, wherein the plurality of aqueous droplets have and/or c) a mass median diameter (MMD) of about less than a volumetric mean diameter (VMD), mass median aerody 5um or about 1 um to about 5um. In some embodiments, the namic diameter (MMAD), and/or mass median diameter liquid nebulizer: (iv) provides a fine particle fraction (MMD) of less than about 5.0Lum. In some embodiments, the (FPF=%55 microns) of droplets emitted from the liquid plurality of aqueous droplets was produced from a liquid nebulizer of at least about 30%, at least about 35%, at least nebulizer and an aqueous solution of pirfenidone or pyridone about 40%, at least about 45%, at least about 50%, at least analog compound. In some embodiments, the aqueous solu about 55%, at least about 60%, at least about 65%, at least tion has concentration of pirfenidone or pyridone analog about 70%, at least about 75%, at least about 80%, at least compound from about 10 mg/mL and about 60 mg/mL and an about 85%, or at least about 90%. In some embodiments, the osmolality from about 50 mOsmol/kg to about 6000 mOs liquid nebulizer: (v) provides an output rate of at least 0.1 mol/kg. In some embodiments, at least 30% of the aqueous mL/min, of at least 0.2 mL/min, of at least 0.3 mL/min, of at droplets in the aerosol have a diameter less than about 5um. least 0.4 mL/min, of at least 0.5 mL/min, of at least 0.6 In some embodiments, the aqueous aerosol is produced by a mL/min, of at least 0.7 mL/min, of at least 0.8 mL/min, of at nebulizing an aqueous solution of pirfenidone or pyridone least 0.9 mL/min, of at least 1.0 mL/min, or less than about 1.0 analog compound as described herein with a nebulizer. In mL/min. In some embodiments, the liquid nebulizer: (vi) some embodiments, the nebulizer is a liquid nebulizer. In provides at least about 25%, at least about 30%, at least about Some embodiments, the nebulizer is a high efficiency liquid 35%, at least about 40%, at least about 45%, at least about nebulizer. 50%, at least about 55%, at least about 60%, at least about 0024. In some embodiments, the nebulizer used in any of 65%, at least about 70%, at least about 75%, at least about the methods described herein is a liquid nebulizer. In some 80%, at least about 85%, or at least about 95%, of the aqueous US 2015/O 196543 A1 Jul. 16, 2015

Solution to the mammal. In some embodiments, the liquid nary hypertension and the mammal is a human. In some nebulizer provides an respirable delivered dose (RDD) of at embodiments, the lung disease is Type 1, 2, 3, 4 and 5 Pul least 5%, at least 6%, at least 7%, at least 8%, at least 10%, at monary Hypertension and the mammal is a human. In some least 12%, at least 16%, at least 20%, at least 24%, at least embodiments, the lung disease is cancer and the mammal is a 28%, at least 32%, at least 36%, at least 40%, at least 45%, at human. In some embodiments, the lung cancer is Small cell least 50%, at least 55%, at least 60%, at least 65%, at least lung cancer and the mammal is a human. In some embodi 70%, at least 75%, at least 80%, at least 85%, or at least 90%. ments, the lung cancer is non-Small cell lung cancer and the 0026. In some embodiments, described herein is a method mammal is a human. In some embodiments, the pulmonary for the treatment of lung disease in a mammal comprising: cancer is large cell carcinoma and the mammal is a human. In administering to mammal in need thereofan aqueous solution Some embodiments, the pulmonary cancer is mesothelioma comprising pirfenidone or a pyridone analog compound with and the mammal is a human. In some embodiments, the a liquid nebulizer. In some embodiments, described herein is pulmonary cancer is lung carcinoid tumors or bronchial car a method for the treatment of lung disease in a mammal dinoids and the mammal is a human. In some embodiments, comprising: administering to mammal in need thereof an the pulmonary cancer is secondary lung cancer resulting from aqueous Solution comprising pirfenidone or a pyridone ana metastatic disease and the mammal is a human. In some log compound with a liquid nebulizer, wherein the aqueous embodiments, the pulmonary cancer is bronchioloalveolar Solution comprises water, pirfenidone, or a pyridone analog carcinoma and the mammal is a human. In some embodi compound, at a concentration from about 0.1 mg/mL to about ments, the pulmonary cancer is sarcoma and the mammal is a 60 mg/mL, and one or more co-solvents, wherein the osmo human. In some embodiments, the pulmonary cancer is a lality of the aqueous solution is from about 50 mOsmol/kg to lymphoma and the mammal is a human. In some embodi about 6000 mOsmol/kg. In some embodiments, the aqueous ments, the liquid nebulizer delivers from about 0.1 mg to Solution comprises water, pirfenidone or pyridone analog about 360 mg of pirfenidone or pyridone analog compound to compound at a concentration from about 10 mg/mL to about the lungs of the mammal in less than about 20 minutes with 60 mg/mL, one or more co-solvents, wherein the total amount mass median diameter (MMAD) particles sizes from about 1 of the one or more co-solvents is about 1% to about 40% w/v. to about 5 micron. where the one or more co-solvents are selected from about 1% 0027. In some embodiments, the lung tissue Cmax and/or to about 25% w/v of ethanol, about 1% to about 25% v/v of AUC of pirfenidone or pyridone analog compound that is propylene glycol, and about 1% to about 25% V/v of glycerol: obtained after a single administration of the aqueous solution and optionally a phosphate buffer that maintains the pH of the to the mammal with a liquid nebulizer is about the same or solution from about pH 6.0 to about pH 8.0. In some embodi greater than the lung tissue Cmax and/or AUC of pirfenidone ments, the aqueous Solution comprises water, pirfenidone or or pyridone analog compound that is obtained after a single pyridone analog compound at a concentration from about 15 dose of orally administered pirfenidone or pyridone analog mg/mL to about 50 mg/mL, one or more co-solvents, wherein compound at a dose that is from about 80% to about 120% of the total amount of the one or more co-solvents if about 1 to the dose administered with the liquid nebulizer; and/or the about 30% w/v, where the one or more co-solvents are selected plasma Cmax and/or AUC of pirfenidone or pyridone analog from about 1% to about 10% V/v of ethanol, and about 1% to compound that is obtained after a single administration of the about 20% v/v of propylene glycol; and optionally a phos aqueous solution to the mammal with a liquid nebulizer is at phate buffer that maintains the pH of the solution from about least 10% or greater than the plasma Cmax and/or AUC of pH 6.0 to about pH 8.0; wherein the osmolality of the aqueous pirfenidone or pyridone analog compound that is obtained solution is from about 400 mOsmol/kg to about 6000 mOs after a single dose of orally administered pirfenidone or pyri mol/kg. In some embodiments, the nebulizer is a jet nebulizer, done analog compound at a dose that is from about 80% to an ultrasonic nebulizer, a pulsating membrane nebulizer, a about 120% of the dose administered with the liquid nebu nebulizer comprising a vibrating mesh or plate with multiple lizer. In some embodiments, the lung tissue Cmax of pirfeni apertures, or a nebulizer comprising a vibration generator and done or pyridone analog compound that is obtained after a an aqueous chamber. In some embodiments, the liquid nebu single administration of the aqueous solution to the mammal lizer: (i) achieves lung deposition of at least 7% of the pir with a liquid nebulizer is greater than the lung tissue Cmax of fenidone or pyridone analog compound administered to the pirfenidone or pyridone analog compound that is obtained mammal; (ii) provides a Geometric Standard Deviation after a single dose of orally administered pirfenidone or pyri (GSD) of emitted droplet size distribution of the aqueous done analog compound at a dose that is from about 80% to solution of about 1.0 Lum to about 2.5um; (iii) provides: a) a about 120% of the dose administered with the liquid nebu mass median aerodynamic diameter (MMAD) of droplet size lizer. In some embodiments, the lung tissue AUC of pirfeni of the aqueous Solution emitted with the high efficiency liquid done or pyridone analog compound that is obtained after a nebulizer of about 1 um to about 5um; b) a volumetric mean single administration of the aqueous solution to the mammal diameter (VMD) of about 1 um to about 5 um; and/or c) a with a liquid nebulizer is greater than the lung tissue AUC of mass median diameter (MMD) of about 1 um to about 5um; pirfenidone or pyridone analog compound that is obtained (iv) provides a fine particle fraction (FPF=% 5 microns) of after a single dose of orally administered pirfenidone or pyri droplets emitted from the liquid nebulizer of at least about done analog compound at a dose that is from about 80% to 30%; (v) provides an output rate of at least 0.1 mL/min: about 120% of the dose administered with the liquid nebu and/or (vi) provides at least about 25% of the aqueous solu lizer. In some embodiments, the plasma Cmax of pirfenidone tion to the mammal. In some embodiments, the mammal is a or pyridone analog compound that is obtained after a single human. In some embodiments, the lung disease is lung fibro administration of the aqueous solution to the mammal with a sis and the mammal is a human. In some embodiments, the liquid nebulizer is at least 10% or greater than the plasma lung disease is idiopathic pulmonary fibrosis and the mammal Cmax of pirfenidone or pyridone analog compound that is is a human. In some embodiments, the lung disease is pulmo obtained after a single dose of orally administered pirfeni US 2015/O 196543 A1 Jul. 16, 2015 done or pyridone analog compound at a dose that is from liquid nebulizer, the solution having a concentration of pir about 80% to about 120% of the dose administered with the fenidone or pyridone analog compound from about 0.1 liquid nebulizer. In some embodiments, the plasma AUC of mg/mL to about 60 mg/mL and the osmolality of the aqueous pirfenidone or pyridone analog compound that is obtained solution is from about 50 mOsmol/kg to about 5000 mOsmol/ after a single administration of the aqueous Solution to the kg; and the liquid nebulizer is a nebulizer comprising a vibrat mammal with a liquid nebulizer is at least 10% or greater than ing mesh or plate with multiple apertures. the plasma AUC of pirfenidone or pyridone analog compound 0035. In some embodiments, the liquid nebulizer delivers that is obtained after a single dose of orally administered about 0.1 mg to about 360 mg of prifenidone or pyridone pirfenidone or pyridone analog compound at a dose that is analog compound to the lungs in less than about 20 minutes from about 80% to about 120% of the dose administered with with mass median diameter (MMAD) particles sizes from the liquid nebulizer. about 1 to about 5 micron. In some embodiments, the aqueous 0028. In some embodiments, the liquid nebulizer delivers solution has a pH from about 4.0 to about 8.0 and an osmo from about 0.1 mg to about 360 mg of pirfenidone or pyridone lality from about 400 mOsmol/kg to about 5000 mOsmol/kg. analog compound to the lungs of the mammal in less than 0036. In some embodiments, described herein is an inha about 20 minutes with mass median diameter (MMAD) par lation system for administration of pirfenidone or pyridone ticles sizes from about 1 to about 5 micron. analog compound to the respiratory tract of a human, the 0029. In some embodiments, administration with the liq system comprising: (a) about 0.5 mL to about 6 mL of an uid nebulizer does not include an initial dose-escalation aqueous solution of pirfenidone or pyridone analog com period. pound; and (b) a high efficiency liquid nebulizer. In some 0030. In some embodiments, described herein is a method embodiments, the aqueous solution is any of the aqueous of reducing the risk of gastrointestinal (GI) adverse events in Solutions described herein. In some embodiments, the con the treatment of a human with pirfenidone or pyridone analog centration of pirfenidone or pyridone analog compound in the compound, comprising: administering to the human in need aqueous solution is from about 0.1 mg/mL and about 60 thereof a nebulized aqueous solution comprising pirfenidone mg/mL and the osmolality of the aqueous solution is from or a pyridone analog compound with a liquid nebulizer; about 400 mOsmol/kg to about 6000 mOsmol/kg. In some wherein the aqueous solution comprises water, pirfenidone, embodiments, the aqueous solution comprises: water, pir or a pyridone analog compound, at a concentration from fenidone, or a pyridone analog compound, at a concentration about 0.1 mg/mL to about 60 mg/mL, and one or more co from about 10 mg/mL to about 50 mg/mL, optionally a phos solvents, wherein the osmolality of the aqueous solution is phate buffer that maintains the pH of the solution from about from about 50 mOsmol/kg to about 6000 mOsmol/kg. In pH 6.0 to about pH 8.0; about 1% to about 8% of ethanol: Some embodiments, the aqueous solution comprises water; and/or about 2% to about 16% of propylene glycol. In some pirfenidone or pyridone analog compound at a concentration embodiments, the aqueous solution is as described herein. from about 10 mg/mL to about 60 mg/mL, one or more 0037. In one aspect, described herein is a method of co-solvents, wherein the total amount of the one or more achieving a lung tissue Cmax of pirfenidone or pyridone co-solvents is about 1% to about 40% V/V, where the one or analog compound that is at least 1.5 times, at least 2 times, at more co-solvents are selected from about 1% to about 25% least 3 times, at least 4 times, at least 5 times, at least 6 times, V/v of ethanol, about 1% to about 25% V/v of propylene at least 1.5 times, at least 1.5 times, at least 1.5 times, at least glycol, and about 1% to about 25% V/v of glycerol; and 1.5 times, at least 7 times, at least 8 times, at least 9 times, at optionally a phosphate buffer that maintains the pH of the least 10 times, at least 1.5-20 times, at least 1.5-15 times, at solution from about pH 6.0 to about pH 8.0. least 1.5-10 times, at least 1.5-5 times, or at least 1.5-3 times 0031. In some embodiments, the aqueous solution com a Cmax of up to 801 mg of an orally administered dosage of prises water, pirfenidone or pyridone analog compound at a pirfenidone or pyridone analog compound, the method com concentration from about 15 mg/mL to about 50 mg/mL, one prising nebulizing an aqueous solution comprising pirfeni or more co-solvents, wherein the total amount of the one or done or pyridone analog compound and administering the more co-solvents if about 1 to about 30% V/V, where the one nebulized aqueous solution to a human. In some embodi or more co-solvents are selected from about 1% to about 10% ments, described herein is a method of achieving a lung tissue V/v of ethanol, and about 1% to about 20% v/v of propylene Cmax of pirfenidone or pyridone analog compound that is at glycol, and optionally a phosphate buffer that maintains the least equivalent to or greater than a Cmax of up to 801 mg of pH of the solution from about pH 6.0 to about pH 8.0: wherein an orally administered dosage of pirfenidone or pyridone the osmolality of the aqueous solution is from about 400 analog compound, the method comprising nebulizing an mOsmol/kg to about 6000 mOsmol/kg. In some embodi aqueous solution comprising pirfenidone or pyridone analog ments, the pirfenidone or pyridone analog is administered to compound and administering the nebulized aqueous solution treat lung disease in the human. In some embodiments, lung to a human. disease is idiopathic pulmonary fibrosis. 0038. In one aspect, described herein is a method of 0032. In some embodiments, the liquid nebulizer delivers achieving a lung tissue AUC of pirfenidone or pyridone about 0.1 mg to about 360 mg of prifenidone or pyridone analog compound that is at least 1.5 times, at least 2 times, at analog compound to the lungs in less than about 20 minutes least 3 times, at least 4 times, at least 5 times, at least 6 times, with mass median diameter (MMAD) particles sizes from at least 1.5 times, at least 1.5 times, at least 1.5 times, at least about 1 to about 5 micron. 1.5 times, at least 7 times, at least 8 times, at least 9 times, at 0033. In some embodiments, administration with the liq least 10 times, at least 1.5-20 times, at least 1.5-15 times, at uid nebulizer does not include an initial dose-escalation least 1.5-10 times, at least 1.5-5 times, or at least 1.5-3 times period. AUCo. of up to 801 mg of an orally administered dosage of 0034. In some embodiments, about 0.5 mL to about 6 mL pirfenidone or pyridone analog compound, the method com of the aqueous Solution is administered to the mammal with a prising nebulizing an aqueous solution comprising pirfeni US 2015/O 196543 A1 Jul. 16, 2015

done or pyridone analog compound and administering the 0042. In one aspect, described herein is a method of nebulized aqueous solution to a human. In some embodi administering pirfenidone or a pyridone analog compound to ments, described herein is a method of achieving a lung tissue a human, comprising administering a nebulized aqueous AUC of pirfenidone or pyridone analog compound that is Solution containing the pirfenidone or pyridone analog, at least equivalent to or greater than AUC of up to 801 mg wherein the lung tissue AUC achieved with the nebulized of an orally administered dosage of pirfenidone or pyridone Solution is at least 1.5 times, at least 2 times, at least 3 times, analog compound, the method comprising nebulizing an at least 4 times, at least 5 times, at least 6 times, at least 1.5 aqueous solution comprising pirfenidone or pyridone analog times, at least 1.5 times, at least 1.5 times, at least 1.5 times, compound and administering the nebulized aqueous solution at least 7 times, at least 8 times, at least 9 times, at least 10 to a human. 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 0039. In one aspect, described herein is a method of lung tissue AUC achieved with an orally administered administering pirfenidone or a pyridone analog compound to pirfenidone or pyridone analog compound dosage that is from a human, comprising administering a nebulized aqueous 80% to 120% of the dosage of pirfenidone or pyridone analog Solution containing the pirfenidone or pyridone analog, compound in the nebulized aqueous solution of pirfenidone wherein the lung tissue Cmax achieved with the nebulized or pyridone analog compound. In some embodiments, Solution is at least 1.5 times, at least 2 times, at least 3 times, described herein is a method of administering pirfenidone or at least 4 times, at least 5 times, at least 6 times, at least 1.5 a pyridone analog compound to a human, comprising admin times, at least 1.5 times, at least 1.5 times, at least 1.5 times, istering a nebulized aqueous Solution containing the pirfeni at least 7 times, at least 8 times, at least 9 times, at least 10 done or pyridone analog, wherein the lung tissue AUCo times, at least 1.5-20 times, at least 1.5-15 times, at least achieved with the nebulized solution is at least 1.5 times the 1.5-10 times, at least 1.5-5 times, or at least 1.5-3 times the lung tissue AUC achieved with an orally administered lung tissue Cmax achieved with an orally administered pir pirfenidone or pyridone analog compound dosage that is from fenidone or pyridone analog compound dosage that is from 80% to 120% of the dosage of pirfenidone or pyridone analog 80% to 120% of the dose amount ofpirfenidone that is admin compound in the nebulized aqueous solution of pirfenidone istered by nebulization. or pyridone analog compound. 0040. In one aspect, described herein is a method of 0043. In one aspect, provided herein is a method of administering pirfenidone or a pyridone analog compound to improving the pharmacokinetic profile obtained in a human a human, comprising administering a nebulized aqueous following a single oral dose administration of pirfenidone or Solution containing the pirfenidone or pyridone analog, pyridone analog. In some embodiments, the pirfenidone or wherein the lung tissue Cmax achieved with the nebulized pyridone analog is administered to the human to treat lung Solution is at least 1.5 times, at least 2 times, at least 3 times, disease. In some embodiments, the lung disease is lung fibro at least 4 times, at least 5 times, at least 6 times, at least 1.5 sis. In some embodiments, the lung disease is idiopathic times, at least 1.5 times, at least 1.5 times, at least 1.5 times, pulmonary fibrosis. In some embodiments, the single oral at least 7 times, at least 8 times, at least 9 times, at least 10 dose comprises up to about 801 mg of pirfenidone orpyridone times, at least 1.5-20 times, at least 1.5-15 times, at least analog compound. In some embodiments, the method of 1.5-10 times, at least 1.5-5 times, or at least 1.5-3 times the improving the pharmacokinetic profile comprises the step of lung tissue Cmax achieved with an orally administered pir administering pirfenidone or pryridone analog by inhalation. fenidone or pyridone analog compound dosage that is from In some embodiments, the pharmacokinetic profile com 80% to 120% of the dosage of pirfenidone or pyridone analog prises the lung tissue pharmacokinetic profile. In some compound in the nebulized aqueous solution of pirfenidone embodiments, the pharmacokinetic profile comprises the or pyridone analog compound. In some embodiments, lung tissue pharmacokinetic profile and/or plasma pharma described herein is a method of administering pirfenidone or cokinetic profile. In some embodiments, the pirfenidone or a pyridone analog compound to a human, comprising admin pryridone analog is administered as an aqueous Solution with istering a nebulized aqueous Solution containing the pirfeni a liquid nebulizer. In some embodiments, the aqueous solu done or pyridone analog, wherein the lung tissue Cmax tion of pirfenidone or pyridone analog is as described herein. achieved with the nebulized solution is at least equivalent to In some embodiments, the method of improving the pharma or greater than the lung tissue Cmax achieved with an orally cokinetic profile further comprises a comparison of the phar administered pirfenidone or pyridone analog compound dos macokinetic parameters following inhalation administration age that is from 80% to 120% of the dosage of pirfenidone or to the same parameters obtained following oral administra pyridone analog compound in the nebulized aqueous Solution tion. In some embodiments, the improvement in pharmaco of pirfenidone or pyridone analog compound that is admin kinetic profile is substantially the same as depicted in FIG.1. istered. In some embodiments, the initial improvement in pharmaco 0041. In some embodiments, described herein is a method kinetic profile is substantially the same as depicted in FIG. 1, of administering pirfenidone or a pyridone analog compound but the pulmonary half-life is extended providing longer pull to a human, comprising administering a nebulized aqueous monary residence time. In some embodiments, a prolonged Solution containing the pirfenidone or pyridone analog, improvement in pharmacokinetic profile is obtained by wherein the plasma AUC achieved with the nebulized repeated and frequent administrations of the aqueous Solution Solution is at least 10% or greater than the plasma AUCo of pirfenidone or pyridone analog as described herein by achieved with an orally administered pirfenidone or pyridone inhalation. In some embodiments, repeated administration of analog compound dosage that is from 80% to 120% of the pirfenidone or pyridone analog by inhalation provides more dosage of pirfenidone or pyridone analog compound in the frequent direct lung exposure benefiting the human through nebulized aqueous Solution of pirfenidone or pyridone analog repeat high Cmax levels. In some embodiments, the inhaled compound that is administered. pirfenidone or pyridone analog doses are administered once a US 2015/O 196543 A1 Jul. 16, 2015 day, twice a day, three times a day, four time a day, every other tion comprises a second anti-fibrotic agent Suitable for pull day, twice a week, three times a week, four times a week, five monary delivery. In some embodiments, the composition times a week, six times a week, seven times a week, or any comprises a second anti-inflammatory agent Suitable for pull combination thereof. In some embodiments, the improve monary delivery. ment in pharmacokinetic profile is Substantially the same as depicted in FIG. 2. In some embodiments, the initial improve 0045. In some embodiments, described herein is a phar ment in pharmacokinetic profile is Substantially the same as maceutical composition for pulmonary delivery, comprising depicted in FIG. 2, but the pulmonary half-life is extended a solution of pirfenidone or pyridone analog and a taste mask providing longer pulmonary residence time. In some embodi ing agent, wherein the Solution has an osmolality greater than ments, a prolonged improvement in pharmacokinetic profile about 100 mOsmol/kg, and a pH greater than about 4.0. In is obtained by repeated and frequent administrations of the Some embodiments, the pirfenidone or pyridone analog con aqueous solution of pirfenidone or pyridone analog as centration is greater than about 34 mcg/mL. In some embodi described herein by inhalation. In some embodiments, ments, the pirfenidone or pyridone analog concentration is repeated administration of pirfenidone or pyridone analog by greater than about 1.72 mg/mL. In some embodiments, the inhalation provides more frequent direct lung exposure ben pirfenidone or pyridone analog concentration is greater than efiting the human through repeat high Cmax levels. In some about 86 mg/mL. In some embodiments, the pirfenidone or embodiments, the inhaled pirfenidone or pyridone analog pyridone analog solution has a permeant ion concentration doses are administered once a day, twice a day, three times a from about 30 mM to about 300 mM. In some embodiments, day, four time a day, every other day, twice a week, three times the permeant ion is chloride or bromide. In some embodi a week, four times a week, five times a week, six times a week, ments, the pirfenidone or pyridone analog solution has a pH seven times a week, or any combination thereof. In some from about 4.0 to about 8.0. In some embodiments, the pir embodiments, the improvement in pharmacokinetic profile is fenidone or pyridone analog solution has an osmolality from substantially the same as depicted in FIG. 5. In some embodi about 100 mOsmol/kg to about 1000 mOsmol/kg. In some ments, the initial improvement in pharmacokinetic profile is embodiments, the pirfenidone or pyridone analog Solution substantially the same as depicted in FIG. 5, but the pulmo has an osmolality from about 50 mOsmol/kg to about 5000 nary half-life is extended providing longer pulmonary resi mOsmol/kg. In some embodiments, the composition com dence time. In some embodiments, a prolonged improvement prises a taste masking agent. In some embodiments, the taste in pharmacokinetic profile is obtained by repeated and fre masking agent is selected from the group consisting of lac quent administrations of the aqueous solution of pirfenidone tose, sucrose, dextrose, saccharin, aspartame. Sucrulose, or pyridone analog as described herein by inhalation. In some ascorbate and citrate. In some embodiments, the composition embodiments, repeated administration of pirfenidone or pyri comprises a mucolytic agent Suitable for pulmonary delivery. done analog by inhalation provides more frequent direct lung In some embodiments, the composition comprises a second exposure benefiting the human through repeat high Cmax anti-fibrotic agent Suitable for pulmonary delivery. In some levels. In some embodiments, the inhaled pirfenidone or pyri embodiments, the composition comprises a second anti-in done analog doses are administered once a day, twice a day, flammatory agent Suitable for pulmonary delivery. three times a day, four time a day, every other day, twice a 0046. In some embodiments, described herein is a sterile, week, three times a week, four times a week, five times a single-use container comprising from about 0.1 mL to about week, six times a week, seven times a week, or any combi 20 mL of a solution of pirfenidone or pyridone analog having nation thereof. a concentration greater than about 34 mcg/mL, having an 0044. In some embodiments, described herein is a phar osmolality greater than about 100 mOsmol/kg, and having a maceutical composition for pulmonary delivery, comprising pH greater than about 4.0. In some embodiments, the pirfeni a solution of pirfenidone or pyridone analog having a con done or pyridone analog concentration is greater than about centration greater than about 34 mcg/mL, having an osmola 1.72 mg/mL. In some embodiments, the pirfenidone or pyri lity greater than about 100 mOsmol/kg, and having a pH done analog concentration is greater than about 86 mg/mL. In greater than about 4.0. In some embodiments, the pirfenidone Some embodiments, the pirfenidone or pyridone analog solu or pyridone analog concentration is greater than about 1.72 tion has a permeant ion concentration from about 30 mM to mg/mL. In some embodiments, the pirfenidone or pyridone about 300 mM. In some embodiments, the permeant ion is analog concentration is greater thanabout 86 mg/mL. In some chloride or bromide. In some embodiments, the pirfenidone embodiments, the pirfenidone or pyridone analog Solution or pyridone analog solution has a pH from about 4.0 to about has a permeant ion concentration from about 30 mM to about 8.0. In some embodiments, the pirfenidone or pyridone ana 300 mM. In some embodiments, the permeantion is chloride log solution has an osmolality from about 100 mOsmol/kg to or bromide. In some embodiments, the pirfenidone or pyri about 1000 mOsmol/kg. In some embodiments, the pirfeni done analog solution has a pH from about 4.0 to about 8.0. In done or pyridone analog Solution has an osmolality from Some embodiments, the pirfenidone or pyridone analog solu about 50 mOsmol/kg to about 5000 mOsmol/kg. In some tion has an osmolality from about 100 mOsmol/kg to about embodiments, the container further comprises a taste mask 1000 mOsmol/kg. In some embodiments, the pirfenidone or ing agent. In some embodiments, the taste masking agent is pyridone analog Solution has an osmolality from about 50 selected from the group consisting of lactose. Sucrose, dex mOsmol/kg to about 5000 mOsmol/kg. In some embodi trose, saccharin, aspartame. Sucrulose, ascorbate and citrate. ments, the composition comprises a taste masking agent. In In some embodiments, the container further comprises a Some embodiments, the taste masking agent is selected from mucolytic agent Suitable for pulmonary delivery. In some the group consisting of lactose, Sucrose, dextrose, Saccharin, embodiments, the container further comprises a second anti aspartame. Sucrulose, ascorbate and citrate. In some embodi fibrotic agent suitable for pulmonary delivery. In some ments, the composition comprises a mucolytic agent Suitable embodiments, the container further comprises a second anti for pulmonary delivery. In some embodiments, the composi inflammatory agent Suitable for pulmonary delivery. US 2015/O 196543 A1 Jul. 16, 2015

0047. In one aspect, described herein is a method to treat a seconds. In some embodiments, the inhaling step is per pulmonary disease comprising inhaling an aerosol of pirfeni formed in less than about 5 breaths. In some embodiments, done or pyridone analog Solution having a concentration the inhaling step is performed in less than about 3 breaths. greater than about 34 mcg/mL, having an osmolality greater 0048. In some embodiments, described herein is a phar than about 100 mOsmol/kg, and having a pH greater than maceutical composition for pulmonary delivery, comprising about 4.0. In some embodiments, the pirfenidone or pyridone a solution of pirfenidone or pyridone analog and a taste mask analog concentration is greater than about 1.72 mg/mL. In ing agent, wherein the Solution has an osmolality greater than Some embodiments, the pirfenidone or pyridone analog con about 50 mOsmol/kg, and a pH greater than about 4.0. In centration is greater than about 86 mg/mL. In some embodi Some embodiments, the pirfenidone or pyridone analog con ments, the pirfenidone or pyridone analog Solution has a centration is greater than about 34 mcg/mL. In some embodi permeant ion concentration from about 30 mM to about 300 ments, the pirfenidone or pyridone analog concentration is mM. In some embodiments, the permeant ion is chloride or greater than about 1.72 mg/mL. In some embodiments, the bromide. In some embodiments, the pirfenidone or pyridone pirfenidone or pyridone analog concentration is greater than analog solution has a pH from about 4.0 to about 8.0. In some about 86 mg/mL. In some embodiments, the pirfenidone or embodiments, the pirfenidone or pyridone analog Solution pyridone analog solution has a permeant ion concentration has an osmolality from about 100 mOsmol/kg to about 1000 from about 30 mM to about 300 mM. In some embodiments, mOsmol/kg. In some embodiments, the pirfenidone or pyri the permeant ion is chloride or bromide. In some embodi done analog Solution has an osmolality from about 50 mOS ments, the pirfenidone or pyridone analog solution has a pH mol/kg to about 5000 mOsmol/kg. In some embodiments, the from about 4.0 to about 8.0. In some embodiments, the pir pirfenidone or pyridone analog solution has a taste masking fenidone or pyridone analog solution has an osmolality from agent. In some embodiments, the taste masking agent is about 50 mOsmol/kg to about 2000 mOsmol/kg. In some selected from the group consisting of lactose. Sucrose, dex embodiments, the composition comprises a taste masking trose, saccharin, aspartame. Sucrulose, ascorbate and citrate. agent. In some embodiments, the taste masking agent is In some embodiments, the method further comprises admin selected from the group consisting of lactose. Sucrose, dex istering a mucolytic agent Suitable for pulmonary delivery. In trose, saccharin, aspartame. Sucrulose, ascorbate and citrate. Some embodiments, the method further comprises adminis In some embodiments, the composition comprises a muco tering a second anti-fibrotic agent Suitable for pulmonary lytic agent Suitable for pulmonary delivery. In some embodi delivery. In some embodiments, the method further com ments, the composition comprises a second anti-fibrotic prises administering a second anti-inflammatory agent suit agent suitable for pulmonary delivery. In some embodiments, able for pulmonary delivery. In some embodiments, the pull the composition comprises a second anti-inflammatory agent monary disease is interstitial lung disease. In some suitable for pulmonary delivery. In some embodiments, the embodiments, the interstitial lung disease is idiopathic pull composition comprises a second anti-cancer agent Suitable monary fibrosis. In some embodiments, the interstitial lung for pulmonary delivery. In some embodiments, the composi disease is radiation-therapy-induced pulmonary fibrosis. In tion comprises a second anti-pulmonary hypertension agent Some embodiments, the pulmonary disease is chronic suitable for pulmonary delivery. obstructive pulmonary disease. In some embodiments, the 0049. In one aspect, described herein is a method to treat a pulmonary disease is chronic bronchitis. In some embodi pulmonary disease comprising inhaling an aerosol of pirfeni ments, the pulmonary disease is asthma. In some embodi done or pyridone analog Solution having a concentration ments, the aerosol comprises particles having a mean aero greater than about 34 mcg/mL, having an osmolality greater dynamic diameter from about 1 micronto about 5 microns. In than about 50 mOsmol/kg, and having a pH greater than about Some embodiments, the aerosol has a mean particle size from 4.0. In some embodiments, the pirfenidone or pyridone ana about 1 microns to about 5 microns Volumetric mean diameter log concentration is greater than about 0.1 mg/mL. In some and a particle size geometric standard deviation of less than or embodiments, the pirfenidone or pyridone analog concentra equal to 3 microns. In some embodiments, the inhaling step tion is greater than about 86 mg/mL. In some embodiments, delivers a dose of a least 6.8 mcg pirfenidone or pyridone the pirfenidone or pyridone analog solution has a permeant analog. In some embodiments, the inhaling step delivers a ion concentration from about 30 mM to about 300 mM. In dose of a least 340 mcg pirfenidone or pyridone analog. In Some embodiments, the permeantion is chloride or bromide. Some embodiments, the inhaling step delivers a dose of a least In some embodiments, the pirfenidone or pyridone analog 740 mcg pirfenidone or pyridone analog. In some embodi solution has a pH from about 4.0 to about 8.0. In some ments, the inhaling step delivers a dose of a least 1.7 mg embodiments, the pirfenidone or pyridone analog Solution pirfenidone or pyridone analog. In some embodiments, the has an osmolality from about 50 mOsmol/kg to about 2000 inhaling step delivers a dose of a least 93 mg pirfenidone or mOsmol/kg. In some embodiments, the pirfenidone or pyri pyridone analog. In some embodiments, the inhaling step done analog solution has a taste masking agent. In some delivers a dose of a least 463 mg pirfenidone or pyridone embodiments, the taste masking agent is selected from the analog. In some embodiments, the inhaling step is performed group consisting of lactose, Sucrose, dextrose, Saccharin, in less than about 20 minutes. In some embodiments, the aspartame. Sucrulose, ascorbate and citrate. In some embodi inhaling step is performed in less than about 10 minutes. In ments, the method further comprises administering a muco Some embodiments, the inhaling step is performed in less lytic agent Suitable for pulmonary delivery. In some embodi than about 7.5 minutes. In some embodiments, the inhaling ments, the method further comprises administering a second step is performed in less than about 5 minutes. In some anti-fibrotic agent Suitable for pulmonary delivery. In some embodiments, the inhaling step is performed in less than embodiments, the method further comprises administering a about 2.5 minutes. In some embodiments, the inhaling step is second anti-inflammatory agent Suitable for pulmonary deliv performed in less than about 1.5 minutes. In some embodi ery. In some embodiments, the pulmonary disease is intersti ments, the inhaling step is performed in less than about 30 tial lung disease and the mammal is a human. In some US 2015/O 196543 A1 Jul. 16, 2015 embodiments, the interstitial lung disease is idiopathic pull anti-infective agent Suitable for pulmonary delivery. In some monary fibrosis and the mammal is a human. In some embodiments, the method further comprises administering a embodiments, the interstitial lung disease is radiation second anti-inflammatory agent Suitable for pulmonary deliv therapy-induced pulmonary fibrosis and the mammal is a ery. In some embodiments, the composition may be co-ad human. In some embodiments, the pulmonary disease is ministered with a second anti-fibrotic or anti-cancer, anti chronic obstructive pulmonary disease and the mammal is a pulmonary hypertension or anti-infective agent Suitable for human. In some embodiments, the pulmonary disease is pulmonary delivery. In some embodiments, the composition chronic bronchitis and the mammal is a human. In some co-administered a second anti-inflammatory agent Suitable embodiments, the pulmonary disease is asthma and the mam for pulmonary delivery. In some embodiments, the method mal is a human. In some embodiments, the aerosol comprises further comprises administering a second anti-fibrotic agent particles having a mean aerodynamic diameter from about 1 suitable for pulmonary delivery. In some embodiments, the micronto about 5 microns. In some embodiments, the aerosol method further comprises administering a second anti-in has a mean particle size from about 1 microns to about 5 flammatory agent Suitable for pulmonary delivery. In some microns Volumetric mean diameter and a particle size geo embodiments, the pulmonary disease is lung cancer. In some metric standard deviation of less than or equal to 3 microns. In embodiments, the lung cancer is Small cell lung cancer. In Some embodiments, the inhaling step delivers a dose of a least Some embodiments, the lung cancer is non-Small cell lung 6.8 mcg pirfenidone or pyridone analog. In some embodi cancer. In some embodiments, the pulmonary cancer is large ments, the inhaling step delivers a dose of a least 340 mcg cell carcinoma. In some embodiments, the pulmonary cancer pirfenidone or pyridone analog. In some embodiments, the is mesothelioma. In some embodiments, the pulmonary can inhaling step delivers a dose of a least 740mcg pirfenidone or cer is lung carcinoid tumors or bronchial cardinoids. In some pyridone analog. In some embodiments, the inhaling step embodiments, the pulmonary cancer is secondary lung cancer delivers a dose of a least 1.7 mg pirfenidone or pyridone resulting from metastatic disease. In some embodiments, the analog. In some embodiments, the inhaling step delivers a pulmonary cancer is bronchioloalveolar carcinoma. In some dose of a least 93 mg pirfenidone or pyridone analog. In some embodiments, the pulmonary cancer may be sarcoma. In embodiments, the inhaling step delivers a dose of a least 463 Some embodiments, the pulmonary cancer is may be a lym mg pirfenidone or pyridone analog. In some embodiments, phoma. In some embodiments, the aerosol comprises par the inhaling step is performed in less than about 20 minutes. ticles having a mean aerodynamic diameter from about 1 In some embodiments, the inhaling step is performed in less micronto about 5 microns. In some embodiments, the aerosol than about 10 minutes. In some embodiments, the inhaling has a mean particle size from about 1 microns to about 5 step is performed in less than about 7.5 minutes. In some microns Volumetric mean diameter and a particle size geo embodiments, the inhaling step is performed in less than metric Standard deviation of less than or equal to 3 microns. In about 5 minutes. In some embodiments, the inhaling step is Some embodiments, the inhaling step delivers a dose of a least performed in less than about 2.5 minutes. In some embodi 6.8 mcg pirfenidone or pyridone analog. In some embodi ments, the inhaling step is performed in less than about 1.5 ments, the inhaling step delivers a dose of a least 340 mcg minutes. In some embodiments, the inhaling step is per pirfenidone or pyridone analog. In some embodiments, the formed in less than about 30 seconds. In some embodiments, inhaling step delivers a dose of a least 740mcg pirfenidone or the inhaling step is performed in less than about 5 breaths. In pyridone analog. In some embodiments, the inhaling step Some embodiments, the inhaling step is performed in less delivers a dose of a least 1.7 mg pirfenidone or pyridone than about 3 breaths. analog. In some embodiments, the inhaling step delivers a 0050. In one aspect, described herein is a method to treat a dose of a least 93 mg pirfenidone or pyridone analog. In some pulmonary disease comprising inhaling an aerosol of pirfeni embodiments, the inhaling step delivers a dose of a least 463 done or pyridone analog Solution having a concentration mg pirfenidone or pyridone analog. In some embodiments, greater than about 34 mcg/mL, having an osmolality greater the inhaling step is performed in less than about 20 minutes. than about 100 mOsmol/kg, and having a pH greater than In some embodiments, the inhaling step is performed in less about 4.0. In some embodiments, the pirfenidone or pyridone than about 10 minutes. In some embodiments, the inhaling analog concentration is greater than about 0.1 mg/mL. In step is performed in less than about 7.5 minutes. In some Some embodiments, the pirfenidone or pyridone analog con embodiments, the inhaling step is performed in less than centration is greater than about 86 mg/mL. In some embodi about 5 minutes. In some embodiments, the inhaling step is ments, the pirfenidone or pyridone analog Solution has a performed in less than about 2.5 minutes. In some embodi permeant ion concentration from about 30 mM to about 300 ments, the inhaling step is performed in less than about 1.5 mM. In some embodiments, the permeant ion is chloride or minutes. In some embodiments, the inhaling step is per bromide. In some embodiments, the pirfenidone or pyridone formed in less than about 30 seconds. In some embodiments, analog solution has a pH from about 4.0 to about 8.0. In some the inhaling step is performed in less than about 5 breaths. In embodiments, the pirfenidone or pyridone analog Solution Some embodiments, the inhaling step is performed in less has an osmolality from about 50 mOsmol/kg to about 2000 than about 3 breaths. mOsmol/kg. In some embodiments, the pirfenidone or pyri 0051. In one aspect, described herein is a method to treat a done analog solution has a taste masking agent. In some pulmonary disease comprising inhaling an aerosol of pirfeni embodiments, the taste masking agent is selected from the done or pyridone analog Solution having a concentration group consisting of lactose, Sucrose, dextrose, Saccharin, greater than about 34 mcg/mL, having an osmolality greater aspartame. Sucrulose, ascorbate and citrate. In some embodi than about 100 mOsmol/kg, and having a pH greater than ments, the method further comprises administering a muco about 4.0. In some embodiments, the pirfenidone or pyridone lytic agent Suitable for pulmonary delivery. In some embodi analog concentration is greater than about 0.1 mg/mL. In ments, the method further comprises administering a second Some embodiments, the pirfenidone or pyridone analog con anti-fibrotic or anti-cancer, anti-pulmonary hypertension or centration is greater than about 86 mg/mL. In some embodi US 2015/O 196543 A1 Jul. 16, 2015

ments, the pirfenidone or pyridone analog Solution has a formed in less than about 5 breaths. In some embodiments, permeant ion concentration from about 30 mM to about 300 the inhaling step is performed in less than about 3 breaths. mM. In some embodiments, the permeant ion is chloride or 0052. In one aspect, described herein is a method to bromide. In some embodiments, the pirfenidone or pyridone administer an anti-fibrotic agent to lungs of a patient, com analog solution has a pH from about 4.0 to about 8.0. In some prising: introducing in a nebulizer a pirfenidone or pyridone embodiments, the pirfenidone or pyridone analog Solution analog solution having a concentration greater than about 34 has an osmolality from about 50 mOsmol/kg to about 2000 mcg/mL, having an osmolality greater than about 100 mOS mOsmol/kg. In some embodiments, the pirfenidone or pyri mol/kg, and having a pH greater than about 4.0. In another done analog solution has a taste masking agent. In some aspect, described herein is a method to administer an anti embodiments, the taste masking agent is selected from the inflammatory agent to lungs of a patient, comprising: intro group consisting of lactose, Sucrose, dextrose, Saccharin, ducing in a nebulizer a pirfenidone or pyridone analog solu aspartame. Sucrulose, ascorbate and citrate. In some embodi tion having a concentration greater than about 34 mcg/mL, ments, the method further comprises administering a muco having an osmolality greater than about 100 mOsmol/kg, and lytic agent Suitable for pulmonary delivery. In some embodi having a pH greater than about 4.0. In some embodiments, the ments, the method further comprises administering a second pirfenidone or pyridone analog concentration is greater than anti-fibrotic or anti-cancer, anti-pulmonary hypertension or about 1.72 mg/mL. In some embodiments, the pirfenidone or anti-infective agent Suitable for pulmonary delivery. In some pyridone analog concentration is greater than about 86 embodiments, the method further comprises administering a mg/mL. In some embodiments, the pirfenidone or pyridone second anti-inflammatory agent Suitable for pulmonary deliv analog Solution has a permeant ion concentration from about ery. In some embodiments, the composition may be co-ad 30 mM to about 300 mM. In some embodiments, the per ministered with a second anti-fibrotic or anti-cancer, anti meant ion is chloride or bromide. In some embodiments, the pulmonary hypertension or anti-infective agent Suitable for pirfenidone or pyridone analog Solution has a pH from about pulmonary delivery. In some embodiments, the composition 4.0 to about 8.0. In some embodiments, the pirfenidone or co-administered a second anti-inflammatory agent Suitable pyridone analog Solution has an osmolality from about 100 for pulmonary delivery. In some embodiments, the method mOsmol/kg to about 1000 mOsmol/kg. In some embodi further comprises administering a second anti-fibrotic agent ments, the pirfenidone or pyridone analog solution has an suitable for pulmonary delivery. In some embodiments, the osmolality from about 50 mOsmol/kg to about 5000 mOs method further comprises administering a second anti-in mol/kg. In some embodiments, the pirfenidone or pyridone flammatory agent suitable for pulmonary delivery. In some analog Solution has a taste masking agent. In some embodi embodiments, the pulmonary disease is pulmonary hyperten ments, the taste masking agent is selected from the group Sion. In some embodiments, the pulmonary hypertension is consisting of lactose, Sucrose, dextrose, Saccharin, aspar Type 1. In some embodiments, the pulmonary hypertension is tame. Sucrulose, ascorbate and citrate. In some embodiments, Type 2. In some embodiments, the pulmonary hypertension is the method further comprises administering a mucolytic Type 3. In some embodiments, the pulmonary hypertension is agent Suitable for pulmonary delivery. In some embodiments, Type 4. In some embodiments, the pulmonary hypertension is the mucolytic agent is inhaled separately from the pirfeni Type 5. In some embodiments, the pulmonary hypertension is done or pyridone analog Solution. In some embodiments, the secondary to pulmonary fibrosis. In some embodiments, the method further comprises administering a second anti-fi aerosol comprises particles having a mean aerodynamic brotic agent Suitable for pulmonary delivery. In some diameter from about 1 micron to about 5 microns. In some embodiments, the method further comprises administering a embodiments, the aerosol has a mean particle size from about second anti-inflammatory agent Suitable for pulmonary deliv 1 microns to about 5 microns Volumetric mean diameter and ery. a particle size geometric standard deviation of less than or 0053. In one aspect, described herein is a method to treat equal to 3 microns. In some embodiments, the inhaling step an extrapulmonary disease target comprising inhaling an delivers a dose of a least 6.8 mcg pirfenidone or pyridone aerosol of pirfenidone or pyridone analog Solution having a analog. In some embodiments, the inhaling step delivers a concentration greater than about 34 mcg/mL, having an dose of a least 340 mcg pirfenidone or pyridone analog. In osmolality greater than about 100 mOsmol/kg, and having a Some embodiments, the inhaling step delivers a dose of a least pH greater than about 4.0 for the purpose of absorbing into the 740 mcg pirfenidone or pyridone analog. In some embodi pulmonary vasculature and exposing downstream disease tar ments, the inhaling step delivers a dose of a least 1.7 mg gets to delivered pirfenidone or pyridone analog. In some pirfenidone or pyridone analog. In some embodiments, the embodiments, the pirfenidone or pyridone analog concentra inhaling step delivers a dose of a least 93 mg pirfenidone or tion is greater than about 1.72 mg/mL. In some embodiments, pyridone analog. In some embodiments, the inhaling step the pirfenidone or pyridone analog concentration is greater delivers a dose of a least 463 mg pirfenidone or pyridone than about 86 mg/mL. In some embodiments, the pirfenidone analog. In some embodiments, the inhaling step is performed or pyridone analog Solution has a permeantion concentration in less than about 20 minutes. In some embodiments, the from about 30 mM to about 300 mM. In some embodiments, inhaling step is performed in less than about 10 minutes. In the permeant ion is chloride or bromide. In some embodi Some embodiments, the inhaling step is performed in less ments, the pirfenidone or pyridone analog solution has a pH than about 7.5 minutes. In some embodiments, the inhaling from about 4.0 to about 8.0. In some embodiments, the pir step is performed in less than about 5 minutes. In some fenidone or pyridone analog solution has an osmolality from embodiments, the inhaling step is performed in less than about 100 mOsmol/kg to about 1000 mOsmol/kg. In some about 2.5 minutes. In some embodiments, the inhaling step is embodiments, the pirfenidone or pyridone analog Solution performed in less than about 1.5 minutes. In some embodi has an osmolality from about 50 mOsmol/kg to about 5000 ments, the inhaling step is performed in less than about 30 mOsmol/kg. In some embodiments, the pirfenidone or pyri seconds. In some embodiments, the inhaling step is per done analog solution has a taste masking agent. In some US 2015/O 196543 A1 Jul. 16, 2015

embodiments, the taste masking agent is selected from the done or pyridone analog Solution has an osmolality from group consisting of lactose, Sucrose, dextrose, Saccharin, about 50 mOsmol/kg to about 5000 mOsmol/kg. In some aspartame. Sucrulose, ascorbate and citrate. In some embodi embodiments, the aerosol further comprises a taste masking ments, the method further comprises administering a muco agent. In some embodiments, the taste masking agent is lytic agent Suitable for pulmonary delivery. In some embodi selected from the group consisting of lactose. Sucrose, dex ments, the mucolytic agent is inhaled separately from the trose, saccharin, aspartame. Sucrulose, ascorbate and citrate. pirfenidone or pyridone analog Solution. In some embodi In some embodiments, the method further comprises admin ments, the method further comprises administering a second istering a mucolytic agent Suitable for intranasal delivery. In anti-fibrotic agent Suitable for pulmonary delivery. In some Some embodiments, the method further comprises adminis embodiments, the method further comprises administering a tering a second anti-fibrotic agent Suitable for intranasal second anti-inflammatory agent Suitable for pulmonary deliv delivery. In some embodiments, the method further com ery. In some embodiments, the extrapulmonary disease target prises administering a second anti-inflammatory agent Suit is the heart. In some embodiments, the extrapulmonary dis able for intranasal delivery. In some embodiments, the neu ease target is the kidney. In some embodiments, the extrapul rologic disease is multiple Sclerosis. In some embodiments, monary disease target is the liver. the aerosol comprises particles having a mean aerodynamic 0054. In any of the methods described herein using an diameter from about 1 micron to about 20 microns. In some aerosol or nebeulizer to deliver a pirfenidone or pyridone embodiments, the aerosol has a mean particle size from about analog compound to the lungs, the aerosol comprises par 1 microns to about 20 microns Volumetric mean diameter and ticles having a mean aerodynamic diameter from about 1 a particle size geometric standard deviation of less than or micronto about 5 microns. In some embodiments, the aerosol equal to 3 microns. In some embodiments, the inhaling step has a mean particle size from about 1 microns to about 5 delivers a dose of a least 6.8 mcg pirfenidone or pyridone microns Volumetric mean diameter and a particle size geo analog. In some embodiments, the inhaling step delivers a metric standard deviation of less than or equal to 3 microns. In dose of a least 340 mcg pirfenidone or pyridone analog. In Some embodiments, the inhaling step delivers a dose of a least Some embodiments, the inhaling step delivers a dose of a least 6.8 mcg pirfenidone or pyridone analog. In some embodi 740 mcg pirfenidone or pyridone analog. In some embodi ments, the inhaling step delivers a dose of a least 340 mcg ments, the inhaling step delivers a dose of a least 1.7 mg pirfenidone or pyridone analog. In some embodiments, the pirfenidone or pyridone analog. In some embodiments, the inhaling step delivers a dose of a least 740mcg pirfenidone or inhaling step delivers a dose of a least 93 mg pirfenidone or pyridone analog. In some embodiments, the inhaling step pyridone analog. In some embodiments, the inhaling step delivers a dose of a least 17 mg pirfenidone or pyridone delivers a dose of a least 463 mg pirfenidone or pyridone analog. In some embodiments, the inhaling step delivers a analog. In some embodiments, the inhaling step is performed dose of a least 93 mg pirfenidone or pyridone analog. In some in less than about 20 minutes. In some embodiments, the embodiments, the inhaling step delivers a dose of a least 463 inhaling step is performed in less than about 10 minutes. In mg pirfenidone or pyridone analog. In some embodiments, Some embodiments, the inhaling step is performed in less the inhaling step is performed in less than about 20 minutes. than about 7.5 minutes. In some embodiments, the inhaling In some embodiments, the inhaling step is performed in less step is performed in less than about 5 minutes. In some than about 10 minutes. In some embodiments, the inhaling embodiments, the inhaling step is performed in less than step is performed in less than about 7.5 minutes. In some about 2.5 minutes. In some embodiments, the inhaling step is embodiments, the inhaling step is performed in less than performed in less than about 1.5 minutes. In some embodi about 5 minutes. In some embodiments, the inhaling step is ments, the inhaling step is performed in less than about 30 performed in less than about 2.5 minutes. In some embodi seconds. In some embodiments, the inhaling step is per ments, the inhaling step is performed in less than about 1.5 formed in less than about 5 breaths. In some embodiments, minutes. In some embodiments, the inhaling step is per the inhaling step is performed in less than about 3 breaths. formed in less than about 30 seconds. In some embodiments, 0056. In some embodiments, described herein is a method the inhaling step is performed in less than about 5 breaths. In to administer an anti-demylination agent to nasal cavity of a Some embodiments, the inhaling step is performed in less patient, comprising: introducing in a nebulizer a pirfenidone than about 3 breaths. or pyridone analog Solution having a concentration greater 0055. In one aspect, described herein is a method to treat a than about 34 mcg/mL, having an osmolality greater than neurologic disease comprising intranasal inhalation of an about 100 mOsmol/kg, and having a pH greater than about aerosol of pirfenidone or pyridone analog Solution having a 4.0. In some embodiments, the pirfenidone or pyridone ana concentration greater than about 34 mcg/mL, having an log concentration is greater than about 1.72 mg/mL. In some osmolality greater than about 100 mOsmol/kg, and having a embodiments, the pirfenidone or pyridone analog concentra pH greater than about 4.0. In some embodiments, the pirfeni tion is greater than about 86 mg/mL. In some embodiments, done or pyridone analog concentration is greater than about the pirfenidone or pyridone analog solution has a permeant 1.72 mg/mL. In some embodiments, the pirfenidone or pyri ion concentration from about 30 mM to about 300 mM. In done analog concentration is greater than about 86 mg/mL. In Some embodiments, the permeantion is chloride or bromide. Some embodiments, the pirfenidone or pyridone analog solu In some embodiments, the pirfenidone or pyridone analog tion has a permeant ion concentration from about 30 mM to solution has a pH from about 4.0 to about 8.0. In some about 300 mM. In some embodiments, the permeant ion is embodiments, the pirfenidone or pyridone analog Solution chloride or bromide. In some embodiments, the pirfenidone has an osmolality from about 100 mOsmol/kg to about 1000 or pyridone analog solution has a pH from about 4.0 to about mOsmol/kg. In some embodiments, the pirfenidone or pyri 8.0. In some embodiments, the pirfenidone or pyridone ana done analog solution has an osmolality from about 50 mOS log solution has an osmolality from about 100 mOsmol/kg to mol/kg to about 5000 mOsmol/kg. In some embodiments, the about 1000 mOsmol/kg. In some embodiments, the pirfeni Solution further comprises a taste masking agent. In some US 2015/O 196543 A1 Jul. 16, 2015

embodiments, the taste masking agent is selected from the pyridone analog concentration is greater than about 86 group consisting of lactose, Sucrose, dextrose, Saccharin, mg/mL. In some embodiments, the pirfenidone or pyridone aspartame. Sucrulose, ascorbate and citrate. In some embodi analog Solution has a permeant ion concentration from about ments, the method further comprises administering a muco 30 mM to about 300 mM. In some embodiments, the per lytic agent Suitable for intranasal delivery. In some embodi meant ion is chloride or bromide. In some embodiments, the ments, the mucolytic agent is inhaled separately from the pirfenidone or pyridone analog Solution has a pH from about pirfenidone or pyridone analog Solution. In some embodi 4.0 to about 8.0. In some embodiments, the pirfenidone or ments, the method further comprises administering a second pyridone analog Solution has an osmolality from about 100 agent suitable for intranasal delivery. mOsmol/kg to about 1000 mOsmol/kg. In some embodi 0057. In any of the methods described herein involving ments, the pirfenidone or pyridone analog solution has an introducing in a nebulizer a pirfenidone or pyridone analog osmolality from about 50 mOsmol/kg to about 5000 mOs Solution, the method involves a step of opening a sterile mol/kg. In some embodiments, the solution further comprises single-use container containing between about 0.5 mL to a taste masking agent. In some embodiments, the taste mask about 10 mL of a solution of pirfenidone or pyridone analog ing agent is selected from the group consisting of lactose, solution for introduction into a nebulizer. Sucrose, dextrose, saccharin, aspartame. Sucrulose, ascorbate 0058. In any of the methods described herein involving a and citrate. In some embodiments, the kit further comprises a nebulizer, the aerosol comprises particles having a mean mucolytic agent Suitable for pulmonary delivery. In some aerodynamic diameter from about 1 micron to about 5 embodiments, the kit further comprises a second anti-fibrotic microns. In some embodiments, the aerosol has a mean par agent Suitable for pulmonary delivery. In some embodiments, ticle size from about 1 microns to about 5 microns volumetric the kit further comprises a second anti-inflammatory agent mean diameter and a particle size geometric standard devia suitable for pulmonary delivery. tion of less than or equal to 3 microns. In some embodiments, 0060. In another aspect, provided herein is a kit compris the aerosol comprises particles having a mean aerodynamic ing: a pharmaceutical composition comprising a pirfenidone diameter from about 1 micron to about 20 microns. In some or pyridone analog Solution in a sterile container, wherein the embodiments, the aerosol has a mean particle size from about pirfenidone or pyridone analog Solution has a concentration 1 microns to about 20 microns Volumetric mean diameter and greater than about 34 mcg/mL, an osmolality greater than a particle size geometric standard deviation of less than or about 100 mOsmol/kg, and a pH greater than about 4.0, and a equal to 3 microns. In some embodiments, the inhaling step nebulizer adapted to aerosolize the pirfenidone or pyridone delivers a dose of a least 6.8 mcg pirfenidone or pyridone analog solution for delivery to the nasal cavity through intra analog. In some embodiments, the inhaling step delivers a nasal inhalation. dose of a least 340 mcg pirfenidone or pyridone analog. In 0061. In some embodiments, the pirfenidone or pyridone Some embodiments, the inhaling step delivers a dose of a least analog concentration is greater than about 1.72 mg/mL. In 740 mcg pirfenidone or pyridone analog. In some embodi Some embodiments, the pirfenidone or pyridone analog con ments, the inhaling step delivers a dose of a least 1.7 mg centration is greater than about 86 mg/mL. In some embodi pirfenidone or pyridone analog. In some embodiments, the ments, the pirfenidone or pyridone analog solution has a inhaling step delivers a dose of a least 93 mg pirfenidone or permeant ion concentration from about 30 mM to about 300 pyridone analog. In some embodiments, the inhaling step mM. In some embodiments, the permeant ion is chloride or delivers a dose of a least 463 mg pirfenidone or pyridone bromide. In some embodiments, the pirfenidone or pyridone analog. In some embodiments, the inhaling step is performed analog solution has a pH from about 4.0 to about 8.0. In some in less than about 20 minutes. In some embodiments, the embodiments, the pirfenidone or pyridone analog Solution inhaling step is performed in less than about 10 minutes. In has an osmolality from about 100 mOsmol/kg to about 1000 Some embodiments, the inhaling step is performed in less mOsmol/kg. In some embodiments, the pirfenidone or pyri than about 7.5 minutes. In some embodiments, the inhaling done analog solution has an osmolality from about 50 mOS step is performed in less than about 5 minutes. In some mol/kg to about 5000 mOsmol/kg. In some embodiments, the embodiments, the inhaling step is performed in less than Solution further comprises a taste masking agent. In some about 2.5 minutes. In some embodiments, the inhaling step is embodiments, the taste masking agent is selected from the performed in less than about 1.5 minutes. In some embodi group consisting of lactose, Sucrose, dextrose, Saccharin, ments, the inhaling step is performed in less than about 30 aspartame. Sucrulose, ascorbate and citrate. In some embodi seconds. In some embodiments, the inhaling step is per ments, the kit further comprises a mucolytic agent Suitable for formed in less than about 5 breaths. In some embodiments, intranasal delivery. In some embodiments, the kit further the inhaling step is performed in less than about 3 breaths. In comprises a second anti-fibrotic agent Suitable for intranasal Some embodiments, the inhaling step is performed in one delivery. In some embodiments, the kit further comprises a breath. second anti-inflammatory agent Suitable for intranasal deliv 0059. In one aspect, provided herein is a kit comprising: a ery. pharmaceutical composition comprising a pirfenidone or 0062. In one aspect, described herein is a method for treat pyridone analog solution in a sterile container, wherein the ing lung disease, comprising administering pirfenidone or pirfenidone or pyridone analog Solution has a concentration pyridone analog to a middle to lower respiratory tract of a greater than about 34 mcg/mL, an osmolality greater than Subject having or Suspected of having interstitial lung disease about 100 mOsmol/kg, and a pH greater than about 4.0, and a through oral inhalation of an aerosol comprising pirfenidone nebulizer adapted to aerosolize the pirfenidone or pyridone or pyridone analog, wherein the disease is selected from analog solution for delivery to the middle to lower respiratory interstitial lung disease, including idiopathic pulmonary tract through oral inhalation. In some embodiments, the pir fibrosis and radiation therapy-induced fibrosis; chronic fenidone or pyridone analog concentration is greater than obstructive pulmonary disease; and asthma. In some embodi about 1.72 mg/mL. In some embodiments, the pirfenidone or ments, the Subject is identified as having interstitial lung US 2015/O 196543 A1 Jul. 16, 2015

disease. In some embodiments, the Subject is identified as tent is greater than about 17 mg. In some embodiments, the having idiopathic pulmonary fibrosis. In some embodiments, pirfenidone or pyridone analog content is greater than about the Subject is identified as having radiation therapy-induced 463 mg. In some embodiments, the dry powder further com pulmonary fibrosis. In some embodiments, the Subject is prises a blending agent. In some embodiments, the blending identified as having chronic obstructive pulmonary disease. agent is lactose. In some embodiments, the pulmonary dis In some embodiments, the Subject is identified as having ease is interstitial lung disease. In some embodiments, the chronic bronchitis. In some embodiments, the Subject is iden interstitial lung disease is idiopathic pulmonary fibrosis. In tified as having asthma. In some embodiments, the Subject is Some embodiments, the interstitial lung disease is radiation a subject being mechanically ventilated. therapy-induced pulmonary fibrosis. In some embodiments, 0063 A method for treating extrapulmonary disease, the pulmonary disease is chronic obstructive pulmonary dis comprising administering pirfenidone orpyridone analog to a ease. In some embodiments, the pulmonary disease is chronic middle to lower respiratory tract of a Subject having or Sus bronchitis. In some embodiments, the pulmonary disease is pected of having extrapulmonary fibrosis, inflammatory and/ asthma. In some embodiments, the aerosol comprises par or toxicity-related diseases through oral inhalation of an aero ticles having a mean aerodynamic diameter from about 1 Sol comprising pirfenidone or pyridone analog for purposes micronto about 5 microns. In some embodiments, the aerosol of pulmonary vascular absorption and delivery to extrapul has a mean particle size from about 1 microns to about 5 monary diseased tissues, wherein the disease is selected from microns Volumetric mean diameter and a particle size geo cardiac fibrosis, kidney fibrosis, hepatic fibrosis, kidney tox metric Standard deviation of less than or equal to 3 microns. In icity and heart toxicity. In some embodiments, the Subject is Some embodiments, the inhaling step delivers a dose of a least identified as having cardiac fibrosis. In some embodiments, 6.8 mcg pirfenidone or pyridone analog. In some embodi the Subject is identified as having kidney fibrosis. In some ments, the inhaling step delivers a dose of a least 340 mcg embodiments, the Subject is identified as having hepatic pirfenidone or pyridone analog. In some embodiments, the fibrosis. In some embodiments, the subject is identified as inhaling step delivers a dose of a least 740mcg pirfenidone or having kidney toxicity. In some embodiments, the Subject is pyridone analog. In some embodiments, the inhaling step identified as having heart toxicity. In some embodiments, the delivers a dose of a least 1.7 mg pirfenidone or pyridone Subject is a Subject being mechanically ventilated. analog. In some embodiments, the inhaling step delivers a 0064. In one aspect, described herein is a method for treat dose of a least 93 mg pirfenidone or pyridone analog. In some ing neurologic disease, comprising administering pirfeni embodiments, the inhaling step delivers a dose of a least 463 done or pyridone analog to the nasal cavity of a subject having mg pirfenidone or pyridone analog. In some embodiments, or Suspected of having neurologic disease through intranasal the inhaling step is performed in less than about 5 breaths. In inhalation of an aerosol comprising pirfenidone or pyridone Some embodiments, the inhaling step is performed in less analog for purposes of nasal vascular absorption and delivery than about 3 breaths. In some embodiments, the inhaling step to central nervous system, wherein the disease is multiple is performed in less than about 2 breaths. In some embodi Sclerosis. In some embodiments, the Subject is identified as ments, the inhaling step is performed in one breath. having multiple Sclerosis. In some embodiments, the Subject 0067. In one aspect, provided herein is a method to admin is a Subject being mechanically ventilated. ister an anti-fibrotic agent to lungs of a subject, comprising: 0065. In one aspect, described herein is a pharmaceutical introducing in a dry powder inhalerapirfenidone or pyridone composition for pulmonary delivery, comprising a dry pow analog dry powder formulation having a dosage content der containing pirfenidone or pyridone analog having a dos greater than about 1%. In another aspect, provided herein is a age content greater than about 1%. In some embodiments, the method to administer an anti-inflammatory agent to lungs of pirfenidone or pyridone analog dose content is greater than a subject, comprising: introducing in a dry powder inhaler a about 6.8 mcg. In some embodiments, the pirfenidone or pirfenidone or pyridone analog dry powder formulation hav pyridone analog content is greater than about 340 mcg. In ing a dosage content greater than about 1%. In yet another Some embodiments, the pirfenidone or pyridone analog con aspect, provided herein is a method to treat an extrapulmo tent is greater than about 17 mg. In some embodiments, the nary disease target comprising inhalation of a dry powder pirfenidone or pyridone analog content is greater than about aerosol containing pirfenidone or pyridone dosage content 463 mg. In some embodiments, the powder further comprises greater than about 1%. In some embodiments, the extrapul a blending agent. In some embodiments, the blending agentis monary disease target is the heart. In some embodiments, the selected from the group consisting of lactose. extrapulmonary disease target is the kidney. In some embodi 0066. In one aspect, described herein is a pharmaceutical ments, the extrapulmonary disease target is the liver. In yet composition for pulmonary delivery, comprising a dry pow another aspect, provided herein is a method to treat a neuro der containing pirfenidone or pyridone analog having a dos logic disease comprising intranasal inhalation of a dry pow age content greater than about 1%. In yet another aspect, der aerosol containing pirfenidone or pyridone dosage con described herein is a sterile, single-use container comprising tent greater than about 1%. In some embodiments, the from about 0.5 mg to about 100 mg dry powder containing neurologic disease is multiple Sclerosis. In yet another aspect, pirfenidone or pyridone analog having a dosage content provided herein is a method to administer an anti-demylina greater than about 1%. In a further aspect, described is a tion agent to nasal cavity of a subject, comprising: introduc method to treat a pulmonary disease comprising inhalation of ing in a dry powder inhaler a pirfenidone or pyridone analog a dry powder aerosol containing pirfenidone or pyridone dos dry powder formulation having a dosage content greater than age content greater than about 1%. In some embodiments, the about 1%. In some embodiments, the pirfenidone or pyridone pirfenidone or pyridone analog dose content is greater than analog dose content is greater than about 6.8 mcg. In some about 6.8 mcg. In some embodiments, the pirfenidone or embodiments, the pirfenidone or pyridone analog content is pyridone analog content is greater than about 340 mcg. In greater than about 340 mcg. In some embodiments, the pir Some embodiments, the pirfenidone or pyridone analog con fenidone or pyridone analog content is greater than about 17 US 2015/O 196543 A1 Jul. 16, 2015 mg. In some embodiments, the pirfenidone or pyridone ana pyridone analog to a middle to lower respiratory tract of a log content is greater than about 463 mg. In some embodi Subject having or Suspected of having interstitial lung disease ments, the dry powder comprises a blending agent. In some through oral inhalation of an aerosol comprising pirfenidone embodiments, the blending agent is lactose. In some embodi or pyridone analog, wherein the disease is selected from ments, the aerosol comprises particles having a mean aero interstitial lung disease, including idiopathic pulmonary dynamic diameter from about 1 micronto about 5 microns. In fibrosis and radiation therapy-induced fibrosis; chronic Some embodiments, the aerosol has a mean particle size from obstructive pulmonary disease; and asthma. In some embodi about 1 microns to about 5 microns Volumetric mean diameter ments, the Subject is identified as having interstitial lung and a particle size geometric standard deviation of less than or disease. In some embodiments, the Subject is identified as equal to 3 microns. In some embodiments, the aerosol com having idiopathic pulmonary fibrosis. In some embodiments, prises particles having a mean aerodynamic diameter from the Subject is identified as having radiation therapy-induced about 1 micron to about 20 microns. In some embodiments, pulmonary fibrosis. In some embodiments, the Subject is the aerosol has a mean particle size from about 1 microns to identified as having chronic obstructive pulmonary disease. about 20 microns Volumetric mean diameter and a particle In some embodiments, the Subject is identified as having size geometric standard deviation of less than or equal to 3 chronic bronchitis. In some embodiments, the Subject is iden microns. In some embodiments, the inhaling step delivers a tified as having asthma. In some embodiments, the Subject is dose of a least 6.8 mcg pirfenidone or pyridone analog. In a Subject being mechanically ventilated. Some embodiments, the inhaling step delivers a dose of a least 0070. In one aspect, described herein is a method for treat 340 mcg pirfenidone or pyridone analog. In some embodi ing lung disease, comprising administering pirfenidone or ments, the inhaling step delivers a dose of a least 740 mcg pyridone analog to a middle to lower respiratory tract of a pirfenidone or pyridone analog. In some embodiments, the Subject having or Suspected of having pulmonary disease inhaling step delivers a dose of a least 1.7 mg pirfenidone or through oral inhalation of an aerosol comprising pirfenidone pyridone analog. In some embodiments, the inhaling step or pyridone analog, wherein the pulmonary disease is cancer. delivers a dose of a least 17 mg pirfenidone or pyridone In some embodiments, the therapeutic target for said pulmo analog. In some embodiments, the inhaling step delivers a nary cancer is tumor stroma. In some embodiments, the Sub dose of a least 93 mg pirfenidone or pyridone analog. In some ject is a Subject being mechanically ventilated. embodiments, the inhaling step delivers a dose of a least 463 0071. In one aspect, described herein is a method for treat mg pirfenidone or pyridone analog. In some embodiments, ing lung disease, comprising administering pirfenidone or the inhaling step is performed in less than about 5 breaths. In pyridone analog to a middle to lower respiratory tract of a Some embodiments, the inhaling step is performed in less Subject having or Suspected of having pulmonary disease than about 3 breaths. In some embodiments, the inhaling step through oral inhalation of an aerosol comprising pirfenidone is performed in less than about 2 breaths. In some embodi or pyridone analog, wherein the pulmonary disease is pulmo ments, the inhaling step is performed in one breath. In some nary hypertension. In some embodiments, the Subject is a embodiments, the method further comprises the step of open Subject being mechanically ventilated. ing a single-use dry powder container holding between about 0072. In one aspect, described herein is a method for treat 0.5 mg to about 10 mg dry powder formulation containing ing extrapulmonary disease, comprising administering pir pirfenidone or pyridone analog for introduction into a dry fenidone or pyridone analog to a middle to lower respiratory powder inhaler. tract of a Subject having or Suspected of having extrapulmo 0068. In one aspect, described herein is a kit comprising: a nary fibrosis, inflammatory and/or toxicity-related diseases pharmaceutical composition comprising a dry powder pir through oral inhalation of an aerosol comprising pirfenidone fenidone or pyridone analog formulation in a container, or pyridone analog for purposes of pulmonary vascular wherein the pirfenidone or pyridone analog dosage content is absorption and delivery to extrapulmonary diseased tissues, greater than about 1%; and a dry powder inhaler adapted to wherein the disease is selected from cardiac fibrosis, kidney aerosolize the pirfenidone or pyridone analog dry powder fibrosis, hepatic fibrosis, kidney toxicity and heart toxicity. formulation for delivery to the middle to lower respiratory 0073. In some embodiments, the subject is identified as tract through oral inhalation. In another aspect, described having cardiac fibrosis. In some embodiments, the Subject is herein is a kit comprising: a pharmaceutical composition identified as having kidney fibrosis. In some embodiments, comprising a dry powder pirfenidone or pyridone analog the Subject is identified as having hepatic fibrosis. In some formulation in a container, wherein the pirfenidone or pyri embodiments, the Subject is identified as having kidney tox done analog dosage content is greater than about 1%, and a icity. In some embodiments, the Subject is identified as having dry powder inhaler adapted to aerosolize the pirfenidone or heart toxicity. In some embodiments, the Subject is a subject pyridone analog dry powder formulation for delivery to the being mechanically ventilated. nasal cavity through intranasal inhalation. In some embodi 0074. In one aspect, described herein is a method for treat ments, the pirfenidone or pyridone analog dose content is ing neurologic disease, comprising administering pirfeni greater than about 6.8 mcg. In some embodiments, the pir done or pyridone analog to the nasal cavity of a subject having fenidone or pyridone analog content is greater than about 340 or Suspected of having neurologic disease through intranasal mcg. In some embodiments, the pirfenidone or pyridone ana inhalation of an aerosol comprising pirfenidone or pyridone log content is greater than about 17 mg. In some embodi analog for purposes of nasal vascular absorption and delivery ments, the pirfenidone or pyridone analog content is greater to central nervous system, wherein the disease is multiple than about 463 mg. In some embodiments, the powderfurther Sclerosis. In some embodiments, the Subject is identified as comprises a blending agent. In some embodiments, the blend having multiple Sclerosis. In some embodiments, the Subject ing agent is lactose. is a Subject being mechanically ventilated. 0069. In one aspect, described herein is a method for treat 0075. In one aspect, described herein is a method of ing lung disease, comprising administering pirfenidone or administering pirfenidone or pyridone analog to treat a US 2015/O 196543 A1 Jul. 16, 2015 patient with idiopathic pulmonary fibrosis (IPF), wherein the pirfenidone or pyridone analog include, but are not limited to patient avoids abnormal liver function exhibited by a grade 2 any one or more of the following: dyspepsia, nausea, diarrhea, or higher abnormality following oral administration in one or gastroesophageal reflux disease (GERD) and Vomiting. In more biomarkers of liver function after pirfenidone or pyri Some embodiments, less than 360 mg per day of pirfenidone done analog administration, comprising administering to said or pyridone analog is delivered to the patient by inhalation. In patient pirfenidone or pyridone analog at doses less than 300 some embodiments, less than 1000 mg, less than 900 mg, less mg per day. In some embodiments, "Grade 2 liver function 600 mg. or less than 300 mg per day of pirfenidone or pyri abnormalities' include elevations in alanine transaminase done analog is delivered to the patient by inhalation. In some (ALT), aspartate transaminase (AST), alkaline phosphatase embodiments, less than 300 mg per day of pirfenidone or (ALP), or gamma-glutamyl transferase (GGT) greater than pyridone analog is delivered per dose to the patient by inhla 2.5-times and less than or equal to 5-times the upper limit of lition. In some embodiments, pirfenidone or pyridone analog normal (ULN). Grade 2 liver function abnormalities also is delivered by inhalaltion once per day, twice per day, three include elevations of bilirubin levels greater than 1.5-times time a day, or four time a day. and less than or equal to 3-times the ULN. In some embodi 0079. In some embodiments, up to about 360 mg of pir ments, the pirfenidone or pyridone analog is delivered to the fenidone or pyridone analog is delivered to the patient by patient by oral inhalation or intranasal inhalation. In some inhalation per dose. In some embodiments, about limg to embodiments, said one or more biomarkers of liver function about 360 mg, about 10 mg to about 360 mg, about 20 mg to is selected from the group consisting of alanine transaminase, about 360 mg, about 30 mg to about 360 mg, about 40 mg to aspartate transaminase, bilirubin, and alkaline phosphatase. about 360 mg, about 50 mg to about 360 mg, about 60 mg to In some embodiments, the method further comprises the step about 70 mg, about 80 mg to about 360 mg, about 90 mg to of measuring one or more biomarkers of liver function. In about 360 mg, about 100 mg to about 360 mg, about 120 mg Some embodiments, the blood Cmax following administra to about 360 mg, about 140 mg to about 360 mg, about 160 tion of pirfenidone or pyridone analog is less than 10 mcg/ mg to about 360 mg, about 180 mg to about 360 mg. or about mL. In some embodiments, the blood Cmax following 200 mg to about 360 mg. of pirfenidone or pyridone analog is administration of pirfenidone or pyridone analog is greater delivered to the patient by inhalation per dose. In some than 10 mcg/mL. embodiments, pirfenidone or pyridone analog is delivered by 0076. In one aspect, described herein is a method of inhalation once per day, twice per day, three time a day, or administering pirfenidone or pyridone analog to treat a four time a day. patient with idiopathic pulmonary fibrosis (IPF), wherein the 0080. In one aspect, described herein is a pharmaceutical patient avoids the incidence of photosensitivity reaction composition comprising atherapeutically effective amount of observed following oral administration, comprising adminis an inhaled agent, wherein the agentispirfenidone or pyridone tering to said patient pirfenidone or pyridone analog at doses analog, wherein the agent is in a particle less than 5 microns less than 360 mg per day. In some embodiments, the pirfeni in mass mean aerodynamic diameter or less than 10 microns done or pyridone analog is delivered to the patient by oral Volumetric mean diameter wherein the composition, upon inhalation or intranasal inhalation. In some embodiments, the inhalation, delivers a dose to the lung greater than 1 mcg incidence of photosensitivity reaction adverse events is less pirfenidone or pyridone analog compound per gram of adult than about 12%. In some embodiments, the blood Cmax human lung tissue. following administration of pirfenidone or pyridone analog is I0081. In one aspect, described herein is a pharmaceutical less than 10 mcg/mL. In some embodiments, the blood Cmax composition for aerosol delivery to the lung, comprising a following administration of pirfenidone or pyridone analog is Solution of pirfenidone or pyridone analog containing a diva greater than 10 mcg/mL. lent cation. In some embodiments, the divalent cation is 0077. In one aspect, described herein is a method of selected from the group consisting of calcium, iron, magne administering pirfenidone or pyridone analog to treat a sium, and beryllium. In some embodiments, the ratio of pir patient with idiopathic pulmonary fibrosis (IPF), wherein the fenidone or pyridone analog to divalent cation is within the patient avoids the incidence of phototoxicity observed fol molar range of 1 to about 0.1 to 10, in unit increments of about lowing oral administration, comprising administering to said 0.01. By example, 1 to about 10, 1 to about 9, 1 to about 8, 1 patient pirfenidone or pyridone analog at doses less than 360 to about 7, 1 to about 6, 1 to about 5, 1 to about 4, 1 to about mg per day. In some embodiments, the pirfenidone or pyri 3, 1 to about 2, 1 to about 1.5, 1 to about 1, 1 to about 0.75, 1 done analog is delivered to the patient by oral inhalation or to about 0.5, 1 to about 0.25, and 1 to about 0.1. In some intranasal inhalation. In some embodiments, the incidence of embodiments, the active pharmaceutical ingredientispirfeni photosensitivity reaction adverse events is less than about done or pyridone analog concentration is between 0.1 mg/mL 12%. In some embodiments, the blood Cmax following and 50 mg/mL in unit increments of about 0.01 mg/mL com administration of pirfenidone or pyridone analog is less than position. By example, about 0.1 mg/mL, about 0.5 mg/mL, 10 mcg/mL. In some embodiments, the blood Cmax follow about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 ing administration of pirfenidone or pyridone analog is mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, greater than 10 mcg/mL. about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 15 0078. In one aspect, described herein is a method of mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, administering pirfenidone or pyridone analog to treat a about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 patient with idiopathic pulmonary fibrosis (IPF), wherein the mg/mL, about 50 mg/mL, about 55 mg/mL, and about 60 patient avoids the incidence of gastrointestinal adverse events mg/mL. In some embodiments, the active pharmaceutical observed following oral administration, by delivering pirfeni ingredient is not a salt of pirfenidone or pyridone analog. In done orpyridone analog directly to the lung by oral inhalation Some embodiments, the composition is a stable, water or intranasal inhalation. In some embodiments, gastrointesti soluble formulation. In some embodiments, the osmolality is nal adverse events observed following oral administration of greater than about 50 mOsmol/kg composition in unit incre US 2015/O 196543 A1 Jul. 16, 2015 ments of about 1 mOsmol/kg. By example, greater than about pharmaceutical ingredient. Sparging gases may be selected 50 mOsmol/kg, about 100 mOsmol/kg, about 150 mOsmol/ from the group consisting of carbon dioxide, argon or nitro kg, about 200 mOsmol/kg, about 250 mOsmol/kg, about 300 gen. In some embodiments, oxygen is reduced by sparging mOsmol/kg, about 350 mOsmol/kg, about 400 mOsmol/kg, the formulation diluent after addition of the active pharma about 450 mOsmol/kg, about 500 mOsmol/kg, about 550 ceutical ingredient. Sparging gases may be selected from the mOsmol/kg, about 600 mOsmol/kg, about 650 mOsmol/kg, group consisting of carbon dioxide, argon or nitrogen. In about 700 mOsmol/kg, about 750 mOsmol/kg, about 800 Some embodiments, oxygen exposure is reduced by replacing mOsmol/kg, about 850 mOsmol/kg, about 900 mOsmol/kg, the ambient gas headspace of the formulation container with about 950 mOsmol/kg, about 1000 mOsmol/kg, greater than an inert gas. Inert gases may be selected from the group about 1500 mOsmol/kg, about 2000 mOsmol/kg, about 2500 consisting of argon or nitrogen. mOsmol/kg, greater than about 3000 mOsmol/kg, about 3500 I0084. In some embodiments, oxygen exposure is reduced mOsmol/kg, about 4000 mOsmol/kg, greater than about 4500 by replacing the ambient gas headspace of the primary pack mOsmol/kg, about 5000 mOsmol/kg, about 5500 mOsmol/ aging container with an inert gas. Inert gases may be selected kg, about 6000 mOsmol/kg, or greater than about 6000 mOs from the group consisting of argon or nitrogen. mol/kg. In some embodiments, the pH is greater than about I0085. In some embodiments, oxygen exposure is reduced 3.0 in pH unit increments of about 0.1. By example, a pH of by inserting the primary packaging into a gas-impermeable about 3, a pH of about 3.5, a pH of about 4, a pH of about 4.5, Secondary packaging container. a pH of about 5, a pH of about 5.5, a pH of about 6, a pH of I0086. In some embodiments, oxygen exposure is reduced about 6.5, a pH of about 7, a pH of about 7.5, a pH of about 8, by replacing the ambient gas headspace of the secondary a pH of about 8.5, a pH of about 9, a pH of about 9.5, a pH of packaging with an inert gas. Inert gases may be selected from about 10 a pH of about 10.5, and a pH of about 11. In some the group consisting of argon or nitrogen. embodiments, the pH is balanced by the inclusion of an organic buffer selected from the group consisting of citric I0087. In some embodiments, the aerosol for delivery to the acid, citrate, malic acid, malate, pyridine, formic acid, for lungs of a mammal described herein contains a fine particle mate, piperazine. Succinic acid, Succinate, histidine, maleate, fraction between 10 and 100% with increment units of 1%. bis-tris, pyrophosphate, phosphoric acid, phosphate, PIPES, By example, about 10%, about 15%, about 20%, about 25%, ACES, MES, cacodylic acid, carbonic acid, carbonate, ADA about 30%, about 35%, about 40%, about 45%, about 50%, (N-(2-Acetamido)-2-iminodiacetic acid). In some embodi about 55%, about 60%, about 65%, about 70%, about 75%, ments, the pirfenidone or pyridone analog solution contains a about 80%, about 85%, about 90%, about 95%, and about permeant ion concentration. In some embodiments, the per 100%. In some embodiments, the fine particle dose is meant ion is selected from the group consisting of bromine, between about 0.1 mg to about 360 mgs prifenidone or pyri chloride, and lithium. In some embodiments, the permeant done analog, in 0.1 mg increments. By example, about 0.1 ion concentration is from about 30 mM to about 300 mM in mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about about 0.1 mM increments. By example, about 30 mM, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 40 mM, about 50 mM, about 60 mM, about 70 mM, about 80 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, mM, about 90 mM, about 100 mm, about 150 mM, about 200 about 14 mg, about 15 mg, about 16 mg, about 17 mg, about mM, about 250 mM, and about 300 mM. In some embodi 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg. ments, the composition further comprises a taste masking about 35 mg, about 40 mg, about 45 mg, about 50 mg, about agent. In some embodiments, the taste masking agent is 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg. selected from the group consisting of lactose. Sucrose, dex about 150 mg, about 200 mg, about 220 mg, about 240 mg. trose, saccharin, aspartame. Sucrulose, ascorbate, multivalent about 260 mg, about 280 mg, about 300 mg, about 320 mg. cation and citrate. In some embodiments, the taste masking about 340 mg. or about 360 mg. agent concentration is from 0.01 mM to about 50 mM in about I0088. In some embodiments, the compositions further 0.01 mM increments. By examples, about 0.01 mM, about comprise a mucolytic agent Suitable for pulmonary delivery. 0.05 mM, about 0.1 mM, about 0.2 mM, about 0.3 mM, about In some embodiments, the compositions further comprise a 0.4 mM, about 0.5 mM, about 0.6 mM, about 0.7 mM, about second anti-fibrotic agent Suitable for pulmonary delivery. In 0.8 mM, about 0.9 mM, about 1 mM, about 2 mM, about 3 Some embodiments, the compositions further comprise a sec mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, ond anti-inflammatory agent Suitable for pulmonary delivery. about 8 mM, about 9 mM, about 10 mM, about 15 mM, about I0089. These and other aspects of the invention will be 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 evident upon reference to the following detailed description. mM, about 45 mM, and about 50 mM. All of the U.S. patents, U.S. patent application publications, 0082 In some embodiments, the formulations described U.S. patent applications, foreign patents, foreign patent appli herein are filled into a primary package. In some embodi cations and non-patent publications referred to in this speci ments, primary packaging material is taken from the group fication, are incorporated herein by reference in their entirety, consisting of glass or plastic, wherein plastic materials may as if each was incorporated individually. Aspects of the inven be selected from the group consisting of low-density polyeth tion can be modified, if necessary, to employ concepts of the ylene (LDPE), high-density polypropylene (HDPP), or high various patents, applications and publications to provide yet density polyethylene (HDPE). In some embodiments, the further embodiments of the invention. primary packaging consists of a vial, Syringe or ampoule. In Some embodiments, the composition is protected from light. BRIEF DESCRIPTION OF THE FIGURES 0083. In some embodiments, the compositions described 0090 FIG. 1 shows a modeled nebulized aerosol admin herein are formulated under or to result in conditions of istration of pirfenidone and oral administration of pirfenidone reduced oxygen. In some embodiments, oxygen is reduced by to a human Subject. Model incorporates Scaled pharmacoki sparging the formulation diluent prior to addition of the active netics from Example 6. US 2015/O 196543 A1 Jul. 16, 2015 20

0091 FIG. 2. Modeled Nebulized Aerosol Administration regions of the organ or a failure to halt the repair process after to a Human -50 mcg/gram target lung tissue Cmax and cor the injury has healed. In Such cases the Scarring process related lung tissue and plasma pharmacokinetics. Model becomes uncontrolled and deregulated. In some forms of incorporates Scaled pharmacokinetics from Examples 6 and fibrosing disease Scarring remains localized to a limited 7. region, but in others it can affect a more diffuse and extensive 0092 FIG. 3. Hydroxyproline results from bleomycin area resulting in direct or associated organ failure. model of pulmonary fibrosis. Demonstrates pirfenidone 0097. In neurologic disease, inflammatory destruction of U-shaped dose response. Also indicates that Small dose, myelin (demylination) is considered the initial event in dis direct-lung aerosol delivery enables pirfenidone anti-fibrotic eases such as multiple Sclerosis. Demyelination causes scar efficacy within limitations of the AUC-dependent, U-shaped ring and hardening (Sclerosis) of nerve tissue in the spinal dose response. Hydroxyrproline delta values were obtained cord, brain, and optic nerves. Demyelination slows conduc by first Subtracting sham results, and then Subtracting that tion of nerve impulses, which results in weakness, numbness, value from the bleomycin-only control. Obtained p-values: pain, and vision loss. i=0.012 (same lung Cmax), *=0.084 (same lung Cmax), and 0098. In epithelial injury, epithelial cells are triggered to 4–0.075 (same plasma AUC); a. Trivdei etal, Nanotechnol release several pro-fibrotic mediators, including the potent ogy. 23(50):505101, 2012. fibroblast growth factors transforming growth factor-beta 0093 FIG. 4. Histopathology (fibrosis score) results from (TGF-beta), tumor necrosis factor (TNF), endothelin, cytok bleomycin model of pulmonary fibrosis. Demonstrates pir ines, metalloproteinases and the coagulation mediator tissue fenidone U-shaped dose response. Also indicates that Small factor. Importantly, the triggered epithelial cell becomes Vul dose, direct-lung aerosol delivery enables pirfenidone anti nerable to apoptosis, and together with an apparent inability fibrotic efficacy within limitations of the AUC-dependent, to restore the epithelial cell layer are the most fundamental U-shaped dose response. Fibrosis score delta values were abnormalities in fibrotic disease. In the case of demylination, obtained by first Subtracting sham results, and then subtract abnormal TNF expression or activity is considered a primary ing that value from the bleomycin-only control. Obtained cause of multiple Sclerosis and other neurologic disorders, p-values: it-0.007 (same lung Cmax), *=0.042 (same lung Such as rheumatoid disease. Cmax), and 4–0.143 (same plasma AUC). 0099. In conditions such as pulmonary, kidney, cardiac 0094 FIG.5. Modeled human inhaled aerosol pirfenidone and ocular fibrosis, multiple Sclerosis and rheumatoid dis pharmacokinetics. Demonstrates that aerosol inhalation ease, physiological responses characterized by control of pro enables abroad pirfenidone therapeutic range within the limi inflammatory and pro-fibrotic factors with pyridone analogs, tations of the pirfenidone U-shaped dose response. Model Such as pirfenidone may be beneficial to attenuate and/or incorporates Scaled pharmacokinetics from Example 8 Inha reverse fibrosis and demyelination. Therapeutic strategies lation offers a broad therapeutic range within limitations of exploiting such pyridone analog and/or pirfenidone effects in the pirfenidone U-shaped dose response. Compared to the these and other indications are contemplated herein. 801 mg oral pirfenidone dose (taken with food; Rubino et al., 0100 TNF-alpha is expressed in asthmatic airways and Pulm Pharmacol Ther. 22(4):279-85, 2009), a 120 mg pir may play a key role in amplifying asthmatic inflammation fenidone RDD inhaled over 5 minutes results in an equivalent through the activation of NF-kappaB, AP-1 and other tran plasma AUC and 43-fold greater lung tissue Cmax; a 50 mg scription factors. IgE receptor activation induces TNF-alpha pirfenidone RDD inhaled over 5 minutes results in a 2.4-fold release from human lung tissue and upregulates eosinophil lowerplasma AUC and 18-fold greater lung tissue Cmax; and TNF mRNA levels. TNF-alpha causes transient bronchial a 2.5 mg pirfenidone RDD inhaled over 1 minute results in a hyper-responsiveness likely through a muscarinic receptor 50-fold lower plasma AUC and equivalent lung tissue Cmax. expression-mediated response. Upper panel inset illustrates pirfenidone pharmacokinetics 0101 TNF-alpha is also believed to play a central role in between 0-10 mcg/gram human lung tissue pirfenidone and the pathophysiology of COPD. It is produced by alveolar 0-4 hours. macrophages, neutrophils, T cells, mast cells and epithelial cells following contact with different pollutants including DETAILED DESCRIPTION cigarette Smoke. TNF-alpha has been shown in animal mod 0095. A number of undesirable pulmonary diseases such els to induce pathological features associated with COPD, as interstitial lung disease (ILD; and Sub-class diseases Such as an inflammatory cell infiltrate into the lungs, pulmo therein), chronic obstructive pulmonary disease (COPD; and nary fibrosis and emphysema. Intriguingly, TNF-alpha levels Sub-class diseases therein), asthma, and fibrotic indications of in sputum increase significantly during acute exacerbations the lungs, kidney, heart and eye, are initiated from an external of COPD. challenge. By non-limiting example, these effectors can 0102 The mechanism of action for pyridone analogs, such include infection, cigarette Smoking, environmental expo as pirfenidone is believed to be both anti-inflammatory and Sure, radiation exposure, Surgical procedures and transplant anti-fibrotic. Pirfenidone inhibits synthesis and release of rejection. However, other causes related to genetic disposi pro-inflammatory cytokines and reduces the accumulation of tion and the effects of aging may also be attributed. inflammatory cells in response to various stimuli. Pirfenidone 0096. In epithelium, scarring serves a valuable healing also attenuates fibroblast proliferation, production of fibrosis role following injury. However, epithelium tissue may associated proteins and cytokines, and the increased biosyn become progressively scarred following more chronic and or thesis and accumulation of extracellular matrix in response to repeated injuries resulting in abnormalfunction. In the case of cytokine growth factors such as TGF-beta and platelet-de idiopathic pulmonary fibrosis (IPF; and other subclasses of rived growth factor (PDGF). ILD), if a sufficient proportion of the lung becomes scarred 0103) In in vitro cell-based assays, pirfenidone suppressed respiratory failure can occur. In any case, progressive Scarring the proliferation of fibroblasts; inhibited lipopolysaccharide may result from a recurrent series of insults to different (LPS)-stimulated release of PDGF, tumor necrosis factor US 2015/O 196543 A1 Jul. 16, 2015 alpha (TNF-alpha), and TGF-beta1; and inhibited collagen otherwise be removed from therapy, for example, dose de synthesis. Depending on the assay conditions, these in vitro escalation of up to and greater than 50%. Further, clinical activities were evident at pirfenidone concentrations of about studies utilizing the use of food to enable dose tolerability 30 microM to about 10 mM (about 5.5 mcg/mL to about 1.85 may also be attempted. In both cases, the plasma Cmax is mg/mL). Given that the oral Cmax of pirfenidone in IPF reduced dose-proportionately. More specifically, the fed-state patients is about 42 microM in the recommended fed-state to results in about a 50% reduction in Cmax, about a seven-fold about 84 microM in the fasting-state (or about 7.9 mcg/mL to increase in Tmax and a reduction in overall exposure of about 15.7 mcg/mL, respectively), these same activities may 10-15%. Both fed and fasted state resulted in a plasma half be promoted in vivo, albeit in the lower range of observed life of about 2.5 hours. While this approach may reduce efficacy. gastrointestinal-related adverse events, the lack of clinically 0104 Oral administration of pirfenidone to LPS-chal significant efficacy in recent orally-administered clinical lenged mice resulted in dose-dependent decreased mortality, studies may have been influenced by these approaches. reduced serum levels of the pro-inflammatory cytokines 0110 Based upon clinical observations and adverse events TNF-alpha, interleukin (IL-12) and interferon gamma, and as well as observed toxicities, oral pirfenidone therapy is increased serum levels of the anti-inflammatory cytokine, limited to doses up to about 1800 mg/day to about 2400 IL-10. Pirfenidone treatment also prevented LPS-related mg/day (from 600 mg TID or 801 mg TID, respectively). hemorrhagic necrosis and apoptosis in the liver, and Sup Thus, while pirfenidone exhibits a wide range of non-human pressed increases in TGF-beta. efficacy, human adverse events and toxicities have limited 0105. In vitro studies suggest that pirfenidone may also oral dosing to the lower end of this range. suppress fibrogenesis through selective inhibition of p38 0111 Regulatory risk-benefit analysis between observed mitogen-activated protein kinase (MAPK). These observa efficacy and associated adverse events of orally administered tions have been associated with an attenuation of TGF-beta pirfendione has led to concerns that these doses do not pro induced collagen synthesis. The parallel observation that vide sufficient efficacy to warrant the safety risk: even in a silencing p38 may also restore sensitivity to coriticosteroids terminal population of unmet clinical need. Provided herein in COPD is also promising for this and other disease popula in certain embodiments, is a method of administering an tions. Unfortunately, compounds that inhibit p38 MAPK have equivalent or increased pirfenidone or pyridone analog dose also proven toxic and have been withdrawn from the clinical directly to the disease site (e.g., inhalation delivery to the setting. These compounds have each employed oral adminis lung) would provide equivalent or improved efficacy over tration. oral routes. In certain embodiments, these doses require less 0106. In rat, hamster, and mouse models of bleomycin administered drug. In certain embodiments, this approach of induced lung fibrosis, prophylactic administration of pirfeni administering pirfenidone by inhalation may also benefit done reduced pulmonary fibrosis assessed by both histo from reduced systemic exposure and an increased safety mar pathological analysis and quantitative determination of gin when compared to oral administration of pirfenidone. collagen content. Pirfenidone treatment also reduced pulmo Described herein are compositions of pirfenidone or a pyri nary edema and pulmonary levels of TGF-beta, basic fibro done analog compound that are suitable for delivery to a blast growth factor (bFGF), and various pro-inflammatory mammal by inhalation and methods of using Such composi cytokines. tions. 0107. In rat, pirfenidone decreased collagen production 0112. It is unclear from the existing data whether pirfeni and deposition in hepatic fibrosis, reversed cardiac and renal done anti-inflammatory oranti-fibrotic mechanism or mecha fibrosis, and attenuated the increase in diastolic stiffness of nisms of action are driven by Cmax or exposure (area under diabetic hearts from streptozotocin-treated animals without the curve, AUC). In some embodiments, low to moderately normalizing cardiac contractility or renal function. In observed clinical efficacy may be associated with pirfenidone DOCA-salt hypertensive rats, pirfenidone also reversed and plasma levels about or greater than 5 mcg/mL, exposures prevented cardiac remodeling, and reversed and prevented (AUCO-infinity) about or greater than 50 mg.hr/L, and/or a increased cardiac stiffness without reversing the increased plasma elimination rate of about 2.5 hours. vascular responses to noradrenaline. 0113. In some embodiments, intravenous or oral adminis 0108 Human studies have shown some clinical anti-in tration of pirfenidone may result in lung epithelial lining fluid flammatory and anti-fibrotic benefit of oral pirfenidone. Pho (ELF) levels comparable to that observed in plasma, and thus, totoxicity, gastrointestinal disorders and abnormal liver func in Some embodiments, clinically-measured plasma Cmax of tion test values may result in human populations following about or greater than 5 mcg/mL are directly associated with oral administration of pirfenidone. As a consequence patient low to moderately-observed clinical pulmonary efficacy. In dosing must be closely monitored. In Phase 3 clinical studies Some embodiments, plasma levels of pirfendione resulting with orally administered pirfenidone, initial dose escalation from oral administration are associated with lower efficacy, was required to establish gastrointestinal tolerance. However, and thus is some embodiments the resultant ELF and lung dose levels are also limited during or following escalation due tissue levels are also associated with lower efficacy. In other to occurrence of nausea, rash, dyspepsia, dizziness, Vomiting, embodiments, intravenous or oral administration of pirfeni photosensitivity reaction, anorexia, and elevated AST and done may result in lung epithelial lining fluid (ELF) levels ALT serum transaminases. In some cases, oral administration less than that observed as efficacious from the plasma. In of pirfendione may result in dose de-escalation or discontinu some embodiments, ELF levels corresponding with oral or ation of pirfenidone administration. intravenous-delivered, plasma-observed efficacious levels 0109. In addition to required pirfenidone dose escalation may be 0.1 mcg/mL to about 5 mcg/mL. In some embodi to establish gastrointestinal tolerance, dose de-escalation and ments, ELF levels corresponding with plasma-observed effi the use of food has been employed to enable oral administra cacious levels may be 0.1 mcg/mL to about 1 mcg/mL. In tion to individuals unable to achieve tolerance and would some embodiments, ELF levels corresponding with oral or US 2015/O 196543 A1 Jul. 16, 2015 22 intravenous-delivered, plasma-observed efficacious levels resultina similar efficacious dose to the kidney in the absence may be 0.5 mcg/mL to about 5 mcg/mL. In some embodi of elevated systemic adverse events or toxicities observed ments, ELF levels corresponding with oral or intravenous with oral dosing. In some embodiments, intranasal inhalation delivered, plasma-observed efficacious levels may be 0.3 delivery of aerosolized pirfenidone or pyridone analog to the mcg/mL to about 3 mcg/mL. In some embodiments, direct nasal cavity may result in efficacious delivery of pirfenidone administration of pirfenidone to the lung, results in delivery or pyridone analog to the central nervous system (CNS). In of about or greater than 5 mcg pirfenidone to one mL ELF, some embodiments, inhalation delivery of pirfenidone or and may result in equivalent pulmonary efficacy without pyridone analog to the nasal cavity will become readily avail elevated systemic levels associated with adverse events and able to the CNS. In some embodiments, providing a nasal toxicities observed with administration. By non-limiting cavity-delivered dose equivalent to about 0.1 mcg/mL to example, this may be accomplished by oral or intranasal about 5 mcg/mL ELF or 0.004 mcg/gram to about 0.7 mcg/ inhaled delivery of aerosolized pirfenidone or pyridone ana gram lung tissue pirfenidone or pyridone analog may result in log to the lung providing about or greater than 0.1 mcg/mL, similar efficacy in the CNS in the absence elevated systemic for example greater than about 0.2 mcg/mL, 0.4 mcg/mL, 0.6 adverse events or toxicities observed with oral dosing. mcg/mL, 0.8 mcg/mL, 1.0 mcg/mL, 2 mcg/mL, 3 mcg/mL, 4 0.115. In some embodiments, topical delivery of aero mcg/mL, 5 mcg/mL, 6 mcg/mL, 7 mcg/mL, 8 mcg/mL, 9 Solized, liquid or cream pirfenidone or pyridone analog to a mcg/mL, or greater than 10 mcg/mL of pirfenidone or pyri site of desired effect providing about 0.004 mcg/gram to done analog to the ELF. Once in the ELF, pirfenidone or about 0.7 mcg/gram tissue weight may result in a similar pyridone analog will in Some embodiments penetrate lung efficacious dose in the absence of systemic adverse events or tissue resulting in between about 0.004 mcg and 0.7 mcg toxicities. In some embodiments, topical delivery of aero pirfenidone or pyridone analog to one gram lung tissue (about Solized, liquid or cream pirfenidone or pyridone analog to 0.1 mcg/mL in about 25 mL ELF to about 5 mcg/mL in about damaged skin epithelium may prevent or reverse scarring, 75 mL ELF, about 600 grams adult human lung tissue fibrosis and/or inflammation. This damage could be the result weight). of infection, burn, Surgery, acute of chronic injury (Such as 0114. In some embodiments, pirfenidone may readily bed soars), or other event. In some embodiments, topical equilibrate between the plasma and lung, and/or other organs. delivery of liquid or dry powder pirfenidone or pyridone In some embodiments, organ pirfenidone levels may also analog to the bladder may prevent scarring, fibrosis and/or mimic that of plasma, such as for example, the lung, heart, inflammation associated with bladder infection, bladder can kidney or nervous system. In some embodiments, delivery of cer, in-dwelling catheter or other event. In some embodi about or greater than 0.004 mcg to 0.7 mcg pirfenidone to one ments, topical delivery of liquid pirfenidone or pyridone ana gram tissue may provide a similar therapeutic benefit to other log to the eye may prevent development of post-operative organs. In some embodiments, providing additional pirfeni fibrosis in the conjunctiva and/or episclera following glau done or pyridone analog may provide additional efficacy. In coma Surgery. Some embodiments, this may be accomplished by inhalation 0116. In some embodiments, injection delivery of liquid (i.e. oral inhalation or intranasal inhalation) delivery of aero pirfenidone or pyridone analog to a site of desired effect Solized pirfenidone or pyridone analog to the lung. In some providing about 0.004 mcg/gram to about 0.7 mcg/gram tis embodiments, pirfenidone or pyridone analog delivered to Sue weight pirfenidone or pyridone analog may result in a the lung may, in Some embodiments, become readily avail similar efficacious dose in the absence of systemic adverse able to the heart. In some embodiments, providing about 0.1 events or toxicities. In some embodiments, injection delivery mcg/mL to about 5 mcg/mL ELF or 0.004 mcg/gram to about of liquid pirfenidone or pyridone analog to skeletaljoints may 0.7 mcg/gram lung tissue pirfenidone or pyridone analog prevent scarring, fibrosis and/or inflammation associated pyridone analog to the ELF or 0.2 to 0.7 mcg/gram lung tissue with autoimmune diseases, arthritis, rheumatoid arthritis, pirfenidone or pyridine analog may result in a similar effica infection or other event. cious dose to the heart in the absence of elevated systemic 0117. In some embodiments, in addition to Cmax, and in adverse events or toxicities observed with oral dosing. In additional embodiments, pirfenidone exposure (AUC) to the Some embodiments, intranasal inhalation or oral inhalation disease site may also be critical for efficacy. In some embodi delivery of aerosolized pirfenidone or pyridone analog to the ments, plasma AUCO-infinity about or greater than 50 lung may result in efficacious delivery of pirfenidone or pyri mghr/L is also associated with pulmonary efficacy. In some done analog to the liver. In some embodiments, pirfenidone or embodiments, partial or ready equilibrium of pirfenidone pyridone analog delivered to the lung will become available between the plasma and lung ELF and between the plasma to the liver. In some embodiments, providing about 0.1 mcg/ and lung tissue, in Some embodiments, may provide that AUC mL to about 5 mcg/mL ELF or 0.004 mcg/gram to about 0.7 may also be mimicked in the lung. In other embodiments, mcg/gram lung tissue pirfenidone or pyridone analog pyri lung ELF and tissue AUC may be less. done analog may result in a similar efficacious dose to the 0118. In some embodiments, individually or in combina liver in the absence of elevated systemic adverse events or tion Cmax, AUC and/or half-life are required for efficacy, and toxicities observed with oral dosing. In some embodiments, thus in some embodiments are provided a conservative model intranasal or oral inhalation delivery of aerosolized pirfeni with all three parameters (Cmax, AUC and half-life) required done or pyridone analog to the lung may result in efficacious for efficacy. In some embodiments, and by non-limiting delivery of pirfenidone or pyridone analog to the kidney. In example, direct inhalation delivery of about 0.1 mcg to about Some embodiments, pirfenidone or pyridone analog delivered 5 mcg pirfenidone or pyridone analog to one mL lung ELF. to the lung will become available to the kidney. In some providing an ELF AUCO-infinity about 1.0 mg.hr/L or about embodiments, providing about 0.1 mcg/mL to about 5 mcg/ 50 mg.hr/L, and maintaining these levels for the same period mL ELF or 0.004 mcg/gram to about 0.7 mcg/gram lung of time as that delivered via the oral route are equivalently tissue pirfenidone or pyridone analog pyridone analog may efficacious. Similarly, in other embodiments, direct inhala US 2015/O 196543 A1 Jul. 16, 2015 tion delivery of about or greater than 0.2004 to 0.7 mcg 0.135 By non-limiting example, based upon the above pirfenidone or pyridone analog to one gram lung tissue, pro assumptions and in certain embodiments, a dose of approxi vides a tissue AUCO-infinity less than to equivalent or sub mately 4 mg in a device delivering pirfenidone or pyridone stantially equivalent to that of the plasma following oral analog with 30% efficiency may result in lung ELF levels at or delivery, and in further embodiments, maintaining these lev above 5 mcg/mL for the same duration as that obtained fol els for the same period of time as that delivered via the oral lowing 801 mg administered orally. Moreover, while the route is equivalently efficacious. In some embodiments, the minimally efficacious pirfenidone dose may be maintained following assumptions and theoretical calculations are for this duration, local pirfenidone levels may also exhibit described for inhalation therapy: significantly higher ELF Cmax levels providing improved 0119 ELF Delivery Assumptions: efficacy. In some embodiments, delivery of 4 mg pirfenidone 0120 1. The total volume of human ELF is 25 mL: or pyridone analog with a 30% efficiency device may result in I0121 2. The inhaled route of administration is depen a lung ELF Cmax up to about 48 mcg/mL (4 mgx30%-1.2 dent upon a respirable delivered dose (RDD); RDD is mg. 1.2 mg/25 mL ELF-48 mcg/mL). In some embodiments, the fraction of drug inhaled in aerosol particles less than based upon the above assumptions a dose of approximately 5 microns in diameter, 66 mg in a device delivering pirfenidone or pyridone analog I0122) 3. RDD oftypical dry powder, liquid nebulization with 70% efficiency may resultina lung ELF Cmax up to 1.85 or meter-dose inhalation devices ranges from 10% to mg/mL (66 mgx70%=46.2 mg. 46.2 mg/25 mL ELF=1.85 70%. In some embodiments, higher and lower efficiency mg/mL). In some embodiments, based upon the above devices with RDDs greater than 70% and less than 10% assumptions a dose of approximately 154 mg in a device are contemplated. delivering pirfenidone or pyridone analog with 30% effi ciency may also result in a lung ELF Cmax up to 1.85 mg/mL I0123 4. Plasma pirfenidone or pyridone analog half (154 mgx30%–46.2 mg. 46.2 mg/25 mL ELF=1.85 mg/mL). life following oral administration is around 2.5 hours. In In some embodiments, based upon the above assumptions a Some embodiments, intestinal absorption affects this dose of approximately 12 mg in a device delivering pirfeni yule but for exemplary purposes of this model the lung done or pyridone analog with 70% efficiency may result in a ELF pirfenidone half-life following inhalation delivery lung ELF Cmax up to 336 mcg/mL (12 mgx70%–8.4 mg. 8.4 is assumed to be one-half that following oral adminis mg/25 mL ELF-336 mcg/mL). In some embodiments, based tration (e.g. 2.5 hours/2=1.25 hours). Half-life values upon the above assumptions a dose of approximately 28 mg in may be Supported by measurements indicating intrave a device delivering pirfenidone or pyridone analog with 30% nous administration of pirfenidone results in a lung ELF efficiency may also result in a lung ELF Cmax up to 336 half-life of around one-half that following oral admin mcg/mL (28 mgx30%–8.4 mg. 8.4 mg/25 mL ELF-336 mcg/ istration; mL). In some embodiments, this dose may result in maintain 0.124 5. In some embodiments, a lung ELF level of 5 ing at or above the 5 mcg/mL minimally efficacious dose for mcg/mL may be the lower limit of efficacy; and about 6 half-lifes, or about 15 hours. In some embodiments, 0.125 6.801 mg oral pirfenidone results in a plasma the embodiments described for inhalation therapy provide level at or greater than 5 mcg/mL for 4 hours (human beneficial efficacy through an increased Cmax and maintain measured value). For purposes of comparing routes, this ing drug exposure at or above the 5 mcg/mL minimal efficacy model will assume lung ELF pirfenidone levels follow range for a longer duration than that currently limited by oral ing oral administration remain at or above 5 mcg/mL dosing. In some embodiments, prolonged exposure may lung ELF for the same duration as plasma. enable a reduced dosing interval (by example once-a-day or 0126 Exemplary ELF Calculations: twice-a-day versus the current three times a day oral dosing I0127. 1. Mcg pirfenidone delivered to 25 mL ELF to regimen). In some embodiments, while delivery is directly to make 5 mcg/mL 125 mcg; the lung, these doses may result in very low systemic plasma I0128 2. Based upon an RDD efficiency of 30%, the unit levels (e.g. around 2 mcg/mL pirfenidone). In some embodi dose required is 416 mcg (125 mcg/0.3–416 mcg); ments, although about 28 mg pirfenidone or pyridone analog I0129. 3. Based upon an RDD efficiency of 50%, the unit delivered with a 30% efficiency aerosol device may initially dose required is 250 mcg (125 mcg/0.5–250 mcg); result in elevated levels in vasculature and tissues immedi I0130. 4. Based upon an RDD efficiency of 70%, the unit ately downstream of the lung (or nasal cavity), the dilute dose required is 179 mcg (125 mcg/0.7=179 mcg); and systemic plasma concentration may be around 1.7 mcg/mL 0131 Compensating to maintain at or above these levels (28 mgx30%-8.4 mg. 8.4 mg/5 L total body blood=1.7 mcg/ for 3.2 half lives of 1.25 hours each (4 hours at or above 5 mL). In some embodiments, delivery of about 46 mg pirfeni mcg/mL with a lung half-life of 1.25 hours—3.2 half lives): done or pyridone analog may result in a dilute systemic (0132) 5. For an RDD efficiency of 30%, the unit dose plasma concentration of about 9.3 mcg/mL. required to maintain the lower limit of clinically-ob 0.136. One of skill in the art will recognize from the dis served efficacy (in this case 416 mcg) for 3.2 half lives is cussions herein that doses calculated in the above model will 3994 mcg: change if the actual measured lung ELF half-life of pirfeni (0.133 6. For an RDD efficiency of 50%, the unit dose done or pyridone analog elimination changes. If the half-life required to maintain the lower limit of clinically-ob is shorter, more administered pirfenidone or pyridone analog served efficacy (in this case 250 mcg) for 3.2 half lives will be required to maintain the lung ELF concentration 2400 mcg; and above that considered the minimal efficacious level. Addi I0134 7. For an RDD efficiency of 70%, the unit dose tional increases in administered pirfenidone or pyridone ana required to maintain the lower limit of clinically-ob log may be desired to further improve efficacy. Further, in served efficacy (in this case 179 mcg) for 3.2 half lives addition to delivering desired lung tissue Cmax and AUC, oral 1718 mcg. inhaled or intranasal inhaled delivery of aerosol pirfenidone US 2015/O 196543 A1 Jul. 16, 2015 24 or pyridone analog may also serve an efficient route for sys 70%. Higher and lower efficiency devices with RDDs temic delivery. In some embodiments, dosing schemes are greater than 70% and less than 10% also exist; contemplated that enable inhaled delivery of pirfenidone or 0152 8. As discussed above, lung tissue pirfenidone pyridone analog to initially achieve desired lung tissue Cmax half-life is much longer than the intravenously delivered and AUC, with plasma half-life slower than that of the lung plasma pirfenidone half-life (by as much or greater than ELF, and targeting the delivery of specific plasma concentra 2-4x). Plasma pirfenidone half-life following oral tions may in turn prolong lung ELF-pirfenidone or pyridone administration is around 2.5 hours. However, continued analog exposure. intestinal absorption affects this number and hence is 0.137 Exemplary Lung Tissue Delivery Assumptions: much longer than that following intravenous delivery. 0.138 1. The total wet weight of the adult human lung is Therefore, for purposes of this model the lung tissue about 685 to 1,050 grams (for calculations, conserva pirfenidone half-life following inhalation delivery will tively about 1,000 grams); be considered equivalent to that following oral admin 0.139 2. The adult human lung blood volume is about istration (e.g. 2.5 hours); 450 mL: 0153. 9. From the above observations and calculations, 0140. 3. The tissue weight of the adult human lung is the lower limit of efficacy in lung tissue is 8 mcg/gram; conservatively 1,050 grams wet weight minus 450 mL and blood weight (assuming density of 1.0), equals 600 0154) 10. Incorporating that 801 mg oral pirfenidone grams; results in a human plasma level at or greater than 5 0.141. 4. In some embodiments, following intravenous mcg/mL for 4 hours and that 5 mcg/mL plasma results in push of pirfenidone to a mouse: 0.7 mcg/gram lung tissue pirfenidone, what is delivered by oral or intranasal inhalation must be at or above 0.7 0.142 plasma pirfenidone Tmax is equivalent to lung mcg/gram lung tissue pirfenidone for at least 4 hours for Tmax equivalent lung fibrosis efficacy to the oral dose. 0.143 40 mg/kg intravenous dose results in plasma 0155 Exemplary Lung Tissue Calculations: Cmax of about 55 mcg/mL and a lung Cmax of 30 0156 1. Mcg pirfenidone delivered to 1000 grams wet mcg/gram wet tissue lung tissue (blood plus lung tissue) to make 0.7 mcg/ 0144 Conservatively, blood makes up about 40% of gram=700 mcg: the wet lung weight. Given that the plasma and lung Tmax are, in Some embodiments, equivalent, it fol (O157 2. Based upon an RDD efficiency of 30%, the unit lows that much of the 30 mcg/gpirfenidone measured dose required is 2.333 mcg (700 mcg/0.3–2.333 mcg); in the wet lung is due to the presence of blood. Con 0158. 3. Based upon an RDD efficiency of 50%, the unit servatively, if blood makes up about 40% of the wet dose required is 1,400 mcg (700 mcg/0.5=1,400 mcg); lung weight, then 40% of the plasma Cmax (or 55 0159. 4. Based upon an RDD efficiency of 70%, the unit mcg/mLX40%) is about 22 mcg/gram pirfenidone in dose required is 1,000 mcg (700 mcg/0.7=1,000 mcg); the measured lung weight is due to blood. Taking the and difference between the wet lung Cmax and this num 0.160 Compensating to maintain at or above these lev ber (or 30mcg/g minus 22 mcg/g), about 8 mcg/g is in els for 2 half lives of 2.5 hours each (4 hours at or above the lung tissue. 0.7 mcg/gram wet lung tissue with a lung half-life of 2.5 0145 a measured wet lung half-life that is about 45% hours=1.6 half lives): longer than the plasma half-life may be considered. (0161 5. For an RDD efficiency of 30%, the unit dose Taking the argument above that about 40% of the wet required to match the lower limit of clinically-observed lung pirfenidone is in the blood, the actual lung tissue oral route efficacy (in this case 2.333 mcg) for 1.6 half half-life is much greater then 45% longer than lives is 3,733 mcg: plasma; (0162 6. For an RDD efficiency of 50%, the unit dose 0146 5. From the above observations and calculations required to match the lower limit of clinically-observed that 55 mcg/mL plasma Cmax results in a lung tissue oral route efficacy (in this case 1,400 mcg) for 1.6 half Cmax of about 8 mcg/gram, the following comparison to lives 2.240 mcg; and (0163 7. For an RDD efficiency of 70%, the unit dose humans can be made: required to match the lower limit of clinically-observed 0147 Taking an early assumption, the lower end of oral route efficacy (in this case 1,000 mcg) for 1.6 half human efficacy is 5 mcg/mL plasma pirfenidone. lives 1,600 mcg. 0148 Assuming the above ratio (55 mcg/mL plasma 0164. By non-limiting example, based upon the above results in 8 mcg/gram lung tissue) is true for humans, assumptions a dose of approximately 3.7 mg in a device 5 mcg/mL divided by 55 mcg/mL is about 9.1%. 9.1% delivering pirfenidone or pyridone analog with 30% effi of 8 mcg/gram is about 0.7 mcg/gram. ciency may result in wet lung tissue levels at or above 0.7 0149 Taken together, 5 mcg/mL plasma pirfenidone mcg/gram for the same duration as that obtained following may result in 0.7 mcg/gram lung tissue pirfenidone. 801 mg administered orally. Moreover, while the minimally Thus, about 0.7 mcg/gram lung tissue pirfenidone is efficacious pirfenidone dose is maintained for this duration, the lower end of efficacy. local pirfenidone levels may exhibit significantly higher wet 0150. 6. The inhaled route of administration is depen lung tissue Cmax levels providing improved efficacy. By dent upon a respirable delivered dose (RDD). The RDD non-limiting example, delivery of 3.7 mg pirfenidone or pyri is the fraction of drug inhaled in aerosol particles less done analog with a 30% efficiency device may result in a wet than 5 microns in diameter, lung tissue Cmax up to about 1.1 mcg/gram (3.7 0151. 7. RDD oftypical dry powder, liquid nebulization mgx30%–1.1 mg. 1.1 mg/1,050 grams wet lung weight=1.1 or meter-dose inhalation devices ranges from 10% to mcg/gram). This number is near about 1.5-fold higher than US 2015/O 196543 A1 Jul. 16, 2015 that delivered following oral delivery. By another non-limit may result in maintaining at or above the 0.7 mcg/gram wet ing example, based upon the above assumptions a dose of lung tissue minimally efficacious dose for about 1 half-lifes, approximately 50 mg in a device delivering pirfenidone or or at least about 2.5 hours; compared to 4 hours following 801 pyridone analog with 30% efficiency may result in a wet lung mg oral dose administration. Similarly, by another non-lim tissue Cmax up to 14.3 mcg/mL (50 mgx30%–15 mg. 15 iting example, based upon the above assumptions a dose of mg/1050 grams wet lung weight 14.3 mcg/gram), or about approximately 75 mg in a device delivering pirfenidone or 20-fold higher than that delivered following oral delivery. pyridone analog with 10% efficiency may result in a wet lung Under this scenario, this dose may result in maintaining at or tissue Cmax up to 21 mcg/mL (75 mgx10%-7.5 mg. 7.5 above the 0.7 mcg/gram wet lung tissue minimally efficacious mg/1050 grams wet lung weight 7.1 mcg/gram), or about dose for at least about 5 half-lifes, or about 12.5 hours; com 10-fold higher than that delivered following oral delivery. pared to 4 hours following 801 mg oral dose administration. Under this scenario, this dose may result in maintaining at or Similarly, by another non-limiting example, based upon the above the 0.7 mcg/gram wet lung tissue minimally efficacious above assumptions a dose of approximately 15 mg in a device dose for about 3.5 half-lifes, or at least about 8.8 hours; delivering pirfenidone or pyridone analog with 70% effi compared to 4 hours following 801 mg oral dose administra ciency may result in a wet lung tissue Cmax up to 10mcg/mL tion. Such duration over 0.7 mcg/gram lung tissue may permit (15 mgx70%–10.5 mg. 10.5 mg/1,050 grams wet lung TID dosing. Such an approach could benefit efficacy through weight 10 mcg/gram), or about 14-fold higher than that an increased Cmax and maintaining drug exposure at or delivered following oral delivery. Under this scenario, this above the 0.7 mcg/gram wet lung tissue minimal efficacy dose may result in maintaining at or above the 0.7 mcg/gram range for a longer duration than that currently limited by oral wet lung tissue minimally efficacious dose for about 4.5 half dosing. Such prolonged exposure may enable a reduced dos lifes, or at least about 11 hours; compared to 4 hours follow ing interval (by example once-a-day or twice-a-day versus the ing 801 mg oral dose administration. Such duration over 0.7 current three times a day oral dosing regimen). Moreover, mcg/gram lung tissue may permit twice a day dosing (BID). while this approach delivers directly to the lung, using the Similarly, by another non-limiting example, based upon the above non-limiting examples these doses may result in above assumptions a dose of approximately 75 mg in a device reduced systemic plasma levels (e.g. Cmax from less than 0.6 delivering pirfenidone or pyridone analog with 70% effi mcg/mL pirfenidone from a 4.5 mg delivered dose to 5,000 ciency may result in a wet lung tissue Cmax up to 50mcg/mL mL blood to less than 2 mcg/mL pirfenidone from a 15 mg (75 mgx70%=52.5 mg. 52.5 mg/1,050 grams wet lung delivered dose to less than 10 mcg/mL from a 75 mg dose). weight=50 mcg/gram), or about 71-fold higher than that delivered following oral delivery. Under this scenario, this 0.165 Doses calculated in the above model will change dose may result in maintaining at or above the 0.7 mcg/gram considerably if the actual measured lung tissue half-life of wet lung tissue minimally efficacious dose for at least about 6 pirfenidone or pyridone analog elimination changes. If the half-lifes, or about 15 hours; compared to 4 hours following half-life is faster, more inhaled pirfenidone or pyridone ana 801 mg oral dose administration. Such duration over 0.7 log will be required to maintain the lung tissue concentration mcg/gram lung tissue may permit BID dosing. Similarly, by above that considered the minimal efficacious level. Addi another non-limiting example, based upon the above assump tional increases in inhaled pirfenidone or pyridone analog tions a dose of approximately 15 mg in a device delivering may be desired to further improve efficacy. Further, in addi pirfenidone or pyridone analog with 30% efficiency may tion to delivering desired lung tissue Cmax and AUC, inhaled result in a wet lung tissue Cmax up to 4.3 mcg/mL (15 delivery of aerosol pirfenidone or pyridone analog may also mgx30%–4.5 mg. 4.5 mg/1,050 grams wet lung weight=4.3 serve an efficient route for systemic delivery. In some mcg/gram), or about 6-fold higher than that delivered follow embodiments, dosing schemes are contemplated that enable ing oral delivery. Under this scenario, this dose may result in inhaled delivery of pirfenidone or pyridone analog to initially maintaining at or above the 0.7 mcg/gram wet lung tissue achieve desired lung tissue Cmax and AUC, and as plasma minimally efficacious dose for at least about 3 half-lifes, or half-life is predicted to be slower than that of the lung tissue, about 7.5 hours; compared to 4 hours following 801 mg oral targeting the delivery of specific plasma concentrations may dose administration. Similarly, by another non-limiting in turn prolong lung tissue-pirfenidone or pyridone analog example, based upon the above assumptions a dose of exposure. approximately 75 mg in a device delivering pirfenidone or 0166 As scarring is irreversible, IPF efficacy is the act of pyridone analog with 30% efficiency may result in a wet lung protecting native lung tissue against invading fibrosis. There tissue Cmax up to 21 mcg/mL (75 mgx30%–22.5 mg. 52.5 fore, maintaining regular efficacious drug levels in unaffected mg/1050 grams wet lung weight 21 mcg/gram), or about tissue is critical for improved patient survival. Clinical and 31-fold higher than that delivered following oral delivery. nonclinical Studies have suggested pirfenidone efficacy is Under this scenario, this dose may result in maintaining at or dose-responsive ranging from slowed-disease progression to above the 0.7 mcg/gram wet lung tissue minimally efficacious improvement. Unfortunately, Substantial gastrointestinal dose for at least about 5 half-lifes, or about 12.5 hours; com (GI) side effects and systemic toxicity have forced an pared to 4 hours following 801 mg oral dose administration. approved oral dose that is limited to the lower end of this Such duration over 0.7 mcg/gram lung tissue may permit BID range. Complicating matters, recommendations for dose-ab dosing. Similarly, by another non-limiting example, based Sorbing food and frequent triggering of dose-reduction/dis upon the above assumptions a dose of approximately 15 mg in continuation protocols addressing these issues further reduce a device delivering pirfenidone or pyridone analog with 10% lung dose and interrupt required maintenance therapy of this efficiency may result in a wet lung tissue Cmax up to 1.4 otherwise promising drug. Inhalation delivery of aerosol pir mcg/mL (15 mgx10%=1.5 mg. 1.5 mg/1,050 grams wet lung fenidone or pyridone analog directly to the lung will reduce or weight 1.4 mcg/gram), or about 2-fold higher than that deliv eliminate these safety or tolerability limitations associated ered following oral delivery. Under this scenario, this dose with the oral route of delivery. US 2015/O 196543 A1 Jul. 16, 2015 26

0167 Oral pirfenidone efficacy has been moderately dem without the need to initially dose-escalate the patient. In some onstrated in human clinical studies and the data Suggests that embodiments, the methods described herein may be used to this effect increases with higher doses. Unfortunately, signifi treat patients diagnosed with mild-to-severe IPF without the cant side effects and toxicity have limited the oral dose to the need to initially dose-escalate the patient. In some embodi lower end of this efficacy range (Esbriet approved up to 2403 ments, the methods described herein may be used to treat mg/d). Jeopardizing this already low efficacy dose, the patients diagnosed with mild-to-moderate IPF without the Esbriet prescription requires an initial dose-escalation need to monitor and dose-reduce or stop therapy due to gas scheme and recommended administration with food to trointestinal, phototoxic or liver enzyme-associated adverse acquire minimal GI tolerance and an acceptable side-effect/ events. In some embodiments, the methods described herein toxicity profile (range up to three 267 mg capsules, or 801 mg may be used to treat patients diagnosed with mild-to-severe IPF without the need to monitor and dose-reduce or stop three times a day (TID)). Unfortunately, not all patients reach therapy due to gastrointestinal, phototoxic or liver enzyme this recommended dose and food further reduces bioavail associated adverse events. In some embodiments, the meth ability (food reduces Cmax and AUC ~50% and ~20%, ods described herein may be used to provide a prophylactic respectively). Further, elevated liver enzyme levels and skin therapy to patients diagnosed with mild-to-moderate IPF. In photoreactivity initiate a physician-guided dose-reduction some embodiments, the methods described herein may be and stoppage protocol that in Phase 3 studies permitted up to used to provide a prophylactic therapy to patients diagnosed a 50% dose reduction before discontinuation (in these studies with mild-to-severe IPF. In some embodiments, the methods between 48% and 67% of patient doses were reduced). As described herein may be used to provide a prophylactic chronic lung tissue dosing of effective drug levels is critical therapy to patients with mild-to-moderate IPF without the for maintenance protection against invading fibrosis, it is need to initially dose-escalate the patient. In some embodi likely that oral pirfenidone prescription and practice result in ments, the methods described herein may be used provide a Sub-efficacious dosing of this otherwise promising drug; a prophylactic therapy to patients diagnosed with mild-to-se hypothesis that may in part explain the moderate efficacy vere IPF without the need to initially dose-escalate the observed in Phase 3 studies. patient. In some embodiments, the methods described herein 0168 For oral administration in the context of treatment of may be used to provide a prophylactic therapy to patients pulmonary fibrosis high oral doses are required to achieve diagnosed with mild-to-moderate IPF without the need to plasma levels required for efficacious lung tissue exposure. monitor and dose-reduce or stop therapy due to gastrointes However, gastrointestinal side-effects and systemic toxicities tinal, phototoxic or liver enzyme-associated adverse events. have limited the approved oral dose to a level restricted to the In some embodiments, the methods described herein may be low end of the efficacy and dose-response curve. In one used to provide a prophylactic therapy to patients diagnosed embodiment, inhaled pirfenidone or pyridone analog with mild-to-severe IPF without the need to monitor and improves pirfenidone treatment effectiveness through dose-reduce or stop therapy due to gastrointestinal, photo increased lung dose and improved compliance. In one toxic or liver enzyme-associated adverse events. In some embodiment, inhalation of pirfenidone or pyridone analog embodiments, the methods described herein may be used to (e.g. with a nebulizer) delivers pirfenidone or pyridone ana slow disease progression of patients diagnosed with mild-to log directly to the lung and whole-body dilution of the deliv moderate IPF without the need to initially dose-escalate the ered dose is minimized. In some embodiments, inhalation of patient. In some embodiments, the methods described herein pirfenidone reduces or eliminates GI exposure and/or sys may be used to slow disease progression of patients diag temic toxicities that are common with oral administration of nosed with mild-to-severe IPF without the need to initially pirfenidone or pyridone analog. In some embodiments, inha dose-escalate the patient. In some embodiments, the methods lation delivery of pirfenidone or pyridone analog provided described herein may be used to slow disease progression of herein provides higher lung tissue levels of pirfenidone than patients diagnosed with mild-to-moderate IPF without the is possible through oral administration. In some embodi need to monitor and dose-reduce or stop therapy due to gas ments, inhalation delivery of pirfenidone or pyridone analog trointestinal, phototoxic or liver enzyme-associated adverse serves as an efficient means of delivering pirfenidone or pyri events. In some embodiments, the methods described herein done analog to the systemic compartment. In some embodi may be used to slow disease progression of patients diag ments, inhalation delivery of pirfenidone or pyridone analog nosed with mild-to-severe IPF without the need to monitor provides Cmax and AUC benefits over the oral route. In some and dose-reduce or stop therapy due to gastrointestinal, pho embodiments, inhalation delivery of pirfenidone or pyridone totoxic or liver enzyme-associated adverse events. By non analog provides Cmax and AUC benefits over the oral route, limiting example, clincal end points of IPF efficacy include wherein plasma re-circulated, aerosol-delivered pirfenidone reduced decline in forced vital capacity (FVC), reduced or pyridone analog maintains these beneficial properties. In decline in distance walked over a six-minute interval (six some embodiments, the methods described herein may be minute walk test; 6MWT), slowed decline in carbon monox used to treat patients diagnosed with mild-to-moderate IPF. In ide diffusion capacity (DLCO), improved progression-free some embodiments, the methods described herein may be Survival (PFS), reduced mortality and monitoring changes in used to treat patients diagnosed with mild-to-severe IPF. In biomarkers such as MMPI, and CCL18. In some embodi some embodiments, the methods described herein may be ments, a comparison of oral and inhaled aerosol properties used to treat patients diagnosed with mild-to-moderate IPF that may be observed is shown in Table A. US 2015/O 196543 A1 Jul. 16, 2015 27

TABLE A Advantages of inhaling pir?enidone

Oral Pirfenidone Inhaled Pirfenidone High oral dose = minimally-effective lung Lower inhaled dose = Superior lung levels levels Oral route = significant GI side effects Inhaled route = no reduced GIside effects High dose = toxicity Lower dose = reduced toxicity Low efficacy High efficacy 1. Pirfenidone is a low potency drug. The 1. Inhaled route permits use of smaller oral route requires a very high dose to pirfenidone doses to deliver Superior initial deliver Sufficient lung levels. Significant pirfenidone lung tissue Cmax and AUC in GI side effects and to a lesser extent the absence of GI side-effects. In some systemic toxicities limit the oral dose to embodiments, inhaled administration also the lower end of the efficacy and dose serves as non-oral route for systemic response curve. delivery; enabling sufficient circulating 2. Initial dose escalation required to obtain plasma pirfenidone levels to extend the maximum-tolerated maintenance dose. duration of Superior efficacy. Due to poor tolerability, this . Good tolerability permits establishing the maintenance dose is often set below the maintenance dose a the approved level approved dose level . Strong adherence to maintenance therapy 3. Continued intolerability and safety Dose and chronic therapy maintained concerns reduce adherence to Inhaled drug unaffected by food maintenance therapy Safe & well-tolerated; no need for Dose reduced and interrupted special protocols Recommended food absorbs drug Side effects and toxicity trigger dose reduction stoppage protocols

0169. In some embodiments the methods described herein Esbriet therapy and avoided during Esbriet therapy due to the provide for delivery of high concentration, readily bioavail reduced clearance of pirfenidone. Other therapies that are able pirfenidone or pyridone analog compound which in turn inhibitors of both CYP1A2 and one or more other CYP isoen provides improved efficacy over pirfenidone or pyridone ana Zymes involved in the metabolism of pirfenidone (e.g. log compound administered by the oral route or by inhalation CYP2C9, 2019, and 2D6) should also be avoided during of a slow-dissolving or otherwise slowly bioavailable com pirfenidone treatment. pound formulation. In some embodiments, such slow-dis 0172 Also for the oral administration, special care should solving or otherwise slowly bioavailable compound formu also be exercised if CYP1A2 inhibitors are being used con lations for inhalation include, but are not limited to a dry comitantly with potent inhibitors of one or more other CYP powderformulation, a liposomal formulation, a nano-Suspen isoenzymes involved in the metabolism of pirfenidone such sion formulation, or a micro-suspension formulation. In some as CYP2C9 (e.g. amiodarone, fluconazole), 2C19 (e.g. embodiments, the aqueous solutions of pirfenidone or pyri chloramphenicol) and 2D6 (e.g. fluoxetine, paroxetine). done analog described and contemplated herein for adminis 0173 The oral product should be used with caution in tration by inhalation are completely homogeneous and patients treated with other moderate or strong inhibitors of soluble. CYP1A2 (e.g. ciprofloxacin, amiodarone, propafenone). 0170 In some embodiments, an obstacle to patient com 0.174 As many products effecting CYP enzymes are use pliance with oral pirfenidone therapy is GI intolerability. ful to fibrosis patients, permitting their use would be benefi Pirfenidone blood levels may also be important has they have cial. While the oral route is already at the maximum permis been implicated in other observed toxicities. Thus, factors sible dose (which provides only moderate efficacy), any contributing to increased blood levels must be considered. inhibition of the enzymes described above elevates pirfeni For the oral route of administration, toxicity and GI intoler done blood levels and increases the rate and severity of the ability have limited the dose to 801 mg three times a day. toxic events described herein. In some embodiments oral While elevated liver enzymes, photosensitivity reaction and inhalation and intranasal inhalation delivery of pirfenidone or phototoxicity occur at this dose, they occur with higher fre pyridone analogs can achieve effective tissue levels with quency and greater severity with higher doses. Secondly, much less drug than that required by the oral product, and in pirfenidone is primarily metabolised by CYP1A2. In vitro Some embodiments result in blood levels are significantly metabolism studies with hepatic microsomes indicate that lower and consequences associated with CYP enzyme inhibi approximately 48% of pirfenidone is metabolised via tory properties described herein are removed. In some CYP1A2 with other CYP isoenzymes including CYP2C9, embodiments, use of these CYP inhibitory enzyme products 2C19, 2D6, and 2E1 each contributing less than 13%. Thus, currently contraindicated with the oral medicine may be inhibiting these enzyme systems results in elevated pirfeni administered with pirfenidone or pyridone analog. done blood levels, resulting in increased incidence and sever 0.175. The primary metabolite of pirfenidone is 5-carboxy ity of toxicity. To this end, items such as grapefruit juice, pirfenidone. Following oral or intravenous administration, fluvoxamine and other inhibitors of CYP1A2 should be this metabolite appears quickly at high concentrations in avoided during oral treatment with pirfenidone. blood. 5-carboxy-pirfenidone does not appear to have anti 0171 Oral administration of pirfenidoen is contraindi fibrotic or anti-inflammatory activity, its high blood levels cated in patients with concomitant use of fluvoxamine. Flu occur at the loss of pirfenidone blood concentrations. Thus, voxamine should be discontinued prior to the initiation of while the oral product is dosed at the highest possible level, US 2015/O 196543 A1 Jul. 16, 2015 28 once pirfenidone enters the blood it is rapidly metabolized to monia (IIP). There are seven distinct IIPs, differentiated by a non-active species further reducing the drugs potential to specific clinical features and pathological patterns. IPF is the achieve sufficient lung levels required for substantital effi most common form of IIP. It is associated with the pathologic cacy. In some embodiments, because oral inhalation and pattern known as usual interstitial pneumonia (UIP); for that intranasal inhalation delivery of pirfenidone or pyridone ana reason, IPF is often referred to as IPF/UIP, IPF is usually fatal, logs can achieve effective lung tissue levels directly, extra with an average Survival of approximately three years from lung metabolism is minimized. the time of diagnosis. There is no single test for diagnosing 0176). In some embodiments, administration of pirfeni pulmonary fibrosis; several different tests including chest done orpyridone analog compound by inhalation has reduced X-ray, pulmonary function test, exercise testing, bronchos gastroinstestinal side-effects when compared to oral admin copy and lung biopsy are used in conjunction with the meth istration. In some embodiments, the reduced gastroinstestinal ods described herein. side-effects with administration by inhalation avoids the need 0181 Idiopathic pulmonary fibrosis (also known as cryp for initial dose-escalation. In some embodiments, adminis togenic fibrosing alveolitis) is the most common form of tration of pirfenidone or pyridone analog by inhalation avoids interstitial lung disease, and may be characterized by chronic or Substantially avoids the gastronintestinal tract and there progressive pulmonary parenchymal fibrosis. It is a progres fore effects observed with oral administration of pirfenidone sive clinical syndrome with unknown etiology; the outcome or pyridone analog compound will be minimized or not is frequently fatal as no effective therapy exists. In some present. In some embodiments, the lack of food effects with embodiments, pirfenidone inhibits fibroblast proliferation administration by inhalation will allow for full dose delivery. and differentiation related to collagen synthesis, inhibits the 0177. In some embodiments, pharmaceutical composi production and activity of TGF-beta, reduces production of tions described herein are used in the treatment of lung dis fibronectiv and connective tissue growth factor, inhibits TNF ease in mammal. In some embodiments, the pharmaceutical alpha and I-CAM, increase production of IL-10, and/or compositions described herein are administered to a mammal reduces levels of platelet-derived growth factor (PDGF). A by oral inhalation or intranasal inhalation methods for the and B in belomycin-induced lung fibrosis. The pirfenidone purpose of treating lung disease in the mammal. In some methods and compositions described herein may provide tol embodiments, lung disease includes, but is not limited to, erability and usefulness in patients with advanced idiopathic asthma, chronic obstructive pulmonary disease (COPD), pull pulmonary fibrosis and other lung diseases. In some embodi monary fibrosis, idiopathic pulmonary fibrosis, radiation ments, pirfenidone methods and compositions described induced fibrosis, silicosis, asbestos induced pulmonary or herein may provide tolerability and usefulness in patients pleural fibrosis, acute lung injury, acute respiratory distress with mild to moderate idiopathic pulmonary fibrosis. In some syndrome (ARDS), sarcoidosis, usual interstitial pneumonia embodiments, increased patient Survival, enhanced vital (UIP), cystic fibrosis, Chronic lymphocytic leukemia (CLL)- capacity, reduced episodes of acute exacerbation (compared associated fibrosis, Hamman-Rich syndrome, Caplan Syn to placebo), and/or slowed disease progression are observed drome, coal worker's pneumoconiosis, cryptogenic fibrosing following pirfenidone treatment. In some embodiments alveolitis, obliterative bronchiolitis, chronic bronchitis, inhaled delivery of pirfenidone or pyridone analog may be an emphysema, pneumonitis, Wegner's granulamatosis, lung effective means to prevent, manage or treat idiopathic pulmo Scleroderma, silicosis, interstitial lung disease, asbestos nary fibrosis or other pulmonary fibrotic diseases. induced pulmonary and/or pleural fibrosis. In some embodi 0182. The term “pulmonary fibrosis', includes all intersti ments, lung disease is lung fibrosis (i.e. pulmonary fibrosis). tial lung disease associated with fibrosis. In some embodi In some embodiments, lung disease is idiopathic pulmonary ments, pulmonary fibrosis includes the term "idiopathic pull fibrosis. monary fibrosis” or “IPF. In some embodiments, pulmonary (0178 Pulmonary Fibrosis fibrosis, by non-limiting example, may result from inhalation 0179. In some embodiments, the compositions and meth of inorganic and organic dusts, gases, fumes and vapors, use ods described hereincan treat or slow down the progression of of medications, exposure to radiation or radiation therapy, or prevent pulmonary fibrosis. In some embodiments, pulmo and development of disorders such as hypersensitivity pneu nary fibrosis includes interstitial pulmonary fibrosis. This monitis, coal worker's pneumoconiosis, chemotherapy, group of disorders is characterized by Scarring of deep lung transplant rejection, silicosis, byssinosis and genetic factors. tissue, leading to shortness of breath and loss of functional 0183 Exemplary lung diseases for the treatment or pre alveoli, thus limiting oxygen exchange. Etiologies include vention using the methods described herein include, but are inhalation of inorganic and organic dusts, gases, fumes and not limited, idiopathic pulmonary fibrosis, pulmonary fibro vapors, use of medications, exposure to radiation, and devel sis secondary to systemic inflammatory disease Such as rheu opment of disorders such as hypersensitivity pneumonitis, matoid arthritis, Scleroderma, lupus, cryptogenic fibrosing coal worker's pneumoconiosis, radiation, chemotherapy, alveolitis, radiation induced fibrosis, chronic obstructive pull transplant rejection, silicosis, byssinosis and genetic factors monary disease (COPD), sarcoidosis, Scleroderma, chronic 0180. IPF as described herein refers to "idiopathic pulmo asthma, silicosis, asbestos induced pulmonary or pleural nary fibrosis' and is in Some embodiments a chronic disease fibrosis, acute lung injury and acute respiratory distress (in that manifests over several years and is characterized by scar cluding bacterial pneumonia induced, trauma induced, viral tissue within the lungs, in the absence of known provocation. pneumonia induced, ventilator induced, non-pulmonary sep Exercise-induced breathlessness and chronic dry cough may sis induced, and aspiration induced). be the prominent symptoms. IPF belongs to a family of lung 0.184 Inflammasome and Fibrosis disorders known as the interstitial lung diseases (ILD) or, 0185. The innate immune response comprising the more accurately, the diffuse parenchymal lung diseases. inflammasomes is one of the first lines of defense against Within this broad category of diffuse lung diseases, IPF tissue damage and pathogen invasion. The inflammasome belongs to the Subgroup known as idiopathic interstitial pneu mediates the activation and recruitment of inflammatory cells US 2015/O 196543 A1 Jul. 16, 2015 29 to the site of danger through the release of proinflammatory pathogen or irritant is unable to be cleared, leading to con factors. The inflammasomes are capable of recognizing tinuous inflammasome activation and IL-1B and IL-18 pro endogenous and exogenous alarm signals arising from intra cessing. cellular or extracellular stressors. Endogenous stressors that 0190. The role of IL-1B in fibrosis and wound healing is are known to activate the inflammasome include specific apparent and studies have elucidated some of the downstream chemical alarm signals, such as uric acid, ATP, potassium mechanisms that result in the induction of collagen. IL-1B can efflux from the cell and the newly identified endogenous directly stimulate collagen secretion by fibroblasts in a dose peptide, acALY 18. Exogenous stressors include pathogen dependent manner and the transient over-expression of IL-1B associated molecular patterns derived from a diverse range of by airway epithelial cells increases TGFB1 and collagen conserved molecular motifs that are unique to bacteria, deposition in the lung. viruses and parasites, from exogenous chemicals or ultravio 0191 The transient expression of IL-1B is important for let light. During inflammasome activation apoptosis speck normal wound healing. However, chronic expression of like protein containing a caspase activation and recruitment IL-1B appears to mediate fibrosis. In normal wound healing, domain (CARD) (ASC) moves from the nucleus and IL-1B secretion is found to peak at day 1 and declines during assembles into the inflammasome complex recruiting pro days 3-7 post-injury. Employing a deep incisional wound caspase-1. The resulting association of these proteins causes healing model, mice deficient in the IL-1 receptor had the cleavage and activation of caspase-1. Once caspase-1 is improved wound healing, with less fibrosis and more col lagenolytic activity. The wound fluids contained less TGFB1, activated, it is then able to cleave a number of key pro IL-6 and vascular endothelial growth factor, and wild-type inflammatory cytokines. Such as IL-1B and IL-18. wounds following Anakinra (IL-1 receptor antagonist) treat 0186 The NLRP3 inflammasome is the most extensively ment contained less fibrosis, Suggesting that IL-1 signaling is studied inflammasome and this inflammasome is capable of profibrotic. sensing a wide variety of alarm signals from endogenous and 0.192 Short-term IL-1B and TGFB1 exposure (minutes) in exogenous sources. It has been shown that the assembly of the proximal tubular cells inhibited the phosphorylation of NLRP3 inflammasome requires the presence of reactive oxy Smad3, and this in turn inhibited downstream TGFB1 signal gen species and the positional interaction between the endo ing. In contrast, long exposure (24 h) of proximal tubular cells plasmic reticulum and mitochondria. Quiescent NLRP3 is to IL-1B and TGFB1 increased Smad3 phosphorylation, fur localized to the endoplasmic reticulum. However, once the ther enhancing TGFB1 signaling. Other cells also exhibit inflammasome is activated both NLRP3 and ASC redistribute similar responses to IL-1?, and exposure of microvascular to the perinuclear region of the cell where they co-localize endothelial cells to IL-1B was found to promote the perma with the endoplasmic reticulum and mitochondrial nent transformation of these cells into myofibroblasts. organelles. (0193 IL-18 mRNA is constitutively expressed with low 0187 Assembly and activation of the inflammasome com endogenous levels of protein in normal skin. Upon injury, the plex leads to the cleavage of caspase-1 (IL-1B converting mRNA is rapidly translated into protein. Like IL-1B, IL-18 enzyme? ICE) in a process that is tightly regulated. The active protein in wounded skin is transient and peaks at days 5-7. form of caspase-1 is able to cleave a wide variety of protein Immediately after wounding, there is a rapid decrease in precursors that do not contain a secretion signaling sequence IL-18 mRNA in the skin, but this returns to normal levels by in a manner that appears to occur through an endoplasmic day 13, once re-epithelialization is complete. In wound heal reticulum/Golgi-independent pathway that is now thought to ing, IL-18 induces TGFB1 and can induce IFNY secretion by involve autophagy. In addition to autophagy regulating the inflammatory cells. Interestingly, the inhibition of IFNY sig secretion of IL-1B, it also appears that autophagy may regu naling results in improved wound healing compared to wild late the activation of the inflammasome. It has been shown type mice, Suggesting that IFNY is required for balanced that ASC is secreted from activated myofibroblasts at a higher wound healing and that its absence may promote fibrosis. rate than quiescent fibroblasts and other cells, suggesting that 0194 The involvement of the inflammasome in fibrotic the inflammasome is secreted in a process that regulates its diseases is being elucidated. However, many studies to date own activation. Furthermore, once activated, caspase-1 also have focused on inflammasome activation in inflammatory induces its own secretion, possibly by the same autophagic cells, rather than the activation of the inflammasome in stro mechanism, and we believe that this may also further regulate mal cells or parenchymal cells. Activation of the inflamma the cleavage of proteins that are processed by caspase-1. Some appears to be involved in many chronic idiopathic dis eases in addition to being involved in pathogen recognition or 0188 IL-1B and IL-18 belong to the IL-1 family of pro the recognition of cellular alarm signals (alarmins). It is teins are processed into mature biologically active proteins speculated that fibrosis could be dependent on a number of when caspase-1 is activated. These proteins then become factors, including the initiating events leading to inflamma available for secretion. Numerous other proteins are also Some activation, the specifically activated inflammasome or processed by caspase-1 and many of these proteins are inflammasome combination, the genetic variations that affect involved in inflammation, the cytoskeleton of the cell and the response of the target cell to the activated inflammasome, other functions. inflammasome by-products, such as IL-1B and IL-18, the 0189 Depending on the initiating mechanism, activation level of cytokine secreted from the cell, the cell type in which of the inflammasome can run a well-defined course, with the inflammasome is activated (inflammatory cells versus resolution of inflammation and healing of the injury, or be stromal or parenchymal cells) or the duration of the activation continuous, resulting in chronic disease or fibrosis. It is of the inflammasome. speculated that in acute disease, the injury is able to be com 0.195 Even though stromal cells are not immune cells, pletely resolved, with clearance of the initiating signal, activation of these cells is capable of inducing cytokine secre whereas in chronic disease leading to fibrosis the resulting tion that promotes downstream recruitment of inflammatory US 2015/O 196543 A1 Jul. 16, 2015 30 cells, and this can occur by inflammasome activation. Fibro fibrosis. Furthermore, the pathogenic cell that drives the blasts have not been considered central to the immune increased collagen synthesis in the skin and organs, the myo response, neither have they been considered to be immuno fibroblast, could be phenotypically altered by inhibiting logically relevant in infections. However, they can become caspase-1. Specifically, C-Smooth muscle actin stress fibers activated to release of chemokines and cytokines for the were thinner and contained less protein when caspase-1 Sig recruitment of monocytes and neutrophils to sites when the naling was inhibited. No change in C-Smooth muscle actin skin has been breached or infected by a pathogen. Fibroblasts expression was observed in quiescent fibroblasts and f-actin may be considered a sentinel cell that respond to bacterial expression was unaffected by caspase-1 inactivation. These products and cellular alarm signals due to tissue damage. findings were further recapitulated in NLRP3- and ASC Inflammasome activation induces the differentiation of qui deficient mice in a model of dermal fibrosis. The induction of escent fibroblasts to myofibroblasts. From this, continuous dermal fibrosis with subcutaneous injections of bleomycin inflammasome dysregulation that promotes myofibroblast was inhibited in the knockout mice, as was pulmonary fibro differentiation may be a key factor in excessive extracellular sis. These findings suggest that active caspase-1 regulates SSc matrix accumulation and resulting organ failure. In contrast, fibrosis and Suggests that there may be autocrine signaling in normal wound healing, inflammasome signalling is tightly mediated by IL-1B and/or IL-18 that promotes the profibrotic regulated and, once the wound is closed, the myofibroblasts phenotype in these patients. undergo apoptosis, limiting collagen secretion. 0200 Recently it was found that stimulation of cardiac (0196. Many studies corroborate the role of the NLRP3 fibroblasts, but not cardiomyocytes, with conditions mimick inflammasome in driving collagen deposition in the tissues ing hypoxia and reoxygenation stimulated the inflammasome and the activation of caspase-1 in wound healing: 1. In mice and that this could lead to fibrosis. Under these conditions, deficient in ASC protein had attenuated responses to the profi reactive oxygen species and potassium efflux were the driving brotic compound, bleomycin; 2. In mice deficient in the IL-1 forces behind inflammasome activation. ASC-deficient mice receptor there were also abrogated responses to bleomycin; 3. had attenuated responses to ischaemia-reperfusion and Direct administration of recombinant IL-1B into the lungs of reduced numbers of infiltrating macrophages and neutro wild-type mice, resulted in marked increase in tissue destruc phils. This study provides further evidence that fibroblasts tion with inflammation and collagen deposition; and 4 Inhi may act as sentinel cells capable of sensing danger signals bition of IL-1 signaling with the IL-1 receptor antagonist that are a result of ischaemia and reperfusion, causing an (Anakinra) limited fibrosis and was more effective than the enhanced inflammatory response in the heart and inciting the administration of IL-1B-neutralizing antibodies. deposition of collagens. 0197). In further studies it was found that uric acid was 0201 Endoplasmic Reticulum Stress and Fibrosis released into the lung parenchyma when bleomycin was 0202 The endoplasmic reticulum (ER) is a specialized instilled into the lungs. Uric acid is soluble in the cytosol of cellular organelle that functions as the site for folding of the cell. However, when it is released by injured cells it proteins destined for several cellular compartments or the precipitates, forming monosodium urate crystals that are extracellular milieu. The ER also serves as a site for the microscopic in size, and these crystals stimulate an immune biosynthesis for steroids, cholesterol and other lipids, and for response. It was speculated that the localized increase in uric the storage and cytosolic release of calcium. In addition, the acid resulted in the deposition of crystals that cause mem ER can activate several signaling pathways collectively brane damage to cells, resulting in the activation of NLRP3 called the unfolded protein response (UPR) when it sustains inflammasome and Subsequent release of IL-1B. It was fur stress that challenges its function. In eukaryotic cells, three ther demonstrated that the signaling mediated by uric acid ER-resident transmembrane proteins are crucial for sensing was dependent on the IL-1 receptor and the NLRP3 inflam ER stress and transducing signals during the UPR: inositol masome, and Suggested that an autocrine signaling loop requiring enzyme 1 (IRE1), double-stranded RNA-activated mediating resulting fibrosis. Utilizing the caspase-1 deficient protein kinase-(PKR)-like eukaryotic initiation factor 2C. mouse, it was demonstrated that caspase-1 was necessary for kinase (PERK) and the activating transcription factor-6 the profibrotic effect of bleomycin. (ATF6). During transient and mild ER stress, the UPR 0198 Hepatic stellate cells are able to differentiate into restores ER homeostasis by adaptive mechanisms, including myofibroblasts and up-regulate collagen secretion. Activated the expansion of ER size, enhanced protein folding capacity, hepatic stellate cells can phagocytose pathogen and cellular Suppression of protein synthesis through transcriptional and debris, present antigen, expressa-Smooth muscle actin stress translational controls, and degradation of unfolded or mis fibers, and migrate. It has been shown that monosodium urate folded proteins. However, if the stress is persistent and strong, crystals activated the inflammasome, leading to liver fibrosis. the UPR activates mitochondria-dependent or mitochondria Together, these findings further suggested that the inflamma independent apoptotic pathways. UPR signaling pathways Some is an important signaling pathway central to fibrotic are also involved in the activation of NF-kB, the major tran diseases. In addition, it was shown that progression liver Scription factor regulating inflammatory processes. All three fibrosis was mediated by IL-1C. and IL-1B, peaking on day 1, UPR pathways induced by the ER sensors IRE1C. and PERK, whereas collagen and a-Smooth muscle actin peaked at day 3. and ATF6 potentially contribute to NF-KB activation during 0199. It has been shown that fibrosis in the autoimmune ER stress. During UPR activation the ER-resident IRE1C. disease systemic Sclerosis (SSc.; Scleroderma) is dependent activates NF-kB through the IKB kinase (IKK) complex on the inflammasome. It was shown that collagen secretion by recruited by the formation of a complex between IRE1C. and myofibroblasts could be abrogated if caspase-1 was inhibited TRAF2. The kinase activity of IRE1C. phosphorylates IKK, and, by inhibiting caspase-1, IL-1B and IL-18 were also leading to degradation of I-KB and Subsequent activation of inhibited. These data suggest that the release of IL-1B and NF-kB. PERK-induced phosphorylation of a subunit of the IL-18 in SSc is mediated by an inflammasome activation that eukaryotic initiation factor 2-alpha (eIF2C) decreases the is dependent on caspase-1, and that this process is driving level of IKB protein by repression of I-KB translation, facili US 2015/O 196543 A1 Jul. 16, 2015

tating the nuclear translocation of NF-kB to regulate the doxorubicin has a broad spectrum of therapeutic activity transcription of target genes. In addition to these mecha against various tumors. However, its clinical use is limited by nisms, NF-kB may be activated by calcium-mediated ROS its undesirable systemic toxicity, especially in the heart and production during ER stress. Taken together, NF-KB activa kidney. tion associated with ER stress participates in the priming step 0209. The term “kidney toxicity’ by non-limiting example of IL-1B production and inflammasome activation. may be associated with or caused by exposure to chemothera 0203 Kidney Fibrosis peutic agents having toxic effects. By non-limiting example 0204. In some embodiments, the compositions and meth doxorubicin has a broad spectrum of therapeutic activity ods described hereincan treat or slow down the progression of against various tumors. However, its clinical use is limited by or prevent kidney fibrosis. Kidney fibrosis may develop as a its undesirable systemic toxicity, especially in the heart and result of chronic infection, obstruction of the ureter by cal kidney. culi, malignant hypertension, radiation therapy, transplant 0210 Cardiac Fibrosis rejection, severe diabetic conditions, or chronic exposure to 0211. In some embodiments, the compositions and meth heavy metals. In addition, idiopathic glomerulosclerosis and ods described herein can treat or slow down the progression of renal interstitial fibrosis have been reported in children and or prevent cardiac fibrosis. Cardiac remodeling as in chronic adults. Kidney fibrosis correlates well with the overall loss of hypertension involves myocyte hypertrophy as well as fibro renal function. Studies have shown that oral pirfenidone pro sis, an increased and non-uniform deposition of extracellular vides protective effect against heavy metal challenge and matrix proteins. The extracellular matrix connects myocytes, fibrosis reversal following diabetic challenge in rats. Addi aligns contractile elements, prevents overextending and dis tionally, the antifibrotic action of pirfenidone in renal fibrosis ruption of myocytes, transmits force and provides tensile following partial nephrectomy in rats has also been shown. strength to prevent rupture. Fibrosis occurs in many models of Moreover, clinical studies administering oral pirfenidone hypertension leading to an increased diastolic stiffness, a have shown slowed renal function decline in focal segmental reduction in cardiac function and an increased risk of arrhyth glomeruloschlerosis patients. In some embodiments, because mias. If fibrosis rather than myocyte hypertrophy is the criti the kidneys vasculature is immediately downstream of the cal factor in impaired cardiovascular function, then reversal lung, inhaled delivery of pirfenidone or pyridone analog may of cardiac fibrosis by itself may return cardiac function be an effective means to prevent, manage or treat kidney towards normal. Since collagen deposition is a dynamic pro fibrosis resulting from various medical conditions or proce cess, appropriate pharmacological intervention could selec dures without exposing the systemic compartment to other tively reverse existing fibrosis and prevent further fibrosis and wise toxic drug levels associated with oral administration. thereby improve function, even if the increased systolic blood 0205 The term “kidney fibrosis” by non-limiting example pressure was unchanged. relates to remodeling associated with or resulting chronic 0212 Treatment of DOCA-salt hypertensive rats with pir infection, obstruction of the ureter by calculi, malignant fenidone reversed and prevented fibrosis. Suggesting that hypertension, radiation therapy, transplant rejection, severe pirfenidone or pyridone analog therapy may be an effective diabetic conditions or chronic exposure to heavy metals. In means to attenuate cardiac fibrosis associated with chronic some embodiments, kidney fibrosis correlates well with the hypertension and also the functional impairment of the heart overall loss of renal function. in hypertensive humans. Moreover, the reversal of fibrosis 0206 Heart and Kidney Toxicity following pirfenidone treatment of streptozotocin-diabetic 0207. In some embodiments, the compositions and meth rats was also shown (Miric et al., 2001). Together, and ods described hereincan treat or slow down the progression of because the heart vasculature are immediately downstream of or prevent heart and/or kidney toxicity. Chemotherapeutic the lung, inhaled delivery of pirfenidone or pyridone analog agents have toxic effects upon multiple organ during therapy. may be an effective means to prevent, manage or treat cardiac By non-limiting example doxorubicin has a broad spectrum fibrosis resulting from various medical conditions or proce of therapeutic activity against various tumors. However, its dures, including by non-limiting example viral or bacterial clinical use is limited by its undesirable systemic toxicity, infection, Surgery, Duchenne muscular dystrophy, radiation, especially in the heart and kidney. Treatment with pirfenidone chemotherapy, and transplant rejection. reduced the severity of doxorubicin-induced toxicity as 0213. The term “cardiac fibrosis” by non-limiting assessed by reduced mortality, diminished volume of recov example relates to remodeling associated with or resulting ered fluid in the abdominal cavity, and severity of cardiac and from viral or bacterial infection, Surgery, Duchenne muscular renal lesions at both the biochemical and morphological lev dystrophy, radiation therapy, chemotherapy, transplant rejec els. In some embodiments, because the heart and kidney tion and chronic hypertension where myocyte hypertrophy as vasculature are immediately downstream of the lung, inhaled well as fibrosis is involved and an increased and non-uniform delivery of pirfenidone or pyridone analog may be an effec deposition of extracellular matrix proteins occurs. Fibrosis tive means to prevent, manage or treat chemotherapy-induced occurs in many models of hypertension leading to an cardiac and/or renal inflammation without exposing the sys increased diastolic stiffness, a reduction in cardiac function, temic compartment to otherwise toxic drug levels associated an increased risk of arrhythmias and impaired cardiovascular with oral administration. In some embodiments, inhaled function. delivery of pirfenidone or pyridone analog compound is used 0214) Hepatic Fibrosis in the treatment of heart toxicity and/or kidney toxicity asso 0215. In some embodiments, the compositions and meth ciated with chemotherapy or other therapeutic agents in a ods described herein can treat or slow down the progression of human. or prevent hepatic fibrosis. Hepatic fibrosis occurs conse 0208. The term “heart toxicity’ by non-limiting example quence of severe liver damage in patients with chronic liver may be associated with or caused by exposure to chemothera disease, caused by non-limiting example persistent viral peutic agents having toxic effects. By non-limiting example hepatitis, alcohol overload and autoimmune. Hepatic fibrosis US 2015/O 196543 A1 Jul. 16, 2015 32 involves an abnormal accumulation of extracellular matrix p38 subgroup of mitogen-activated protein kinases components, particularly collagens. Hepatic stellate cells are (MAPKs), a family of signal transduction enzymes that also non-parenchymal liver cells residing in the perisinusoidal include extracellular signal-regulated kinases (ERK) and space. These cells have been shown to be the major cellular c-jun NH2-terminal kinases (INK). JNK and p38 members source of extracellular matrix in hepatic fibrosis. Studies have are activated mainly by cytokines implicated in inflammation shown that oral pirfenidone provides protective effect against and apoptosis. Within the MAPK family, both the JNK and dimethylnitrosamine-induced hepatic fibrosis in preventing the p38 Subgroups are involved in mediating pro-inflamma weight loss, Suppressed loss in liver weight, Suppressed tory responses, though p38 seems to play a prominent role in induction of hepatic fibrosis determined by histological COPD. Pirfenidone has been shown to inhibit both TNF evaluation and reduced hepatic hydroxyproline levels. alpha and p38-gamma MAPK. Moreover, silencing p38 Expression of mRNA for type I collagen and transforming gamma MAPK has been demonstrated to have potential to growth factor-beta in the liver were also suppressed by pir restore COPD sensitivity to corticosteroids (Mercado et al., fenidone treatment. Additionally, clinical studies administer 2007). In some embodiments, inhaled delivery of pirfenidone ing oral pirfenidone have shown decreased fibrosis and or pyridone analog compound is used in the treatment of improved quality of life in Hepatitis C viral-related liver COPD in a human. In some embodiments, inhaled delivery of disease patients. Together, and because the liver vasculature is pirfenidone or pyridone analog may be an effective means to downstream of the lung, these results suggest that inhaled prevent, manage or treat COPD or associated illness without delivery of pirfenidone or pyridone analog may be an effec exposing the systemic compartment to otherwise toxic drug tive means to prevent, manage or treat hepatic fibrosis result levels associated with oral administration. Moreover, inhaled ing from various medical conditions or procedures without delivery of pirfenidone or pyridone analog may serve as con exposing the systemic compartment to otherwise toxic drug junctive therapy with corticosteroids to restore their useful levels associated with oral administration. ness in this indication. 0216. The term “hepatic fibrosis”s by non-limiting 0222. The term "chronic obstructive pulmonary disesase s example may be associated with or caused by severe liver or “COPD by non-limiting example may be associated with damage in patients with chronic liver disease, caused by or caused by exposure to tobacco smoke and preexisting non-limiting example persistent viral hepatitis, alcohol over asthma. COPD describes a wide range of airway disorders load and autoimmune diseases. Hepatic fibrosis involves an that range from simple chronic bronchitis (Smokers cough) to abnormal accumulation of extracellular matrix components, the more severe chronic obstructive bronchitis. The addition particularly collagens. Hepatic stellate cells are non-paren of episodes of airway hyper-reactivity to the above syndrome chymal liver cells residing in the perisinusoidal space. establishes the diagnosis of chronic asthmatic bronchitis. 0217. Multiple Sclerosis Chronic obstructive pulmonary disease includes, but is not 0218. In some embodiments, the compositions and meth limited to, chronic bronchitis, emphysema, and/or pulmonary ods described hereincan treat or slow down the progression of hypertension. or prevent multiple sclerosis. Multiple sclerosis is a demyeli 0223) Asthma nating disorder that is characterized by neurological deficits 0224. In some embodiments, the compositions and meth attributable to demyelinating lesions and progressive axonal ods described herein can treat or slow down the progression of loss in the white matter. The evidence that TNF-alpha plays a or prevent asthma. TNF-alpha has been shown to be a highly pivotal role in the pathogenesis of multiple Sclerosis led to pro-inflammatory cytokine in asthma, as it upregulates adhe evaluation of pirfenidone in this indication. In a clinical study, sion molecules, increases mucin secretion, and promotes air oral pirfenidone improved the Scripps Neurological Rating way remodeling. TNF-alpha is produced by a large number of Scale scores over placebo. Further, pirfenidone reduced the cells in the airways, including mast cells, Smooth muscle incidence of relapses and was associated with a marked cells, epithelial cells, monocytes, and macrophages. This improvement in bladder dysfunction. Together, and because cytokine has been shown to be relevant and increased in the central nervous system vasculature is immediately down patients with asthma. Clinical studies using anti-TNF-alpha stream of the lung, these results suggest that inhaled delivery therapy have produced encouraging results. In one set of of pirfenidone or pyridone analog may be an effective means studies using a soluble form of recombinant human TNF to prevent, manage or treat multiple Sclerosis without expos alpha receptor (etanercept) the medication improved FEV1 ing the systemic compartment to otherwise toxic drug levels and improved quality of life. Another clinical study adminis associated with oral administration. tering an anti-TNF-alpha antibody reduced asthma exacerba 0219. The term “multiple sclerosis” is a demyelinating tion (infliximab). However, because of concerns associated disorder that is characterized by neurological deficits attrib with adverse events future investigation of these therapies in utable to demyelinating lesions and progressive axonal loss in asthma is unlikely. Because pirfenidone has been shown to the white matter. inhibit TNF-alpha, inhaled delivery of pirfenidone or pyri 0220 Chronic Obstructive Pulmonary Disease (COPD) done analog may be an effective means to manage or treat 0221. In some embodiments, the compositions and meth asthma or associated illness without exposing the systemic ods described hereincan treat or slow down the progression of compartment to otherwise toxic drug levels associated with or prevent COPD. Oxidants and oxidative stress due to, by oral administration. In some embodiments, inhaled delivery non-limiting example, cigarette Smoking promote lung of pirfenidone or pyridone analog compound is used in the inflammation, which is mediated, at least in part, by activation treatment of asthma in a human. Moreover, inhaled delivery of the transcription factors nuclear factor (NF)-KB and acti of pirfenidone or pyridone analog may serve as conjunctive vator protein (AP)-1. These coordinate the expression of sev therapy with corticosteroids to restore their usefulness in eral genes thought to be important in COPD, such as inter asthma patients exhibiting steroid resistance. leukin (IL)-8 and TNFC. These pro-inflammatory cytokines 0225. The term “asthma’ is associated with or caused by and chemokines, together with IL-1B, strongly activate the environmental and genetic factors. Asthma is a common US 2015/O 196543 A1 Jul. 16, 2015 chronic inflammatory disease of the airways characterized by 0233. Although the “seed and soil” hypothesis was pre variable and recurring symptoms, reversible airflow obstruc sented more than a century ago, we are now starting to com tion, and bronchospasm. Symptoms include wheezing, prehend the complex crosstalk between the tumor cells (the coughing, chest tightness, and shortness of breath. The term 'seeds') and the tumor-growing microenvironment (the asthma may be used with one or more adjectives to indicate “soil'). We now know that tumor growth is not determined cause. Non-limiting examples of asthma include, but are not only by malignant cells, because interactions between cancer limited to, allergic asthma, non-allergic asthma, acute severe cells and the Stromal compartment have major impacts on asthma, chronic asthma, clinical asthma, nocturnal asthma, cancer growth and progression. Aggressive malignant cells allergen-induced asthma, aspirin-sensitive asthma, exercise are clever at exploiting the tumor microenvironment: tumor induced asthma, child-onset asthma, adult-onset asthma, cells can (1) reside in the stroma and transform it, (2) alter the cough-variant asthma, occupational asthma, steroid-resistant Surrounding connective tissue, and (3) modify the metabo asthma, or seasonal asthma. lism of resident cells, thus yielding a stroma, which is per 0226 Lung Inflammation missive rather than defensive. 0227. In some embodiments, the compositions and meth 0234 Beyond overcoming the microenvironmental con ods described hereincan treat or slow down the progression of trol by the host, key characteristics of cancer cells is their or prevent lung inflammation. Pirfenidone therapy has shown ability to invade the tissue and metastasize distantly. For to have anti-inflammatory effects in addition to anti-fibrotic invasion and metastasis, the concerted interactions between effects. In some embodiments, pirfenidone or pyridone ana fibroblasts, immune cells, and angiogenic cells and factors log compound is administered to a human to treat lung are essential. inflammation. Lung inflammation is associated with or con 0235. The tumor stroma basically consists of (1) the non tributes to the symptoms of bronchitis, asthma, lung fibrosis, malignant cells of the tumor such as CAFs, specialized mes chronic obstructive pulmonary disorder (COPD), and pneu enchymal cell types distinctive to each tissue environment, monitis. innate and adaptive immune cells, and vasculature with endothelial cells and pericytes and (2) the extracellular matrix 0228 Glaucoma Surgery Post-Operative Fibrosis (ECM) consisting of structural proteins (collagen and elas 0229. The success of glaucoma filtration surgery is depen tin), specialized proteins (fibrilin, fibronectin, and elastin), dent on the degree of post-operative wound healing and the and proteoglycans. Angiogenesis is central for cancer cell amount of scar tissue formation. Bleb failure occurs as fibro growth and survival and has hitherto been the most successful blasts proliferate and migrate toward the wound, eventually among stromal targets in anticancer therapy. Initiation of causing Scarring and closure of the fistula tract. This fre angiogenesis requires matrix metalloproteinase (MMP) quently leads to poor postoperative intraocular pressure con induction leading to degradation of the basement membrane, trol with Subsequent progressive optic nerve damage. The use sprouting of endothelial cells, and regulation of pericyte of adjunctive antifibrotic agents such as 5-fluorouracil and attachment. However, CAF's play an important role in Syn mitomycin C has significantly improved the Success rate of chronizing these events through the expression of numerous filtration surgery. However, because of their nonspecific ECM molecules and growth factors, including transforming mechanisms of action, these agents can cause widespread cell growth factor (TGF)-?3, vascular endothelial growth factor death and apoptosis, resulting in potentially sight-threatening (VEGF), and fibroblast growth factor (FGF2). complications such as severe postoperative hypotony, bleb 0236. The normal tissue stroma is essential for mainte leaks, and endophthalmitis. Thus, alternative antifibrotic nance and integrity of epithelial tissues and contains a mul agents are needed. For this purpose, the anti-fibrotic agent titude of cells that collaborate to sustain normal tissue homeo pirfenidone or pyridone analog may prove beneficial. Stasis. There is a continuous and bilateral molecular crosstalk 0230 Cancer between normal epithelial cells and cells of the stromal com 0231 Lung cancer mortality is high, and annual lung can partment, mediated through direct cell-cell contacts or by cer deaths equal prostate, breast, colon, and rectum cancers secreted molecules. Thus, minor changes in one compartment combined. Despite the advancement in knowledge on may cause dramatic alterations in the whole system. molecular mechanisms and the introduction of multiple new 0237. A similarity exists between stroma from wounds therapeutic lung cancer agents, the dismal 5-year Survival rate and tumors, because both entities had active angiogenesis and (11-15%) remains relatively unaltered. This reflects the lim numerous proliferating fibroblasts secreting a complex ECM, ited available knowledge on factors promoting oncogenic all on a background of fibrin deposition. Consequently, the transformation to and proliferation of malignant cells. tumor stroma has been commonly referred to as activated or 0232 Until recent years, the principal focus in cancer reactive stroma. research has mostly been the malignant cell itself. As a con 0238 A genetic alteration during cancer development, sequence, today, there is a significant discrepancy between leading to a malignant cell, will consequently change the the vast knowledge about cancer biology generated in experi stromal host compartment to establish a permissive and Sup mental settings and the translation of this knowledge into portive environment for the cancer cell. During early stages of information that can be used in clinical decision making tumor development and invasion, the basement membrane is Understanding the nature of the tumor environment today degraded, and the activated Stroma, containing fibroblasts, may be equally important for future cancer therapies as inflammatory infiltrates, and newly formed capillaries, comes understanding cancer genetics perse. Cancers are not simply into direct contact with the tumor cells. The basement mem autonomous neoplastic cells but also composed offibroblasts, brane matrix also modifies cytokine interactions between immune cells, endothelial cells, and specialized mesenchy cancer cells and fibroblasts. These cancer-induced alterations mal cells. These different cell types in the stromal environ in the stroma will contribute to cancer invasion. Animal stud ment can be recruited by malignant cells to Support tumor ies have shown that both wounding and activated Stroma growth and facilitate metastatic dissemination. provides oncogenic signals to facilitate tumorigenesis. US 2015/O 196543 A1 Jul. 16, 2015 34

Although normal stroma in most organs contains a minimal Xenografts models, and evidence from translational studies number of fibroblasts in association with physiologic ECM, has revealed a prognostic significance of CAF's in several the activated stroma is associated with more ECM-producing carcinoma types. fibroblasts, enhanced vascularity, and increased ECM pro 0244. In the setting of tumor growth, CAFs are activated duction. This formation of a specific tumor stroma type at and highly synthetic, Secreting, for example, collagen type I sites of active tumor cell invasion is considered an integral and IV, extra domain A-fibronectin, heparin Sulfate proteo part of the tumor invasion and has been termed as tumor glucans, secreted protein acidic and rich in cysteine, tenascin stromatogenesis. C, connective tissue growth factors, MMPs, and plasminogen 0239. The expansion of the tumor stroma with a prolifera activators. In addition to secreting growth factors and cytok tion of fibroblasts and dense deposition of ECM is termed a ines, which affect cell motility, CAFs are an important source desmoplastic reaction. It is secondary to malignant growth for ECM-degrading proteases such as MMPs that play several and can be separated from alveolar collapse, which do not important roles in tumorigenesis. Through degradation of show neither activated fibroblasts nor the dense collagen/ ECM, MMPs can, depending on substrate, promote tumor ECM. Morphologically this is termed desmoplasia and was growth, invasion, angiogenesis, recruitment of inflammatory initially conceived as a defense mechanism to prevent tumor cells, and metastasis. Besides, a number of proinflammatory growth, but data have shown that in established tumors, this cytokines seem to be activated by MMPs. process, quite oppositely, participates in several aspects of 0245. After injection of B16M melanoma cells in mice, tumor progression, Such as angiogenesis, migration, invasion, the formation of liver metastases was associated with an early and metastasis. The latter studies show that fibroblasts and activation of stellate cells (fibroblast-like) in the liver, as these tumor cells can enhance local tissue growth and cancer pro seemed important for creating a metastatic niche and promot gression through secreting ECM and degrading components ing angiogenesis. MMPs have also been linked to tumor of ECM within the tumor stroma. This is in part related to the angiogenesis in various in vivo models. CAFs, when coin release of substances sequestered in the ECM, such as VEGF, jected into mice, facilitated the invasiveness of otherwise and cleavage of products from ECM proteins as a response to noninvasive cancer cells. Furthermore, Xenografts containing secretion of carcinoma-associated MMPs. CAF's apparently grow faster than Xenografts infused with normal fibroblasts. 0240 Profibrotic growth factors, released by cancer cells, 0246. At CAF recruitment and accumulation in the tumor such as TGF-B, platelet-derived growth factor (PDGF), and stroma, these cells will actively communicate with cancer FGF2 govern the volume and composition of the tumor cells, epithelial cells, endothelial cells, pericytes, and inflam stroma as they are all key mediators of fibroblast activation matory cells through secretion of several growth factors, and tissue fibrosis. PDGF and FGF2 play significant roles in cytokines, and chemokines CAF's provide potent oncogenic angiogenesis as well. molecules such as TGF-B and hepatocyte growth factor 0241. In tumors, activated fibroblasts are termed as peri (HGF). tumoral fibroblasts or carcinoma-associated fibroblasts 0247 TGF-B is a pleiotropic growth factor expressed by (CAFs). CAFs, like activated fibroblasts, are highly hetero both cancer and stromal cells. TGF-3 is, in the normal and geneous and believed to derive from the same sources as premalignant cells, a Suppressor of tumorigenesis, but as activated fibroblasts. The main progenitor seems to be the cancer cells progress, the antiproliferative effect is lost, and locally residing fibroblast, but they may also derive from instead, TGF-B promotes tumorigenesis by inducing differ pericytes and Smooth muscle cells from the vasculature, from entiation into an invasive phenotype. TGF-B may also insti bone marrow-derived mesenchymal cells, or by epithelial or gate cancer progression through escape from immunoSurveil endothelial mesenchymal transition. The term CAF is rather lance, and increased expression of TGF-B correlate strongly ambiguous because of the various origins from which these with the accumulation of fibrotic desmoplastic tissue and cells are derived, as is the difference between activated fibro cancer progression. Recently, a small molecule inhibitor of blasts and CAFs. There are increasing evidence for epigenetic TGF-B receptor type I was reported to inhibit the production and possibly genetic distinctions between CAF's and normal of connective tissue growth factor by hepatocellular carci fibroblasts. CAFs can be recognized by their expression of noma (HCC) cells, resulting in reduced stromal component of a-Smooth muscle actin, but due to heterogeneity a-Smooth the HCCs Inhibition of the TGF-B receptor aborted the muscle actin expression alone will not identify all CAFs. crosstalk between HCCs and CAFs and consequently Hence, other used CAF markers are fibroblast-specific pro avoided tumor proliferation, invasion, and metastasis. HGF tein 1, fibroblast activation protein (FAP), and PDGF receptor belongs to the plasminogen family and is tethered to ECM in (PDGFR) C/B. a precursor form. It binds to the high-affinity receptor c-met, and overexpression or constant oncogenic c-Met signaling 0242. In response to tumor growth, fibroblasts are acti lead to proliferation, invasion, and metastasis. vated mainly by TGF-B, chemokines Such as monocyte 0248 PDGFs are regulators of fibroblasts and pericytes chemotactic protein 1, and ECM-degrading agents such as and play important roles in tumor progression. It is a chemo MMPs. Although normal fibroblasts in several in vitro studies tactic and growth factor for mesenchymal and endothelial have demonstrated an inhibitory effect on cancer progression, cells. It has a limited autocrine role in tumor cell replication, today, there is solid evidence for a cancer-promoting role of but is a potential player, in a paracrine fashion, and in tumor CAFs. In breast carcinomas, as much as 80% of stromal stroma development. It induces the proliferation of activated fibroblasts are considered to have this activated phenotype fibroblasts and possibly recruits CAFs indirectly by stimula (CAFs). tion of TGF-3 release from macrophages. 0243 CAF's promote malignant growth, angiogenesis, 0249. A tumor cannot develop without the parallel expan invasion, and metastasis. The roles of CAFS and their poten sion of a tumor stroma. Although we still do not comprehend tial as targets for cancer therapy have been studied in the exact mechanisms regulating fibroblast activation and US 2015/O 196543 A1 Jul. 16, 2015

their accumulation in cancer, the available evidence points to Sickle cell disease, Schistosomiasis. This is an infection the possibility that the tumor stroma or CAF's may be candi caused by a parasite. Schistosomiasis is one of the most date targets for cancer treatment. common causes of PAH in many parts of the world; and PAH (0250 CAFs and MMPs have been considered two of the that is caused by conditions that affect the veins and small key regulators of epithelial-derived tumors representing blood vessels of the lungs. Group 2 Pulmonary Hypertension potential new targets for integrative therapies, affecting both includes PH with left heart disease. Conditions that affect the the transformed and nontransformed components of the left side of the heart, such as mitral valve disease or long-term tumor environment. As commented earlier, the experience high blood pressure, can cause left heart disease and PH. Left with MMP inhibitors have sofar been unsuccessful. Evidence heart disease is likely the most common cause of PH. Group that CAFs are epigenetically and possibly also genetically 3 Pulmonary Hypertension includes PH associated with lung distinct from normal fibroblasts is beginning to define these diseases, such as COPD (chronic obstructive pulmonary dis cells as potential targets for anticancer therapy. FAP, ease) and interstitial lung diseases. Interstitial lung diseases expressed in more than 90% of epithelial carcinomas, cause scarring of the lung tissue. Group 3 also includes PH emerged early as a promising candidate for targeting CAFs, associated with sleep-related breathing disorders, such as and the potential therapeutic benefit of its inhibition was sleep apnea. Group 4 Pulmonary Hypertension includes PH reviewed recently. In preclinical studies, abrogation of FAP caused by blood clots in the lungs or blood clotting disorders. attenuates tumor growth and significantly enhance tumor tis Group 5 Pulmonary Hypertension includes PH caused by Sue uptake of anticancer drugs. In a phase I study, where various other diseases or conditions. Examples include: patients with FAP-positive advanced carcinomas (colorectal Blood disorders, such as polycythemia Vera and essential cancer and NSCLC) were treated with FAP-antibody, the thrombocythemia, Systemic disorders, such as sarcoidosis antibody bound specifically to tumor sites, but no objective and vasculitis. Systemic disorders involve many of the body’s responses were observed. organs, Metabolic disorders, such as thyroid disease and gly 0251. The consistent and repeated findings of cancer cells cogen storage disease. (In glycogen storage disease, the that readily undergo invasion and metastasis in response to body’s cells don't use a form of glucose properly), and Other TGF-B have pointed to the need of novel anticancer agents conditions, such as tumors that press on the pulmonary arter targeting the oncogenic activities of TGF-B. A large number ies and kidney disease. of anti-TGF-B antibodies and TGF-B-receptor I kinases have 0255. Several growth factors have been implicated in the been tested preclinically during the past decade. Because of abnormal proliferation and migration of SMCs, including the lack of success, targeting of the TGF-B signaling system PDGF, basic FGF (bFGF), and EGF. In vitro studies estab still remains elusive. It should be noted that both protumoral lished that PDGF acts as a potent mitogen and chemoattrac and antitumoral effects have been assigned to TGF-B, and the tant for SMCs. Active PDGF is built up by polypeptides (A multifunctional nature of TGF-B apparently represents the and B chain) that form homo- or heterodimers and stimulate greatest barrier to effectively target this ligand, its receptor, or C. and B cell surface receptors. Recently, two additional PDGF downstream effectors. genes were identified, encoding PDGF-C and PDGF-D 0252 Pulmonary Hypertension polypeptides. The PDGF receptors (PDGFRs) belong to a 0253 Pulmonary arterial hypertension (PAH) is a life family of transmembrane receptor tyrosine kinases (RTKs) threatening disease characterized by a marked and Sustained and are supposed to be held together by the bivalent PDGF elevation of pulmonary artery pressure. The disease results in ligands. This complex of dimeric receptor and PDGF results right ventricular failure and death. Current therapeutic in an autophosphorylation of the RTK and an increase in approaches for the treatment of chronic pulmonary hyperten kinase activity. sion mainly provide symptomatic relief, as well as some 0256 Both receptors activate the major signaling trans improvement of prognosis. Although postulated for all treat duction pathways, including Ras/MAPK, PI3K, and phos ments, evidence for direct antiproliferative effects of most pholipase Cy. Recently, upregulation of both PDGFRC. and approaches is missing. In addition, the use of most of the PDGFRB has been shown in lambs with chronic intrauterine currently applied agents is hampered by either undesired side pulmonary hypertension. Pulmonary PDGF-A or PDGF-B effects or inconvenient drug administration routes. Pathologi mRNA, however, did not differ between pulmonary hyper cal changes in hypertensive pulmonary arteries include tensive and control animals. In lung biopsies from patients endothelial injury, proliferation, and hypercontraction of vas with severe pulmonary arterial hypertension (PAH), PDGF-A cular smooth muscle cells (SMCs). chain expression was significantly increased. 0254 The World Health Organization divides pulmonary hypertension (PH) into five groups. These groups are orga (0257 PDGF-A and PDGF-B mRNA synthesis and nized based on the cause of the condition and treatment steady-state levels of PDGF-A and PDGF-B mRNAs and options. In all groups, the average pressure in the pulmonary PDGF isoforms are elevated in bleomycin-treated lungs. Pir arteries is 25 mmHg or higher. The pressure in normal pull fenidone has been observed to suppress PDGF-A and monary arteries is 8-20 mmHg at rest. (Note that group 1 is PDGF-B levels, perhaps via a posttranscriptional or transla called pulmonary arterial hypertension (PAH) and groups 2 tional mechanism resulting in decreased PDGF-A and through 5 are called pulmonary hypertension. However, PDGF-B protein. Further, pirfenidone has been observed to together all groups are called pulmonary hypertension.) reduce bleomycin-induced lung fibrosis by downregulating Group 1 Pulmonary Arterial Hypertension includes PAH that the expression of PDGF-A as well as of PDGF-B proteins. has no known cause; PAH that's inherited; PAH that's caused 0258 As altered PDGF signaling plays an important role by drugs or toxins, such as Street drugs and certain diet medi in the course of PAH, pirfenidone or pyridone analog may cines; PAH that’s caused by conditions such as: Connective also have a positive effect on hemodynamics and pulmonary tissue diseases, HIV infection, Liver disease, Congenital vascular remodeling in PAH and serve as an anti-remodeling heart disease. This is heart disease that’s present at birth, therapy for this disease. US 2015/O 196543 A1 Jul. 16, 2015 36

0259. The present invention provides, in several embodi hereinas pertain to pirfenidone or pyridone analog compound ments as herein disclosed, compositions and methods for concentration, pH, and total solute concentration, tolerability pirfenidone and pyridone analog compound formulations that of formulations at or near the upper portion of the total solute offer unprecedented advantages with respect to localized concentration range can be increased by inclusion of a taste delivery of pirfenidone or pyridone analog in a manner that masking agent as provided herein. permits both rapid and sustained availability of therapeuti cally useful pirfenidone or pyridone analog levels to one or 0266. An unexpected observation is that exposure of more desired tissues. inhaled pirfenidone to the lung surface results in depletion of 0260. In certain preferred embodiments, and as described essential lung-Surface cations and increased propensity for in greater detail below, delivery of the pirfenidone or pyri acute toxicity. The apparent mechanism for this depletion is done analog compound formulation is to the respiratory tract pirfenidones ability to chelate ions such as iron(III) in a ratio tissues in mammalian Subjects, for example, via the respira of three pirfenidone molecules per on iron(III) ion. Chelation tory airways to middle airways and/or pulmonary beds (e.g., of iron(III) occurs at about one-half the chelation strength of alveolar capillary beds) in human patients. According to cer EDTA. One method to prevent lung-surface ion depletion is tain particularly preferred embodiments, delivery to these to formulation prifenidone with a multivalent ion. By non regions of the lung may be achieved by inhalation therapy of limiting example, such multi-valent cations may include iron a pirfenidone or pyridone analog compound formulation as (II), iron(III), calcium, magnesium, etc. By non-limiting described herein. example, formulation of pirfenidone was found to chlate 0261 These and related embodiments will usefully pro magnesium at a ratio of two pirfenidone molecules to one vide therapeutic and/or prophylactic benefit, by making magnesium ion. Thus, formulation of between about two and therapeutically effective pirfenidone or pyridone analog ten pirfenidone molecules with one magnesium molecule available to a desired tissue promptly upon administration, results infilling or Saturating the chelation capacity of prifeni while with the same administration event also offering time done and reduces pirfenidone's to deplete lung-Surface cat periods of Surprisingly Sustained duration during which ions. Coupling this solution with the need to adjust formula locally delivered pirfenidone or pyridone analog is available tion osmolality and permeant ion content, the salt form of for a prolonged therapeutic effect. multivalent ion may also be beneficial. By non-limiting 0262 The compositions and methods disclosed herein example, using magnesium chloride to formulate pirfenidone provide for such rapid and sustained localized delivery of a reduces pirfenidone’s ability to deplete essential lung-Surface pirfenidone or pirfenidone or pyridone analog pyridone ana cations, contributes to adjusting the formulations osmolality log compound to a wide variety of tissues. Contemplated are and serves to provide the formulation a chloride permeant embodiments for the treatment of numerous clinically signifi ion. In certain Such embodiments, for example, a pirfenidone cant conditions including pulmonary fibrosis, chronic or pyridone analog compound formulation that comprises obstructive pulmonary disease (COPD), asthma, cystic fibro pirfenidone or a pyridone analog alone or formulated with sis, cardiac fibrosis, transplantation (e.g., lung, liver, kidney, excipients dissolved in a simple aqueous solution that may be heart, etc.), Vascular grafts, and/or other conditions such as aerosolized and injected or inhaled to the nasal or pulmonary multiple sclerosis for which rapid and sustained bioavailable compartment. Such a formulation may contain a multivalent pirfenidone or pyridone analog therapy may be indicated. cation and/or be buffered to a pH from about 4.0 to about 11.0, 0263. Various embodiments thus provide compositions more preferably from about pH 4.0 to about pH 8.0, at a and methods for optimal prophylactic and therapeutic activity concentration of at least 34 mcg/mL to about 463 mg/mL, and in prevention and treatment of pulmonary fibrosis in human having a total osmolality at least 100 mOsmol/kg to about and/or veterinary Subjects using aerosol administration, and 6000 mOsmol/kg, or 300 to about 5000 mOsmol/kg. Such a through the delivery of high-concentration (or dry formula simple aqueous formulation may further comprise a taste tion), Sustained-release active drug exposure directly to the masking agent thereby to become tolerable for inhalation affected tissue. Specifically, and in certain preferred embodi administration (i.e., to overcome undesirable taste or irritative ments, concentrated doses are delivered of a pirfenidone or properties that would otherwise preclude effective therapeu pyridone analog. tic administration). Hence and as described in greater detail 0264. Without wishing to be bound by theory, according to herein, regulation of formulation conditions with respect to certain of these and related embodiments as described in pH, buffer type, pirfenidone or pyridone analog concentra greater detail herein, a pirfenidone or pyridone analog is tion, total osmolality and potential taste-masking agent, pro provided in a formulation having components that are vides certain therapeutic and other advantages. selected to deliver an efficacious dose of pirfenidone or pyri 0267 In certain such embodiments, for example, apirfeni done analog following aerosolization of a liquid, dry powder done or pyridone analog compound formulation that com or metered-dose formulation providing rapid and Sustained prises pirfenidone or a pyridone analog in a dry powder localized delivery of pirfenidone or pyridone analog to the formulation alone or formulated with an excipient, Such as a site of desired effect. multivalent cation providing improved Stability and/or dis 0265 According to certain related embodiments, regula persion properties. Such that at least 0.1 mg to about 100 mg tion of the total amount of dissolved solutes in a pirfenidone may be dispersed and injected or inhaled to the nasal or or pyridone analog compound formulation is believed, pulmonary compartment. Hence and as described in greater according to non-limiting theory, to result in aqueous pirfeni detail herein, regulation of formulation conditions with done or pyridone analog compound formulations having respect to dispersion excipient, pirfenidone or pyridone ana therapeutically beneficial properties, including the properties log stability (including, by non-limiting example polymorph, of nebulized liquid particles formed from aqueous solutions amorphic content and water content), pirfenidone orpyridone of such formulations. Additionally, and as disclosed herein, it analog amount and potential taste-masking agent, provides has been discovered that within the parameters provided certain therapeutic and other advantages. 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0268. In certain such embodiments, for example, apirfeni ants (e.g. dust, Vapors, fumes, and inorganic and organic done or pyridone analog compound formulation that com fibers), hypersensitivities, silicosis, byssinosis, genetic fac prises pirfenidone or a pyridone analog in a pressurized tors and transplant rejection. meter-dose inhaler configuration providing improved stabil 0273. These and related applications are also contem ity and/or aerosol properties, such that at least 0.1 mg to about plated for use in the diseased lung, sinus, nasal cavity, heart, 100 mg may be aerosolized and injected or inhaled to the kidney, liver, nervous system and associated vasculature. The nasal or pulmonary compartment. Hence and as described in pirfenidone or pyridone analog compound formulations and greater detail herein, regulation of formulation conditions methods described herein may be used with commercially with respect to propellant, Suitable pressurized metered-dose available inhalation devices, or with other devices for aerosol inhaler canister, pirfenidone or pyridone analog stability pro therapeutic product administration. vides certain therapeutic and other advantages. 0274 As a non-limiting example, in a preferred embodi ment, a pyridone analog compound as provided herein (e.g., 0269. In certain preferred embodiments, a pirfenidone or pirfenidone) formulated to permit mist, gas-liquid Suspension pyridone analog compound formulation or salts thereof may or liquid nebulized, dry powder and/or metered-dose inhaled serve as prodrugs, Sustained-release or active Substances in aerosol administration to Supply effective concentrations or the presently disclosed formulations and compositions and amounts conferring desired anti-inflammatory, anti-fibrotic may be delivered, under conditions and for a time sufficient to or tissue-remodeling benefits, for instance, to prevent, man produce maximum concentrations of Sustained-release or age or treat cardiac fibrosis in human and/or veterinary Sub active drug to the respiratory tract (including pulmonary jects. Such embodiments provide for direct and high concen beds, nasal and sinus cavities), and other non-oral topical tration delivery of the pirfenidone or pyridone analog compartments including, but not limited to the skin, rectum, compound to the pulmonary vasculature immediately vagina, urethra, urinary bladder, eye, and ear. As disclosed upstream of the left atrium and hence, to the coronary arterial herein, certain particularly preferred embodiments relate to system with interlumenal atrial and Ventricular exposure. administration, via oral and/or nasal inhalation, of a pirfeni done or pyridone analog compound to the lower respiratory 0275 Because different drug products are known to vary tract, in other words, to the lungs or pulmonary compartment in efficacy depending on the dose, form, concentration and (e.g., respiratory bronchioles, alveolar ducts, and/or alveoli), delivery profile, the presently disclosed embodiments pro as may be effected by such “pulmonary delivery to provide vide specific formulation and delivery parameters that pro effective amounts of the pirfenidone or pyridone analog.com duce protection against and treatment for cardiac fibrosis pound to the pulmonary compartment and/or to other tissues associated, by non-limiting example with infection, Surgery, and organs as may be reached via the circulatory system radiation therapy, chemotherapy and transplant rejection. Subsequent to such pulmonary delivery of the pirfenidone or 0276. As a non-limiting example, in a preferred embodi pyridone analog compound to the pulmonary vasculature. ment, a pyridone analog compound as provided herein (e.g., pirfenidone) formulated to permit mist, gas-liquid Suspension 0270. Because different drug products are known to have or liquid nebulized, dry powder and/or metered-dose inhaled varying efficacies depending on the dose, form, concentration aerosol administration to Supply effective concentrations or and delivery profile, certain presently disclosed embodiments amounts conferring desired anti-inflammatory, anti-fibrotic provide specific formulation and delivery parameters that or tissue-remodeling benefits, for instance, to prevent, man produce anti-inflammatory, anti-fibrotic, anti-demylination age or treat kidney fibrosis. Such embodiments provide for and/or tissue-remodeling results that are prophylactic or direct and high concentration delivery of the pirfenidone or therapeutically significant. These and related embodiments pyridone analog compound to the pulmonary vasculature thus preferably include a pirfenidone or pyridone analog immediately upstream of the left atrium, left ventrical and compound Such as pirfenidone or pyridone analog alone or a hence, to the kidney vasculature. salt thereof. As noted above, however, the invention is not intended to be so limited and may relate, according to par 0277 Because different drug products are known to vary ticularly preferred embodiments, to pirfenidone or a salt in efficacy depending on the dose, form, concentration and thereof. Other contemplated embodiments may relate to delivery profile, the presently disclosed embodiments pro another pyridone analog compound Such as those disclosed vide specific formulation and delivery parameters that pro herein. duce protection against and treatment for kidney fibrosis associated, by non-limiting example with infection, ureter 0271 As a non-limiting example, in a preferred embodi calculi, malignant hypertension, radiation therapy, diabetes, ment, a pyridone analog compound as provided herein (e.g., exposure to heavy metals, chemotherapy and transplant rejec pirfenidone) formulated to permit mist, gas-liquid Suspension tion. or liquid nebulized, dry powder and/or metered-dose inhaled 0278. As a non-limiting example, in a preferred embodi aerosol administration to supply effective concentrations or ment, a pyridone analog compound as provided herein (e.g., amounts conferring desired anti-inflammatory, anti-fibrotic pirfenidone) formulated to permit mist, gas-liquid Suspension or tissue-remodeling benefits, for instance, to prevent, man or liquid nebulized, dry powder and/or metered-dose inhaled age or treat patients with pulmonary fibrosis. aerosol administration to Supply effective concentrations or 0272 Because different drug products are known to vary amounts conferring desired anti-inflammatory benefits, for in efficacy depending on the dose, form, concentration and instance, to prevent, manage or treat heart or kidney toxicity. delivery profile, the presently disclosed embodiments pro Such embodiments provide for direct and high concentration vide specific formulation and delivery parameters that pro delivery of the pirfenidone or pyridone analog compound to duce protection against and treatment for pulmonary fibrosis the pulmonary vasculature immediately upstream of the left associated, by non-limiting example with infection, radiation atrium, left ventrical, and hence, to the heart and kidney therapy, chemotherapy, inhalation of environmental pollut vasculature. US 2015/O 196543 A1 Jul. 16, 2015

0279 Because different drug products are known to vary duce protection against and treatment for COPD associated, in efficacy depending on the dose, form, concentration and by non-limiting example with exposure to pipe, cigar and delivery profile, the presently disclosed embodiments pro cigarette Smoke, secondhand Smoke, air pollution, and vide specific formulation and delivery parameters that pro chemical fumes or dust, and/or alpha-1 antitrypsin deficiency. duce protection against and treatment for heart or kidney 0286 As a non-limiting example, in a preferred embodi toxicity associated, by non-limiting example with chemo ment, a pyridone analog compound as provided herein (e.g., therapy. pirfenidone) formulated to permit mist, gas-liquid Suspension 0280. As a non-limiting example, in a preferred embodi or liquid nebulized, dry powder and/or metered-dose inhaled ment, a pyridone analog compound as provided herein (e.g., aerosol administration to Supply effective concentrations or pirfenidone) formulated to permit mist, gas-liquid Suspension amounts conferring desired anti-inflammatory benefits, for or liquid nebulized, dry powder and/or metered-dose inhaled instance, to prevent, manage or treat patients with asthma. aerosol administration to supply effective concentrations or 0287 Because different drug products are known to vary amounts conferring desired anti-inflammatory, anti-fibrotic in efficacy depending on the dose, form, concentration and or tissue-remodeling benefits, for instance, to prevent, man delivery profile, the presently disclosed embodiments pro age or treat hepatic fibrosis. Such embodiments provide for vide specific formulation and delivery parameters that pro direct and high concentration delivery of the pirfenidone or duce protection against and treatment for asthma associated, pyridone analog compound to the pulmonary vasculature by non-limiting example with exercise, genetics, airborne immediately upstream of the left atrium, left ventrical and allergens, inhaled irritants such as pipe, cigar and cigarette hence, to the hepatic vasculature. Smoke, and childhood respiratory infection. 0281 Because different drug products are known to vary 0288. As a non-limiting example, in a preferred embodi in efficacy depending on the dose, form, concentration and ment, a pyridone analog compound as provided herein (e.g., delivery profile, the presently disclosed embodiments pro pirfenidone) formulated to permit mist, gas-liquid Suspension vide specific formulation and delivery parameters that pro or liquid nebulized, dry powder and/or metered-dose inhaled duce protection against and treatment for hepatic fibrosis aerosol administration to Supply effective concentrations or associated, by non-limiting example with hepatic infection, amounts conferring desired anti-fibrotic, anti-inflammatory hepatitis, alcohol overload, autoimmune disease, radiation or tissue-remodeling benefits, for instance, to prevent, man therapy, chemotherapy and transplant rejection. age or treat patients with cystic fibrosis. Such embodiments 0282. As a non-limiting example, in a preferred embodi may include co-formulation or co-administration of a pyri ment, a pyridone analog compound as provided herein (e.g., done analog compound with an antibiotic, steroid, hyperos pirfenidone) formulated to permit mist, gas-liquid Suspension molar solution, DNAse or other mucus thinning agent, or or liquid nebulized, dry powder and/or metered-dose nasal other agent. injected or inhaled, or orally-inhaled aerosol administration 0289 Because different drug products are known to vary to Supply effective concentrations or amounts conferring in efficacy depending on the dose, form, concentration and desired anti-inflammatory and/or anti-demylination benefits, delivery profile, the presently disclosed embodiments pro for instance, to prevent, manage or treat multiple Sclerosis. If vide specific formulation and delivery parameters that pro by oral inhalation, such embodiments provide for direct and duce protection against and treatment for cystic fibrosis. high concentration delivery of the pirfenidone or pyridone 0290 For the applications described herein, liquid nebu analog compound to the pulmonary vasculature immediately lized, dry powder or metered-dose aerosol pirfenidone or upstream of the left atrium, left ventrical and hence, to the pyridone analog compound (or salt thereof) may be co-ad central nervous system. If by nasal injection or nasal inhala ministered, administered sequentially or prepared in a fixed tion, Such embodiments provide for direct and high concen combination with an antimicrobial (e.g. tobramycin and/or tration delivery of the pirfenidone or pyridone analog com other aminoglycoside Such as amikacin, aztreonam and/or pound to the nasal and sinus vasculature immediately other beta or mono-bactam, ciprofloxacin, levofloxacin and/ upstream of the central nervous system. or other, fluoroquinolones, azithromycin and/or other mac 0283 Because different drug products are known to vary rollides or ketolides, tetracycline and/or other tetracyclines, in efficacy depending on the dose, form, concentration and quinupristin and/or other streptogramins, lineZolid and/or delivery profile, the presently disclosed embodiments pro other oxazolidinones, Vancomycin and/or other glycopep vide specific formulation and delivery parameters that pro tides, and chloramphenicol and/or other phenicols, and duce protection against and treatment for multiple Sclerosis colisitin and/or other polymyxins), bronchodilator (e.g. associated. beta-2 agonists and muscarinic antagonists), corticosteroids 0284 As a non-limiting example, in a preferred embodi (e.g. salmeterol, fluticaSone and budesonide), glucocorticoids ment, a pyridone analog compound as provided herein (e.g., (e.g. prednisone), Cromolyn, Nedocromil. Leukotriene pirfenidone) formulated to permit mist, gas-liquid Suspension modifiers (e.g. montelukast, Zafirlukast and Zileuton) hyper or liquid nebulized, dry powder and/or metered-dose inhaled osmolar solution, DNAse or other mucus thinning agent, aerosol administration to supply effective concentrations or interferon gamma, cyclophosphamide, colchicine, N-acetyl amounts conferring desired anti-inflammatory, anti-fibrotic cysteine, azathioprine, bromhexine, endothelin receptor or tissue-remodeling benefits, for instance, to prevent, man antagonist (e.g. bosentan and ambrisentan), PDE5 inhibitor age or treat patients with diseases associated with chronic (e.g. sildenafil. Vardenafil and tadalafil), PDE4 inhibitor (e.g. obstructive pulmonary disease (COPD), including emphy roflumilast, cilomilast, oglemilast, tetomilast and sema and chronic bronchitis. SB256066), prostinoid (e.g. epoprostenol, iloprost and tre 0285 Because different drug products are known to vary prostinin), nitric oxide or nitric oxide-donating compound, in efficacy depending on the dose, form, concentration and IL-13 blocker, IL-10 blocker, CTGF-specific antibody, delivery profile, the presently disclosed embodiments pro CCN2 inhibitors, angiotensin-converting enzyme inhibitors, vide specific formulation and delivery parameters that pro angiotensin receptor antagonists, PDGF inhibitors, PPAR US 2015/O 196543 A1 Jul. 16, 2015 39 antagonist, imatinib, CCL2-specific antibody, CXCR2 stroma formation/maintenance through inhibition of PDFG antogonist, triple growth factor kinase inhibitor, anticoagu and transforming growth factor (TGF)-B signaling. By lant, TNF blocker, tetracycline or tetracycline derivative, 5-li another non-limiting example, pirfenidone or pyridone ana poxygenase inhibitor, pituitary hormone inhibitor, TGF-beta log is administered either in fixed combination, co-adminis neutralizing antibody, copper chelator, angiotensin II tered, adminstered sequentially, or co-prescribed with STX receptor antagonist, chemokine inhibitor, NF-kappaB inhibi 100 (monoclonal antibody targeting integrin alpha-V beta-6). tor, NF-kappaB antisense oligonucleotide, IKK-1 and -2 analog or other antibody targeting integrin alpha-V beta-6 or inhibitor (e.g. imidazoquinoxaline orderivative, and quinazo other integrin to reduce tumor stroma and/or fibrosis. By line or derivative), JNK2 and/or p38 MAPK inhibitor (e.g. another non-limiting example, pirfenidone or pyridone ana pyridylimidazolbutyn-I-ol, SB856553, SB681323, diary1 log is administered either in fixed combination, co-adminis urea or derivative, and indole-5-carboxamide), PI3K inhibi tered, adminstered sequentially, or co-prescribed with tor, LTB4 inhibitor, antioxidant (e.g. Mn-pentaazatetracyclo QAX576 (monoclonal antibody targeting interleukin 13 IL hexacosatriene, M40419, N-acetyl-L-cysteine, Mucomyst, 13), analog or other antibody targeting IL-13 to reduce tumor Fluimucil, Nacystelyn, Erdosteine, Ebeselen, thioredoxin, stroma and/or inflammation. By another non-limiting glutathione peroxidase memetrics, Curcumin C3 complex, example, pirfenidone or pyridone analog is administered Resveratrol and analogs, Tempol, catalytic antioxidants, and either in fixed combination, co-administered, adminstered OxSODrol), TNF scavenger (e.g. infliximab, ethercept, sequentially, or co-prescribed with FG-3019 (monoclonal adalumimab, PEG-STNFR 1, afelimomab, and antisense antibody targeting connective tissue growth factor CTGF). TNF-alpha oligonucleotide), Interferon beta-1a (Avonex, analog or other antibody targeting CTGF to reduce tumor Betaseron, or Rebif), glatiramer acetate (Copaxone), mitox stroma and/or fibrosis. By another non-limiting example, pir antrone (Novantrone), natalizumab (Tysabri), Methotrexate, fenidone or pyridone analog is administered either in fixed azathioprine (Imuran), intravenous immunoglobulin (IVIg), combination, co-administered, adminstered sequentially, or cyclophosphamide (Cytoxan), lioresal (Baclofen), tizanidine co-prescribed with CNTO-888 (a monoclonal antibody tar (Zanaflex), benzodiazepine, cholinergic medications, antide geting chemokine C-C motif ligand 2 CCL2), analog or pressants and amantadine. other antibody targeting CCL2 to reduce tumor stroma and/or 0291. As shown as a promising approach to treat cancer fibrosis. By another non-limiting example, pirfenidone or and pulmonary arterial hypertension, to enable “cocktail pyridone analog is administered either in fixed combination, therapy’ or “cocktail prophylaxis' in fibrotic disease, more co-administered, adminstered sequentially, or co-prescribed specifically idiopathic pulmonary fibrosis and other pulmo with Esbriet, Pirespa or Pirfenex (trade names for pirfeni nary fibrotic disease, methods to administer pirfenidone or done), or analog targeting inflammation, tumor stroma and/or pyridone analog as either co-administered, administered fibrosis. By another non-limiting example, pirfenidone or sequentially, or co-prescribed (Such that medicines are pyridone analog is administered either in fixed combination, requested by a prescribing physician to be taken in some co-administered, adminstered sequentially, or co-prescribed sequence as combination therapy to treat the same disease) with BIBF-1 120 (also known as Vargatef; a triple kinase with agents targeting cancer, fibrotic or inflammatory disease inhibitor targeting vascular endothelial growth factor are described. By non-limiting example, pirfenidone or pyri IVEGF, platelet-derived growth factor PDGF and fibro done analog is administered either in fixed combination, co blast growth factor FGF), analog or other triple kinase administered, adminstered sequentially, or co-prescribed inhibitor to reduce fibrosis, tumor stroma and/or inflamma with the monoclonal GS-6624 (formerly known as AB0024), tion. analog or another antibody targeting LOXL2 protein associ 0292. As with administration of pirfenidone, oral and ated with connective tissue biogenesis to reduce inflamma parenteral routes of administration (by non-limiting example, tion, tumor stroma and/or fibrosis. By another non-limiting intravenous and Subcutaneous) of other compounds, mol example, pirfenidone or pyridone analog is administered ecules and antibodies targeting the reduction of inflamma either in fixed combination, co-administered, adminstered tion, tumor stroma and/or fibrosis is often associated with, by sequentially, or co-prescribed with IWOO1 (Type V col non-limiting example, adverse reactions such as gastrointes lagen), analog or other collagen targeting immunogenic tol tinal side effects, liver, kidney, skin, cardiovascular or other erance to reduce inflammation, tumor stroma and/or fibrosis. toxicities. As described herein for pirfenidone or pyridone By another non-limiting example, pirfenidone or pyridone analogs, the benefits of oral or intranasal inhalation directly to analog is administered either in fixed combination, co-admin the lung or tissues immediately downstream of the nasal istered, adminstered sequentially, or co-prescribed with and/or pulmonary compartments will also benefit these com PRM-151 (recombinant pentraxin-2), analog or other mol pounds. Therefore, by non-limiting example, the monoclonal ecule targeting regulation of the injury response to reduce GS-6624 (formerly known as AB0024), analog or another inflammation, tumor stroma and/or fibrosis. By another non antibody targeting LOXL2 protein associated with connec limiting example, pirfenidone or pyridone analog is admin tive tissue biogenesis to reduce inflammation, tumor stroma istered either in fixed combination, co-administered, admin and/or fibrosis may be administered by oral or intranasal stered sequentially, or co-prescribed with CC-930 (Junkinase inhalation for direct delivery to the lung or tissues immedi inhibitor), analog or other Jun kinase inhibitor to reduce the ately downstream of the nasal or pulmonary compartments. inflammatory response. By another non-limiting example, By another non-limiting example, PRM-151 (recombinant pirfenidone or pyridone analog is administered either in fixed pentraxin-2), analog or othermolecule targeting regulation of combination, co-administered, adminstered sequentially, or the injury response to reduce inflammation and/or fibrosis co-prescribed with imatinib (a.k.a. Gleeve or Glivec (tyrosin may be administered by oral or intranasal inhalation for direct kinase inhibitor)), analog or other tyrosine inhibitor to inhibit delivery to the lung or tissues immediately downstream of the lung fibroblast-myofibroblast transformation and prolifera nasal or pulmonary compartments. By another non-limiting tion as well as extracellular matrix production and tumor example, CC-930 (Jun kinase inhibitor), analog or other Jun US 2015/O 196543 A1 Jul. 16, 2015 40 kinase inhibitor to reduce tumor Stroma and/or the inflamma done or pyridone analog is administered either in fixed com tory response may be administered by oral or intranasal inha bination, co-administered, adminstered sequentially, or co lation for direct delivery to the lung or tissues immediately prescribed with IWO01 (Type V collagen), analog or other downstream of the nasal or pulmonary compartments. By collagen targeting immunogenic tolerance to reduce inflam another non-limiting example, imatinib (a.k.a. Gleeve or mation, pulmonary hypertension and/or fibrosis. By another Glivec (tyrosin kinase inhibitor)), analog or other tyrosine non-limiting example, pirfenidone or pyridone analog is inhibitor to inhibit lung fibroblast-myofibroblast transforma administered either in fixed combination, co-administered, tion and proliferation as well as extracellular matrix produc adminstered sequentially, or co-prescribed with PRM-151 tion and tumor stroma formation/maintenance through inhi (recombinant pentraxin-2), analog or other molecule target bition of PDFG and transforming growth factor (TGF)-f ing regulation of the injury response to reduce inflammation, signaling may be administered by oral or intranasal inhalation pulmonary hypertension and/or fibrosis. By another non-lim for direct delivery to the lung or tissues immediately down iting example, pirfenidone or pyridone analog is administered stream of the nasal or pulmonary compartments. By another either in fixed combination, co-administered, adminstered non-limiting example, STX-100 (monoclonal antibody tar sequentially, or co-prescribed with CC-930 (Jun kinase geting integrin alpha-V beta-6), analog or other antibody tar inhibitor), analog or other Jun kinase inhibitor to reduce the geting integrin alpha-V beta-6 or other integrin to reduce inflammatory response. By another non-limiting example, tumor stroma and/or fibrosis may be administered by oral or pirfenidone or pyridone analog is administered either in fixed intranasal inhalation for direct delivery to the lung or tissues combination, co-administered, adminstered sequentially, or immediately downstream of the nasal or pulmonary compart co-prescribed with imatinib (a.k.a. Gleeve or Glivec (tyrosin ments. By another non-limiting example, QAX576 (mono kinase inhibitor)), analog or other tyrosine inhibitor to inhibit clonal antibody targeting interleukin 13 IL-13), analog or lung fibroblast-myofibroblast transformation and prolifera other antibody targeting IL-13 to reduce tumor stroma and/or tion as well as extracellular matrix production and pulmonary inflammation may be administered by oral or intranasal inha hypertension formation/maintenance through inhibition of lation for direct delivery to the lung or tissues immediately PDFG and transforming growth factor (TGF)-f signaling. By downstream of the nasal or pulmonary compartments. By another non-limiting example, pirfenidone or pyridone ana another non-limiting example, FG-3019 (monoclonal anti log is administered either in fixed combination, co-adminis body targeting connective tissue growth factor CTGF), ana tered, adminstered sequentially, or co-prescribed with STX log or other antibody targeting CTGF to reduce tumor stroma 100 (monoclonal antibody targeting integrin alpha-V beta-6). and/or fibrosis may be administered by oral or intranasal analog or other antibody targeting integrin alpha-v beta-6 or inhalation for direct delivery to the lung or tissues immedi other integrin to reduce pulmonary hypertension and/or fibro ately downstream of the nasal or pulmonary compartments. sis. By another non-limiting example, pirfenidone or pyri By another non-limiting example, CNTO-888 (a monoclonal done analog is administered either in fixed combination, co antibody targeting chemokine C-C motif ligand 2 administered, adminstered sequentially, or co-prescribed CCL2), analog or other antibody targeting CCL2 to reduce with QAX576 (monoclonal antibody targeting interleukin 13 tumor stroma and/or fibrosis may be administered by oral or IL-13), analog or other antibody targeting IL-13 to reduce intranasal inhalation for direct delivery to the lung or tissues pulmonary hypertension and/or inflammation. By another immediately downstream of the nasal or pulmonary compart non-limiting example, pirfenidone or pyridone analog is ments. By another non-limiting example, BIBF-1120 (also administered either in fixed combination, co-administered, known as Vargatef, a triple kinase inhibitor targeting vascular adminstered sequentially, or co-prescribed with FG-3019 endothelial growth factor VEGF, platelet-derived growth (monoclonal antibody targeting connective tissue growth fac factor PDGF and fibroblast growth factor FGF), analog or tor CTGFI), analog or other antibody targeting CTGF to other triple kinase inhibitor to reduce tumor stroma and/or reduce pulmonary hypertension and/or fibrosis. By another fibrosis and/or inflammation may be administered by oral or non-limiting example, pirfenidone or pyridone analog is intranasal inhalation for direct delivery to the lung or tissues administered either in fixed combination, co-administered, immediately downstream of the nasal or pulmonary compart adminstered sequentially, or co-prescribed with CNTO-888 mentS. (a monoclonal antibody targeting chemokine C-C motif 0293 As shown as a promising approach to treat cancer ligand 2 ICCL2), analog or otherantibody targeting CCL2 to and pulmonary arterial hypertension, to enable “cocktail reduce pulmonary hypertension and/or fibrosis. By another therapy’ or “cocktail prophylaxis' in pulmonary hyperten non-limiting example, pirfenidone or pyridone analog is sion secondary to fibrotic disease, more specifically Type 3 administered either in fixed combination, co-administered, Pulmonary Hypertension, methods to administer pirfenidone adminstered sequentially, or co-prescribed with Esbriet, or pyridone analog as either co-administered, administered Pirespa or Pirfenex (trade names for pirfenidone), or analog sequentially, or co-prescribed (Such that medicines are targeting inflammation, pulmonary hypertension and/or requested by a prescribing physician to be taken in some fibrosis. By another non-limiting example, pirfenidone or sequence as combination therapy to treat the same disease) pyridone analog is administered either in fixed combination, with agents targeting pulmonary hypertension, fibrotic or co-administered, adminstered sequentially, or co-prescribed inflammatory disease are described. By non-limiting with BIBF-1 120 (also known as Vargatef; a triple kinase example, pirfenidone or pyridone analog is administered inhibitor targeting vascular endothelial growth factor either in fixed combination, co-administered, adminstered IVEGF, platelet-derived growth factor PDGF and fibro sequentially, or co-prescribed with the monoclonal GS-6624 blast growth factor FGF), analog or other triple kinase (formerly known as AB0024), analog or another antibody inhibitor to reduce fibrosis, pulmonary hypertension and/or targeting LOXL2 protein associated with connective tissue inflammation. By another non-limiting example, pirfenidone biogenesis to reduce inflammation, pulmonary hypertension or pyridone analog is administered either in fixed combina and/or fibrosis. By another non-limiting example, pirfeni tion, co-administered, adminstered sequentially, or co-pre US 2015/O 196543 A1 Jul. 16, 2015 scribed with an endothelin receptor antagonist (e.g., bosentan immediately downstream of the nasal or pulmonary compart or ambrisentan) to treat pulmonary hypertension in associa ments. By another non-limiting example, QAX576 (mono tion with cancer, tumor stroma or fibrosis. By another non clonal antibody targeting interleukin 13 IL-13), analog or limiting example, pirfenidone or pyridone analog is admin other antibody targeting IL-13 to reduce pulmonary hyper istered either in fixed combination, co-administered, tension and/or inflammation may be administered by oral or adminstered sequentially, or co-prescribed with a PDE5 intranasal inhalation for direct delivery to the lung or tissues inhibitor (e.g. sildenafil. Vardenafil and tadalafil) to treat pull immediately downstream of the nasal or pulmonary compart monary hypertension in association with cancer, tumor ments. By another non-limiting example, FG-3019 (mono stroma or fibrosis. By another non-limiting example, pirfeni clonal antibody targeting connective tissue growth factor done or pyridone analog is administered either in fixed com CTGFI), analog or other antibody targeting CTGF to reduce bination, co-administered, adminstered sequentially, or co pulmonary hypertension and/or fibrosis may be administered prescribed with a prostinoid (e.g. epoprostenol, iloprost and by oral or intranasal inhalation for direct delivery to the lung treprostinin) to treat pulmonary hypertension in association or tissues immediately downstream of the nasal or pulmonary with cancer, tumor Stroma or fibrosis. By another non-limit compartments. By another non-limiting example, CNTO-888 ing example, pirfenidone or pyridone analog is administered (a monoclonal antibody targeting chemokine C-C motif either in fixed combination, co-administered, adminstered ligand 2 ICCL2), analog or otherantibody targeting CCL2 to sequentially, or co-prescribed with a nitric oxide or nitric reduce pulmonary hypertension and/or fibrosis may be oxide-donating compound (e.g., nitrate, nitrite or inhaled administered by oral or intranasal inhalation for direct deliv nitrite) to treat pulmonary hypertension in association with ery to the lung or tissues immediately downstream of the cancer, tumor stroma or fibrosis. nasal or pulmonary compartments. By another non-limiting 0294 As with administration of pirfenidone, oral and example, BIBF-1 120 (also known as Vargatef; a triple kinase parenteral routes of administration (by non-limiting example, inhibitor targeting vascular endothelial growth factor intravenous and Subcutaneous) of other compounds, mol IVEGF, platelet-derived growth factor PDGF and fibro ecules and antibodies targeting the reduction of inflamma blast growth factor FGF), analog or other triple kinase tion, pulmonary hypertension and/or fibrosis is often associ inhibitor to reduce pulmonary hypertension and/or fibrosis ated with, by non-limiting example, adverse reactions such as and/or inflammation may be administered by oral or intrana gastrointestinal side effects, liver, kidney, skin, cardiovascu sal inhalation for direct delivery to the lung or tissues imme lar or other toxicities. As described herein for pirfenidone or diately downstream of the nasal or pulmonary compartments. pyridone analogs, the benefits of oral or intranasal inhalation By another non-limiting example, an endothelin receptor directly to the lung or tissues immediately downstream of the antagonist (e.g., bosentan or ambrisentan) to treat pulmonary nasal and/or pulmonary compartments will also benefit these hypertension in association with cancer, tumor Stroma or compounds. Therefore, by non-limiting example, the mono fibrosis. By another non-limiting example, a PDE5 inhibitor clonal GS-6624 (formerly known as AB0024), analog or (e.g. sildenafil. Vardenafil and tadalafil) to treat pulmonary another antibody targeting LOXL2 protein associated with hypertension in association with cancer, tumor Stroma or connective tissue biogenesis to reduce inflammation, pulmo fibrosis. By another non-limiting example, a prostinoid (e.g. nary hypertension and/or fibrosis may be administered by epoprostenol, iloprost and treprostinin) to treat pulmonary oral or intranasal inhalation for direct delivery to the lung or hypertension in association with cancer, tumor Stroma or tissues immediately downstream of the nasal or pulmonary fibrosis. By another non-limiting example, a nitric oxide or compartments. By another non-limiting example, PRM-151 nitric oxide-donating compound (e.g., nitrate, nitrite or (recombinant pentraxin-2), analog or other molecule target inhaled nitrite) to treat pulmonary hypertension in association ing regulation of the injury response to reduce inflammation, with cancer, tumor Stroma or fibrosis. pulmonary hypertension and/or fibrosis may be administered 0295. As shown as a promising approach to treat cancer by oral or intranasal inhalation for direct delivery to the lung and pulmonary arterial hypertension, to enable “cocktail or tissues immediately downstream of the nasal or pulmonary therapy’ or “cocktail prophylaxis' in cancer, more specifi compartments. By another non-limiting example, CC-930 cally lung cancer, methods to administer pirfenidone or pyri (Jun kinase inhibitor), analog or other Jun kinase inhibitor to done analog as either co-administered, administered sequen reduce pulmonary hypertension and/or the inflammatory tially, or co-prescribed (such that medicines are requested by response may be administered by oral or intranasal inhalation a prescribing physician to be taken in Some sequence as for direct delivery to the lung or tissues immediately down combination therapy to treat the same disease) with agents stream of the nasal or pulmonary compartments. By another targeting cancer are described. Anti-cancer agents may non-limiting example, imatinib (a.k.a. Gleeve or Glivec (ty include gefitinib (Iressa, also known as ZD1839). Gefitinib is rosin kinase inhibitor)), analog or other tyrosine inhibitor to a selective inhibitor of epidermal growth factor receptors inhibit lung fibroblast-myofibroblast transformation and pro (EGFR) tyrosine kinase domain. The target protein (EGFR) is liferation as well as extracellular matrix production and pull a family of receptors which includes Herl (erb-B1), Her2(erb monary hypertension through inhibition of PDFG and trans B2), and Her3(erb-B3). EGFR is overexpressed in the cells of forming growth factor (TGF)-B signaling may be certain types of human carcinomas—for example in lung and administered by oral or intranasal inhalation for direct deliv breast cancers. This leads to inappropriate activation of the ery to the lung or tissues immediately downstream of the anti-apoptotic Ras signalling cascade, eventually leading to nasal or pulmonary compartments. By another non-limiting uncontrolled cell proliferation. Research on gefitinib-sensi example, STX-100 (monoclonal antibody targeting integrin tive non-small cell lung cancers has shown that a mutation in alpha-V beta-6), analog or other antibody targeting integrin the EGFR tyrosine kinase domain is responsible for activat alpha-V beta-6 or other integrin to reduce pulmonary hyper ing anti-apoptotic pathways. These mutations tend to confer tension and/or fibrosis may be administered by oral or intra increased sensitivity to tyrosine kinase inhibitors such as nasal inhalation for direct delivery to the lung or tissues gefitinib and erlotinib. Of the types of non-small cell lung US 2015/O 196543 A1 Jul. 16, 2015 42 cancer histologies, adenocarcinoma is the type that most of clinical benefit. Other side effects include diarrhea, loss of often harbors these mutations. These mutations are more appetite, fatigue, rarely, interstitial pneumonitis, which is commonly seen in Asians, women, and non-Smokers (who characterized by cough and increased dyspnea. This may be also tend to more often have adenocarcinoma). Gefitinib severe and must be considered among those patients whose inhibits EGFR tyrosine kinase by binding to the adenosine breathing acutely worsens. It has also been Suggested that triphosphate (ATP)-binding site of the enzyme. Thus the erlotinib can cause hearing loss. Rare side effects include function of the EGFR tyrosine kinase in activating the anti serious gastrointestinal tract, skin, and ocular disorders. In apoptotic Ras signal transduction cascade is inhibited, and addition, some people prescribed erlotinib have developed malignant cells are inhibited. While gefitinib has yet to be serious or fatal gastrointestinal tract perforations; "bullous, proven to be effective in other cancers, there is potential for its blistering, and exfoliative skin conditions, some fatal; and use in the treatment of other cancers where EGFR overex serious eye problems such as corneal lesions. Some of the pression is involved. As gefitinib is a selective chemothera cases, including ones which resulted in death, were Sugges peutic agent, its tolerability profile is better than previous tive of Stevens-Johnson syndrome/toxic epidermal necroly cytotoxic agents. Adverse drug reactions (ADRs) are accept sis. Erlotinib is mainly metabolized by the liver enzyme able for a potentially fatal disease. Acne-like rash is reported CYP3A4. Compounds which induce this enzyme (i.e. stimu very commonly. Other common adverse effects include: diar late its production), such as St John’s wort, can lower erlo rhoea, nausea, vomiting, anorexia, stomatitis, dehydration, tinib concentrations, while inhibitors can increase concentra skin reactions, paronychia, asymptomatic elevations of liver tions. As with other ATP competitive small molecule tyrosine enzymes, asthenia, conjunctivitis, blepharitis. Infrequent kinase inhibitors, such as imatinib in CML, patients rapidly adverse effects include: interstitial lung disease, corneal ero develop resistance. In the case of erlotinib this typically Sion, aberrant eyelash and hair growth. occurs 8-12 months from the start of treatment. Over 50% of 0296 Another anti-cancer agent is Erlotinib (also known resistance is caused by a mutation in the ATP binding pocket as Tarceva). Erlotinib specifically targets the epidermal of the EGFR kinase domain involving substitution of a small growth factor receptor (EGFR) tyrosine kinase, which is polar threonine residue with a large nonpolar methionine highly expressed and occasionally mutated in various forms residue (T790M). While proponents of the gatekeeper muta of cancer. It binds in a reversible fashion to the adenosine tion hypothesis suggest this mutation prevents the binding of triphosphate (ATP) binding site of the receptor. For the signal erlotinib through steric hindrance, research suggests that to be transmitted, two EGFR molecules need to come T790M confers an increase in ATP binding affinity reducing together to form a homodimer. These then use the molecule of the inhibitory effect of erlotinib. Approximately 20% of drug ATP to trans-phosphorylate each other on tyrosine residues, resistance is caused by amplification of the hepatocyte growth which generates phosphotyrosine residues, recruiting the factor receptor, which drives ERBB3 dependent activation of phosphotyrosine-binding proteins to EGFR to assemble pro PI3K. Other cases of resistance can involve numerous muta tein complexes that transduce signal cascades to the nucleus tions, including recruitment of a mutated IGF-1 receptor to or activate other cellular biochemical processes. By inhibit homodimerize with EGFR so forming a heterodimer. This ing the ATP formation of phosphotyrosine residues in EGFR allows activation of the downstream effectors of EGFR even is not possible and the signal cascades are not initiated. Erlo in the presence of an EGFR inhibitor. Some IGR-1R inhibi tinib has shown a survival benefit in the treatment of lung tors are in various stages of development (based either around cancer. Erlotinib is approved for the treatment of locally TKIs such as AG1024 or AG538 or pyrrolo2,3-d-pyrimi advanced or metastatic non-Small cell lung cancer that has dine derivatives such as NVP-AEW541). The monoclonal failed at least one prior chemotherapy regimen. It is also antibody figitumumab which targets the IGF-1R is currently approved in combination with gemcitabine for treatment of undergoing clinical trials. Another cause of resistance can be locally advanced, unresectable, or metastatic pancreatic can inactivating mutations of the PTEN tumor suppressor which cer. In lung cancer, erlotinib has been shown to be effective in allow increased activation of Akt independent of stimulation patients with or without EGFR mutations, but appears to be by EGFR. The most promising approach to combating resis more effective in the group of patients with EGFR mutations. tance is likely to be combination therapy. Commencing treat The response rate among EGFR mutation positive patients is ment with a number of different therapeutic agents with dif approximately 60%. Patients who are non-Smokers, and light fering modes of action is thought to provide the best defense former smokers, with adenocarcinoma or subtypes like BAC against development of T790M and other resistance confer are more likely to have EGFR mutations, but mutations can ring mutations. occur in all types of patients. EGFR positive patients are 0297 Another anti-cancer agentis Bortezomib (originally generally KRAS negative. Erlotinib has recently been shown codenamed PS-341; marketed as Velcade and Bortecad). to be a potent inhibitor of JAK2V617F activity. JAK2V617F Bortezomib is the first therapeutic proteasome inhibitor to be is a mutant of tyrosine kinase JAK2, is found in most patients tested in humans. It is approved in the U.S. for treating with polycythemia Vera (PV) and a substantial proportion of relapsed multiple myeloma and mantle cell lymphoma. In patients with idiopathic myelofibrosis or essential thromb multiple myeloma, complete clinical responses have been ocythemia. The study Suggests that erlotinib may be used for obtained in patients with otherwise refractory or rapidly treatment of JAK2V617F-positive PV and other myelopro advancing disease. Bortezomib was originally synthesized as liferative disorder. Rash occurs in the majority of patients. MG-341. After promising preclinical results, the drug (PS This resembles acne and primarily involves the face and neck. 341) was tested in a small Phase I clinical trial on patients It is self-limited and resolves in the majority of cases, even with multiple myeloma cancer. Bortezomib (Velcade) is with continued use. Interestingly, some clinical studies have approved for use in multiple myeloma. Another commer indicated a correlation between the severity of the skin reac cially available bortezomib product Bortenat, reportedly tions and increased Survival though this has not been quanti contains substantially more active entity than declared, tatively assessed. Cutaneous rash may be a Surrogate marker potentially and even more resulting in increased toxicity. US 2015/O 196543 A1 Jul. 16, 2015

Moreover, Bortenathas some other chemical and formulation JAK2, JAK3, TYK2), thereby interfering with the JAK-STAT deviations from the registered ethic product Velcade, with signaling pathway. These inhibitors have therapeutic appli unclear clinical impact. The boronatom in bortezomib binds cation in the treatment of cancer and inflammatory diseases. the catalytic site of the 26S proteasome with high affinity and Cytokines play key roles in controlling cell growth and the specificity. In normal cells, the proteasome regulates protein immune response. Many cytokines function by binding to and expression and function by degradation of ubiquitylated pro activating type I and type II cytokine receptors. These recep teins, and also cleanses the cell of abnormal or misfolded tors in turn rely on the Janus kinase (JAK) family of enzymes proteins. Clinical and preclinical data Support a role in main for signal transduction. Hence drugs that inhibit the activity taining the immortal phenotype of myeloma cells, and cell of these Janus kinases block cytokine signaling. More spe culture and Xenograft data Support a similar function in Solid cifically, Janus kinases phosphorylate activated cytokine tumor cancers. While multiple mechanisms are likely to be receptors. These phosphorylated receptor in turn recruit involved, proteasome inhibition may prevent degradation of STAT transcription factors which modulate gene transcrip pro-apoptotic factors, permitting activation of programmed tion. The first JAK inhibitor to reach clinical trials was tofaci cell death in neoplastic cells dependent upon Suppression of tinib. Tofacitinib is a specific inhibitor of JAK3 (IC50=2nM) pro-apoptotic pathways. Recently, it was found that bort thereby blocking the activity of IL-2, IL-4, IL-15 and IL-21. eZomib caused a rapid and dramatic change in the levels of Hence Th2 cell differentiation is blocked and thereforetofaci intracellular peptides that are produced by the proteasome. tinib is effective in treating allergic diseases. Tofacitinib to a Some intracellular peptides have been shown to be biologi lesser extent also inhibits JAK1 (IC50=100 nM) and JAK2 cally active, and so the effect of bortezomib on the levels of (IC50=20 nM) which in turn blocks IFN-Y and IL-6 signaling intracellular peptides may contribute to the biological and/or and consequently Th1 cell differentiation. Examples of JAK side effects of the drug. Bortezomib is rapidly cleared follow inhibitors include: Ruxolitinib against JAK1/JAK2 for pso ing intravenous administration. Peak concentrations are riasis, myelofibrosis, and rheumatoid arthritis; Tofacitinib reached at about 30 minutes. Drug levels can no longer be (tasocitinib; CP-690550) against JAK3 for psoriasis and measured after an hour. Pharmacodynamics are measured by rheumatoid arthritis; Baricitinib (LY3009104, INCB28050) measuring proteasome inhibition in peripheral blood mono against JAK1/JAK2 for rheumatoid arthritis: CYT387 against nuclear cells. The much greater sensitivity of myeloma cell JAK2 for myeloproliferative disorders: Lestaurtinib against lines and mantle cell lines to proteasome inhibition compared JAK2, for acute myelogenous leukemia (AML); Pacritinib with normal peripheral blood mononuclear cells and most (SB1518) against JAK2 for relapsed lymphoma and other cancer cell lines is poorly understood. Bortezomib is advanced myeloid malignancies, chronic idiopathic myelofi associated with peripheral neuropathy in 30% of patients: brosis (CIMF); and TG101348 against JAK2 for myelofibro occasionally, it can be painful. This can be worse in patients S1S. with pre-existing neuropathy. In addition, myelosuppression causing neutropenia and thrombocytopenia can also occur 0299. Another family of anti-cancer agent is ALK inhibi and be dose-limiting. However, these side effects are usually tors. ALK inhibitors are potential anti-cancer drugs that action mild relative to bone marrow transplantation and other treat tumors with variations of anaplastic lymphoma kinase (ALK) ment options for patients with advanced disease. Bortezomib such as an EML4-ALK translocation. About 7% of Non is associated with a high rate of shingles, although prophy small cell lung carcinomas (NSCLC) have EML4-ALK lactic acyclovir can reduce the risk of this. Gastro-intestinal translocations. Examples of ALK inhibitors include: Crizo effects and asthenia are the most common adverse events. The tinib (trade name Xalkori) is approved for NSCLC; AP26113 established the efficacy of bortezomib is 1.3 mg/m2 (with or is at the preclinical stage; and LDK378 is developed by without dexamethasone) administered by intravenous bolus Novartis as the second-generation ALK inhibitor. NPM-ALK on days 14.8, and 11 of a 21-day cycle for a maximum of is a different variation/fusion of ALK that drives anaplastic eight cycles in heavily pretreated patients with relapsed/re large-cell lymphomas (ALCLS) and is the target of other ALK inhibitors. Crizotinib has an aminopyridine structure, and fractory multiple myeloma. The demonstrated superiority of functions as a protein kinase inhibitor by competitive binding bortezomib is 1.3 mg/m2 over a high-dose dexamethasone within the ATP-binding pocket of target kinases. About 4% of regimen (by example median TTP 6.2 vs 3.5 months, and patients with non-Small cell lung carcinoma have a chromo 1-year survival 80% vs. 66%). Laboratory studies and clinical Somal rearrangement that generates a fusion gene between trials are investigating whether it might be possible to further EML4 (echinoderm microtubule-associated protein-like 4") increase the anticancer potency of bortezomib by combining and ALK (anaplastic lymphoma kinase'), which results in it with novel types of other pharmacologic agents. For constitutive kinase activity that contributes to carcinogenesis example, clinical trials have indicated that the addition of and seems to drive the malignant phenotype. The kinase thalidomide, lenalidomide, inhibitors of vascular endothelial activity of the fusion protein is inhibited by crizotinib. growth factor (VEGF), or arsenic trioxide might be benefi Patients with this gene fusion are typically younger non cial. In laboratory studies, it was found that bortezomib killed Smokers who do not have mutations in either the epidermal multiple myeloma cells more efficiently when combined, for growth factor receptor gene (EGFR) or in the K-Ras gene. example, with histone deacetylase inhibitors, thapsigargin, or The number of new cases of ALK-fusion NSLC is about celecoxib. There is preclinical evidence that bortezomib is 9,000 per year in the U.S. and about 45,000 worldwide. ALK synergistic with Reolysin in pancreatic cancer. However, the mutations are thought to be important in driving the malig therapeutic efficacy and safety of any of these latter combi nant phenotype in about 15% of cases of neuroblastoma, a nations has not yet been evaluated in cancer patients. rare form of peripheral nervous system cancer that occurs 0298 Another family of anti-cancer agent are Janus almost exclusively in very young children. Crizotinib inhibits kinase inhibitors. Also known as JAK inhibitors, these are a the c-Met/Hepatocyte growth factor receptor (HGFR) type of medication that functions by inhibiting the activity of tyrosine kinase, which is involved in the oncogenesis of a one or more of the Janus kinase family of enzymes (JAK1, number of other histological forms of malignant neoplasms. US 2015/O 196543 A1 Jul. 16, 2015 44

Crizotinib is currently thought to exert its effects through to self-antigens via both central and peripheral tolerance. In modulation of the growth, migration, and invasion of malig the case of defective apoptosis, it may contribute to etiologi nant cells. Other studies suggest that crizotinib might also act cal aspects of autoimmune diseases. The autoimmune dis via inhibition of angiogenesis in malignant tumors. Crizo ease, type 1 diabetes can be caused by defective apoptosis, tinib caused tumors to shrink or stabilize in 90% of 82 patients which leads to aberrant T cell AICD and defective peripheral carrying the ALK fusion gene. Tumors shrank at least 30% in tolerance. Due to the fact that dendritic cells are the most 57% of people treated. Most had adenocarcinoma, and had important antigen presenting cells of the immune system, never Smoked or were former Smokers. They had undergone their activity must be tightly regulated by Such mechanisms as treatment with an average of three other drugs prior to receiv apoptosis. Researchers have found that mice containing den ing crizotinib, and only 10% were expected to respond to dritic cells that are Bim -/-, thus unable to induce effective standard therapy. They were given 250 mg crizotinib twice apoptosis, obtain autoimmune diseases more so than those daily for a median duration of six months. Approximately that have normal dendritic cells. Other studies have shown 50% of these patients suffered at least one side effect, such as that the lifespan of dendritic cells may be partly controlled by nausea, vomiting, or diarrhea. Some responses to crizotinib a timer dependent on anti-apoptotic Bcl-2. Apoptosis plays a have lasted up to 15 months. A phase 3 trial, PROFILE 1007, very important role in regulating a variety of diseases that compares crizotinib to standard second line chemotherapy have enormous Social impacts. For example, Schizophrenia is (pemetrexed or taxotere) in the treatment of ALK-positive a neurodegenerative disease that may result from an abnormal NSCLC. Additionally, a phase 2 trial, PROFILE 1005, studies ratio of pro- and anti-apoptotic factors. There is some evi patients meeting similar criteria who have received more than dence that this defective apoptosis may result from abnormal one line of prior chemotherapy. Crizotinib (Xalkori) is expression of Bcl-2 and increased expression of caspase-3. approved to treat certain late-stage (locally advanced or meta Further research into the family of Bcl-2 proteins will provide static) non-Small cell lung cancers that express the abnormal a more complete picture on how these proteins interact with anaplastic lymphoma kinase (ALK) gene. Approval required each other to promote and inhibit apoptosis. An understand a companion molecular test for the EML4-ALK fusion. ing of the mechanisms involved may help develop new thera 0300 Another anti-cancer agent is Crizotinib. Crizotinib pies for treating cancer, autoimmune conditions, and neuro is also being tested in clinical trials of advanced disseminated logical diseases. Bcl-2 inhibitors include: An antisense anaplastic large-cell lymphoma, and neuroblastoma. oligonucleotide drug Genasense (G3139) that targets Bcl-2. 0301 An anti-cancer target includes Bcl-2 (B-cell lym An antisense DNA or RNA strand is non-coding and comple phoma 2). Encoded by the BCL2 gene, is the founding mem mentary to the coding strand (which is the template for pro ber of the Bcl-2 family of regulator proteins that regulate cell ducing respectively RNA or protein). An antisense drug is a death (apoptosis). Bcl-2 derives its name from B-cell lym short sequence of RNA that hybridises with and inactivates phoma 2, as it is the second member of a range of proteins mRNA, preventing the protein from being formed. It was initially described in chromosomal translocations involving shown that the proliferation of human lymphoma cells (with chromosomes 14 and 18 in follicular lymphomas. Bcl-2 t(14:18) translocation) could be inhibited by antisense RNA orthologs have been identified in numerous mammals for targeted at the start codon region of Bcl-2 mRNA. In vitro which complete genome data are available. The two isoforms studies led to the identification of Genasense, which is of Bcl-2, Isoform 1, also known as 1G5M, and Isoform 2, also complementary to the first 6 codons of Bcl-2 mRNA. Another known as 1G50/1 GJH, exhibit similar fold. However, results BCL-2 inhibitor is ABT-73. ABT-73 is a novel inhibitor of in the ability of these isoforms to bind to the BAD and BAK Bcl-2, Bcl-XL and Bcl-w, known as ABT-737. ABT-737 is one proteins, as well as in the structural topology and electrostatic among many So-called BH3 mimetic Small molecule inhibi potential of the binding groove, Suggest differences in anti tors (SMI) targeting Bcl-2 and Bcl-2-related proteins such as apoptotic activity for the two isoforms. Damage to the Bcl-2 Bcl-XL and Bcl-w but not A1 and Mcl-1, which may prove gene has been identified as a cause of a number of cancers, valuable in the therapy of lymphoma and other blood cancers. including melanoma, breast, prostate, chronic lymphocytic Another inhibitor is ABT-199. ABT-199 is a so-called BH3 leukemia, and lung cancer, and a possible cause of Schizo mimetic drug designed to block the function of the Bcl-2 phrenia and autoimmunity. It is also a cause of resistance to protein in patients with chronic lymphocytic leukemia. cancer treatments. Cancer occurs as the result of a disturbance Another Bcl-2 inhibitors is obatoclax (GX15-070) for small in the homeostatic balance between cell growth and cell cell lung cancer. By inhibiting Bcl-2, Obatoclax induces apo death. Over-expression of anti-apoptotic genes, and under ptosis in cancer cells, preventing tumor growth. expression of pro-apoptotic genes, can result in the lack of 0302) Another family of anti-cancer agents are PARP cell death that is characteristic of cancer. An example can be inhibitors. PARP inhibitors are a group of pharmacological seen in lymphomas. The over-expression of the anti-apoptotic inhibitors of the enzyme poly ADP ribose polymerase Bcl-2 protein in lymphocytes alone does not cause cancer. (PARP). They are developed for multiple indications; the But simultaneous over-expression of Bcl-2 and the proto most important is the treatment of cancer. Several forms of oncogene myc may produce aggressive B-cell malignancies cancer are more dependent on PARP than regular cells, mak including lymphoma. In follicular lymphoma, a chromo ing PARPanattractive target for cancer therapy. In addition to Somal translocation commonly occurs between the fourteenth their use in cancer therapy, PARP inhibitors are considered a and the eighteenth chromosomes-t(14:18)—which places the potential treatment for acute life-threatening diseases, such as Bcl-2 gene next to the immunoglobulin heavy chain locus. stroke and myocardial infarction, as well as for long-term This fusion gene is deregulated, leading to the transcription of neurodegenerative diseases. DNA is damaged thousands of excessively high levels of Bcl-2. This decreases the propen times during each cell cycle, and that damage must be sity of these cells for undergoing apoptosis. Apoptosis also repaired. BRCA1, BRCA2 and PALB2 are proteins that are plays a very active role in regulating the immune system. important for the repair of double-strand DNA breaks by the When it is functional, it can cause immune unresponsiveness error-free homologous recombination repair, or HRR, path US 2015/O 196543 A1 Jul. 16, 2015

way. When the gene for either protein is mutated, the change cancer; Olaparib (AZD-2281) for breast, ovarian and colorec can lead to errors in DNA repair that can eventually cause tal cancer; Rucaparib (AG014699, PF-01367338) for meta breast cancer. When Subjected to enough damage at one time, static breast and ovarian cancer; Veliparib (ABT-888) for the altered gene can cause the death of the cells. PARP1 is a metastatic melanoma and breast cancer, CEP 9722 for non protein that is important for repairing single-strand breaks small-cell lung cancer (NSCLC); MK 4827 which inhibits (nicks in the DNA). If such nicks persist unrepaired until both PARP1 and PARP2; BMN-673 for advanced hemato DNA is replicated (which must precede cell division), then logical malignancies and for advanced or recurrent solid the replication itself can cause double strand breaks to form. tumors; and 3-aminobenzamide. Drugs that inhibit PARP1 cause multiple double strand breaks 0303 Another family of anti-cancer target is the PI3K/ to form in this way, and in tumors with BRCA1, BRCA2 or AKT/mTOR pathway. This pathway is an important signal PALB2 mutations these double strand breaks cannot be effi ing pathway for many cellular functions such as growth con ciently repaired, leading to the death of the cells. Normal cells trol, metabolism and translation initiation. Within this that don’t replicate their DNA as often as cancer cells, and pathway there are many valuable anti-cancer drug treatment that lacks any mutated BRCA1 or BRCA2 still have homolo targets and for this reason it has been Subject to a lot of gous repair operating, which allows them to Survive the inhi research in recent years. A Phosphoinositide 3-kinase inhibi bition of PARP. Some cancer cells that lack the tumor sup tor (PI3K inhibitor) is a potential medical drug that functions pressor PTEN may be sensitive to PARP inhibitors because of by inhibiting a Phosphoinositide 3-kinase enzyme which is down-regulation of RadS1, a critical homologous recombi part of this pathway and therefore, through inhibition, often nation component, although other data Suggest PTEN may results in tumor suppression. There are a number of different not regulate RadS1. Hence PARP inhibitors may be effective classes and isoforms of PI3Ks. Class 1 PI3Ks have a catalytic against many PTEN-defective tumors (e.g. Some aggressive subunit known as p110, with four types (isoforms) p110 prostate cancers). Cancer cells that are low in oxygen (e.g. in alpha, p110beta, p110 gamma and p110 delta. The inhibitors fast growing tumors) are sensitive to PARP inhibitors. PARP being studied inhibit one or more isoforms of the class 1 inhibitors were originally thought to work primarily by PI3Ks. They are being actively investigated for treatment of blocking PARP enzyme activity, thus preventing the repair of various cancers. Examples include: Wortmannin an irrevers DNA damage and ultimately causing cell death. PARP inhibi ible inhibitor of PI3K: demethoxyviridin a derivative of wort tors have an additional mode of action: localizing PARP mannin; and LY294.002 a reversible inhibitor of PI3K. Other proteins at sites of DNA damage, which has relevance to their PI3K inhibitors include: Perifosine, for colorectal cancer and anti-tumor activity. The trapped PARP protein-DNA com multiple myeloma; CAL101 an oral PI3K delta for certain plexes are highly toxic to cells because they block DNA late-stage types of leukemias; PX-866; IPI-145, a novel replication. When the researchers tested three PARP inhibi inhibitor of PI3K delta and gamma, especially for hemato tors for their differential ability to trap PARP proteins on logic malignancies: BAY 80-6946, predominantly inhibiting damaged DNA, they found that the trapping potency of the PI3KO.ö isoforms: BEZ235 a PI3K/mTOR dual inhibitor; inhibitors varied widely. The PARP family of proteins in RP6503, a dual PI3K delta/gamma inhibitor for the treatment humans includes PARP1 and PARP2, which are DNA bind of Asthma and COPD, TGR 1202, oral PI3K delta inhibitor ing and repair proteins. When activated by DNA damage, (also known as RP5264); SF1126, the first PI3KI for B-cell these proteins recruit other proteins that do the actual work of chronic lymphocytic leukemia (CLL); INK1 117, a PI3K repairing DNA. Under normal conditions, PARP1 and alpha inhibitor; GDC-0941 IC50 of 3 nM; BKM120; XL 147 PARP2 are released from DNA once the repair process is (also known as SAR245408): XL765 (also known as underway. However, as this study shows, when they are SAR245.409); Palomid 529; GSK105.9615, where clinical bound to PARP inhibitors, PARP1 and PARP2 become trials were terminated due to lack of sufficient exposure fol trapped on DNA. The researchers showed that trapped PARP lowing single- and repeat-dosing; ZSTK474, a potent inhibi DNA complexes are more toxic to cells than the unrepaired tor against p110a; PWT33597, a dual PI3K-alpha/mTOR single-strand DNA breaks that accumulate in the absence of inhibitor—for advanced solid tumors; IC87114 a selective PARP activity, indicating that PARP inhibitors act as PARP inhibitor of p1108. It has an IC50 of 100 nM for inhibition of poisons. These findings Suggest that there may be two classes p110-6: TG100-115, inhibits all four isoforms but has a 5-10 of PARP inhibitors, catalytic inhibitors that act mainly to fold better potency against p110-Y and p110-8; CAL263; inhibit PARP enzyme activity and do not trap PARP proteins RP6530, a dual PI3K delta/gamma inhibitor for T-cell Lym on DNA, and dual inhibitors that both block PARP enzyme phomas; PI-103 a dual PI3K-mTOR inhibitor; GNE-477, a activity and act as PARP poison. The main function of radio PI3K-alpha and mTOR inhibitor with IC50 values of 4 nM therapy is to produce DNA strand breaks, causing severe and 21 nM; CUDC-907, also an HDAC inhibitor; and AEZS DNA damage and leading to cell death. Radiotherapy has the 136, which also inhibits Erk1/2. potential to kill 100% of any targeted cells, but the dose 0304 Another anti-cancer agent is Apatinib. Also known required to do so would cause unacceptable side effects to as YN968D1, Apatinib is a tyrosine kinase inhibitor that healthy tissue. Radiotherapy therefore can only be given up to selectively inhibits the vascular endothelial growth factor a certain level of radiation exposure. Combining radiation receptor-2 (VEGFR2, also known as KDR). It is an orally therapy with PARP inhibitors offers promise, since the inhibi bioavailable, small molecule agent which is thought to inhibit tors would lead to formation of double strand breaks from the angiogenesis in cancer cells; specifically apatinib inhibits single-strand breaks generated by the radiotherapy in tumor VEGF-mediated endothelial cell migration and proliferation tissue with BRCA1/BRCA2 mutations. This combination thus blocking new blood vessel formation in tumor tissue. could therefore lead to either more powerful therapy with the This agent also mildly inhibits c-Kit and c-SRC tyrosine same radiation dose or similarly powerful therapy with a kinases. Apatinib is an investigational cancer drug currently lower radiation dose. Examples of PARP inhibitors include: undergoing clinical trials as a potential targeted treatment for Iniparib (BSI 201) for breast cancer and squamous cell lung metastatic gastric carcinoma, metastatic breast cancer and US 2015/O 196543 A1 Jul. 16, 2015 46 advanced hepatocellular carcinoma. Cancer patients were Clinical Significance) by excessively signaling cells to grow, administered varied doses of Apatinib daily for 28 days. Apa inhibitors of B-Rafhave been developed for both the inactive tinib was well tolerated at doses below 750 mg/day, 3 of 3 and active conformations of the kinase domain as cancer dose limiting toxicities were reported at 1000 mg/day and the therapeutic candidates. BAY43-9006 (Sorafenib, Nexavar) is maximum tolerated dose is determined to be 850 mg/day. The a V600E mutant B-Raf and C-Raf inhibitor approved by the investigator also reported of 65 cancer patients treated in FDA for the treatment of primary liver and kidney cancer. Phase I/II, 1.54% had a complete response, 12.31% had a Bay43-9006 disables the B-Rafkinase domain by locking the partial response, 66.15% had stable disease and 20% had enzyme in its inactive form. The inhibitor accomplishes this progressive disease. A separate published report on the safety by blocking the ATP binding pocket through high-affinity for and pharmacokinetics of apatinib in Human clinical studies the kinase domain. It then binds key activation loop and DFG concludes that it has encouraging antitumor activity across a motif residues to stop the movement of the activation loop and broad range of cancer types. Some cancer cells have the DFG motif to the active conformation. Finally, a trifluorom ability to develop resistance to the cytotoxic effects of certain ethyl phenyl moiety sterically blocks the DFG motif and cancer drugs (called multidrug resistance). A study con activation loop active conformation site, making it impossible cluded that apatinib may be useful in circumventing cancer for the kinase domainto shift conformation to become active. cells multidrug resistance to certain conventional antine The distal pyridyl ring of BAY43-9006 anchors in the hydro oplastic drugs. The study showed that apatinib reverses the phobic nucleotide-binding pocket of the kinase N-lobe, inter ABCB1 - and ABCG2-mediated multidrug resistance by acting with W531, F583, and F595. The hydrophobic inter inhibiting those functions and increasing the intracellular actions with catalytic loop F583 and DFG motif F595 concentrations of the antineoplastic drugs. This study Sug stabilize the inactive conformation of these structures, gests that apatinib will be potentially effective in combination decreasing the likelihood of enzyme activation. Further therapies with conventional anticancer drugs especially in hydrophobic interaction of K483, L514, and T529 with the cases where resistance to chemotherapy exists. center phenyl ring increase the affinity of the kinase domain 0305 Another family of anti-cancer target is BRAF. for the inhibitor. Hydrophobic interaction of F595 with the BRAF is a human gene that encodes B-Raf. The gene is also center ring as well decreases the energetic favorability of a referred to as proto-oncogene B-Raf and v-Raf murine sar DFG conformation switch further. Finally, polar interactions coma viral oncogene homolog B1, while the protein is more of BAY43-9006 with the kinase domain continue this trend of formally known as serine/threonine-protein kinase B-Raf. increasing enzyme affinity for the inhibitor and stabilizing The B-Raf protein is involved in sending signals inside cells, DFG residues in the inactive conformation. E501 and C532 which are involved in directing cell growth. In 2002, it was hydrogen bond the urea and pyridyl groups of the inhibitor shown to be faulty (mutated) in human cancers. Certain other respectively while the urea carbonyl accepts a hydrogen bond inherited BRAF mutations cause birth defects. Drugs that from D594's backbone amide nitrogen to lock the DFG motif treat cancers driven by BRAF have been developed. Vemu in place. The trifluoromethyl phenyl moiety cements the ther rafenib and dabrafenib are approved for late-stage melanoma. modynamic favorability of the inactive conformation when B-Rafis a member of the Rafkinase family of growth signal the kinase domain is bound to BAY43-9006 by sterically transduction protein kinases. This protein plays a role in blocking the hydrophobic pocket between the ac and al. regulating the MAP kinase/ERKS signaling pathway, which helices that the DFG motif and activation loop would inhabit affects cell division, differentiation, and secretion. B-Rafis a upon shifting to their locations in the active conformation of 766-amino acid, regulated signal transduction serine/threo the protein. PLX4032 (Vemurafenib) is a V600 mutant B-Raf nine-specific protein kinase. Broadly speaking, it is com inhibitor approved by the FDA for the treatment of late-stage posed of three conserved domains characteristic of the Raf melanoma. Unlike BAY43-9006, which inhibits the inactive kinase family: conserved region 1 (CR1), a Ras-GTP-binding form of the kinase domain, Vemurafenib inhibits the active self-regulatory domain, conserved region 2 (CR2), a serine “DFG-in' form of the kinase, firmly anchoring itself in the rich hinge region, and conserved region 3 (CR3), a catalytic ATP-binding site. By inhibiting only the active form of the protein kinase domain that phosphorylates a consensus kinase, Vemurafenib selectively inhibits the proliferation of sequence on protein Substrates. In its active conformation, cells with unregulated B-Raf, normally those that cause can B-Raf forms dimers via hydrogen-bonding and electrostatic cer. Since Vemurafenib only differs from its precursor, interactions of its kinase domains. B-Raf is a serine/threo PLX4720, in a phenyl ring added for pharmacokinetic rea nine-specific protein kinase. As such, it catalyzes the phos sons, PLX4720s mode of action is equivalent to Vemu phorylation of serine and threonine residues in a consensus rafenibs. PLX4720 has good affinity for the ATPbinding site sequence on target proteins by ATP yielding ADP and a partially because its anchor region, a 7-azaindole bicyclic, phosphorylated protein as products. Since it is a highly regu only differs from the natural adenine that occupies the site in lated signal transduction kinase, B-Raf must first bind Ras two places where nitrogen atoms have been replaced by car GTP before becoming active as an enzyme. Once B-Rafis bon. This enables strong intermolecular interactions like N7 activated, a conserved protein kinase catalytic core phospho hydrogen bonding to C532 and N1 hydrogen bonding to rylates protein Substrates by promoting the nucleophilic Q530 to be preserved. Excellent fit within the ATP-binding attack of the activated substrate serine or threonine hydroxyl hydrophobic pocket (C532, W531, T529, L514, A481) oxygenatom on the Y-phosphate group of ATP through bimo increases binding affinity as well. Ketone linker hydrogen lecular nucleophilic substitution. To effectively catalyze pro bonding to water and difluoro-phenyl fit in a second hydro tein phosphorylation via the bimolecular substitution of phobic pocket (A481, V482, K483, V471, 1527, T529, L514, serine and threonine residues with ADP as a leaving group, and F583) contribute to the exceptionally high binding affin B-Raf must first bind ATP and then stabilize the transition ity overall. Selective binding to active Rafis accomplished by state as the Y-phosphate of ATP is transferred. Since consti the terminal propyl group that binds to a Raf-selective pocket tutively active B-Raf mutants commonly cause cancer (see created by a shift of the achelix. Selectivity for the active US 2015/O 196543 A1 Jul. 16, 2015 47 conformation of the kinase is further increased by a pH cancer cells. However, the validity of CDK as a cancer target sensitive deprotonated Sulfonamide group that is stabilized should be carefully assessed because genetic Studies have by hydrogen bonding with the backbone peptide NH of D594 revealed that knockout of one specific type of CDK often does in the active state. In the inactive state, the inhibitor's sulfona not affect proliferation of cells or has an effect only in specific mide group interacts with the backbone carbonyl of that resi tissue types. For example, most adult cells in mice proliferate due instead, creating repulsion. Thus, Vemurafenib binds normally even without both CDK4 and CDK2. Furthermore, preferentially to the active state of B-Rafs kinase domain. specific CDKs are only active in certain periods of the cell Mutations in the BRAF gene can cause disease in two ways. cycle. Therefore, the pharmacokinetics and dosing schedule First, mutations can be inherited and cause birth defects. of the candidate compound must be carefully evaluated to Second, mutations can appear laterin life and cause cancer, as maintain active concentration of the drug throughout the an oncogene. Inherited mutations in this gene cause cardio entire cell cycle. Types of CDK inhibitors include: Broad faciocutaneous syndrome, a disease characterized by heart CDK inhibitors that target a broad spectrum of CDKs; spe defects, mental retardation and a distinctive facial appear cific CDK inhibitors that target a specific type of CDK; and ance. Acquired mutations in this gene have been found in multiple target inhibitors that target CDKs as well as addi cancers, including non-Hodgkin lymphoma, colorectal can tional kinases such as VEGFR or PDGFR. Specific examples cer, malignant melanoma, papillary thyroid carcinoma, non include: P1446A-05 targeting CDK4 and PD-0332991 that Small-cell lung carcinoma, and adenocarcinoma of the lung. targets CDK4 and CDK6 for leukemia, melanoma and solid The V600E mutation of the BRAF gene has been associated tumors. with hairy cell leukemia in numerous studies and has been 0308 Another anti-cancer agent is Salinomycin. Salino Suggested for use in Screening for Lynch syndrome to reduce mycin is an antibacterial and coccidiostat ionophore thera the number of patients undergoing unnecessary MLH1 peutic drug. Salinomycin has been shown to kill breast cancer sequencing. As mentioned above, some pharmaceutical firms stem cells in mice at least 100 times more effectively than the are developing specific inhibitors of mutated B-rafprotein for anti-cancer drug paclitaxel. The study screened 16,000 dif anticancer use because B-Rafis a well-understood, highyield ferent chemical compounds and found that only a small Sub target. Vemurafenib (RG7204 or PLX4032), licensed as set, including salinomycin and etoposide, targeted cancer Zelboraf for the treatment of metastatic melanoma, is the stem cells responsible for metastasis and relapse. The mecha current state-of-the-art example for why active B-Raf inhibi nism of action by which salinomycin kills cancer Stem cells tors are being pursued as drug candidates. Vemurafenib is specifically remains unknown, but is thought to be due to its biochemically interesting as a mechanism to target cancer action as a potassium ionophore due to the detection of nigeri due to its high efficacy and selectivity. B-Raf not only cin in the same compound screen. Studies performed in 2011 increased metastatic melanoma patient chance of Survival but showed that salinomycin could induce apoptosis of human raised the response rate to treatment from 7-12% to 53% in cancer cells. Promising results from a few clinical pilote the same amount of time compared to the former best che studies reveal that salinomycin is able to effectively eliminate motherapeutic treatment: dacarbazine. In spite of the drugs CSCs and to induce partial clinical regression of heavily high efficacy, 20% of tumors still develop resistance to the pretreated and therapy-resistant cancers. The ability of Sali treatment. In mice, 20% of tumors become resistant after 56 nomycin to kill both CSCs and therapy-resistant cancer cells days. While the mechanisms of this resistance are still dis may define the compound as a novel and an effective antican puted, some hypotheses include the overexpression of B-Raf cer drug. It has been also shown that Salinomycin and its to compensate for high concentrations of Vemurafenib and derivatives exhibit potent antiproliferative activity against the upstream upregulation of growth signaling. More general drug-resistant cancer cell lines. Salinomycin is the key com B-raf inhibitors include GDC-0879, PLX-4720, Sorafenib pound in the pharmaceutical company Verastem’s efforts to Tosylate, Dabrafenib and LGX818. produce an anti-cancer-stem-cell drug. 0306 Another family of anti-cancer agent is the MEK 0309 Drugs for non-small cell lung cancer may include: inhibitor. These are a chemical or drug that inhibits the mito Abitrexate (methotrexate), Abraxane (Paclitaxel Albumin gen-activated protein kinase kinase enzymes MEK1 and/or stabilized Nanoparticle Formulation), Afatinib Dimaleate, MEK2. They can be used to affect the MAPK/ERK pathway Alimta (pemetrexed disodium), Avastin (Bevacizumab), Car which is often overactive in some cancers. Hence MEK boplatin, Cisplatin, Crizotinib, Erlotinib Hydrochloride, inhibitors have potential for treatment of some cancers, espe Folex (methotrexate). Folex PFS (methotrexate), Gefitinib cially BRAF-mutated melanoma, and KRAS/BRAF mutated Gilotrif (afatinib dimaleate), Gemcitabine Hydrochloride, colorectal cancer. Examples of MEK inhibitors include: Gemzar (gemcitabine hydrochloride), Iressa (Gefitinib), Trametinib (GSK1120212), for treatment of BRAF-mutated Methotrexate, Methotrexate LPF (methotrexate), Mexate melanoma and possible combination with BRAF inhibitor (methotrexate), Mexate-AQ (methotrexate), Paclitaxel, dabrafenib to treat BRAF-mutated melanoma; Selumetinib, Paclitaxel Albumin-stabilized Nanoparticle Formulation, for non-small cell lung cancer (NSCLC); MEK162, had Paraplat (carboplatin), Paraplatin (carboplatin), Pemetrexed phase 1 trial for biliary tract cancer and melanoma; Disodium, Platinol (cisplatin), Platinol-AQ (Cisplatin), PD-325901, for breast cancer, colon cancer, and melanoma; Tarceva (Erlotinib Hydrochloride), Taxol (Paclitaxel), Taxo XL518; CI-1040 and PD035901. tere or Docecad (docetaxel), and Xalkori (Crizotinib). 0307 Another family of anti-cancer agent is the CDK 0310 Combinations approved for non-small cell lung can (Cyclin-dependent kinase) inhibitor. CDK inhibitors are cer may include: Carboplatin-Taxoland Gemcitabline-Cispl chemicals that inhibits the function of CDKs. It is used to treat atin. cancers by preventing overproliferation of cancer cells. In 0311 Drugs approved for small cell lung cancer may many human cancers, CDKs are overactive or CDK-inhibit include: Abitrexate (methotrexate), Etopophos (etoposide ing proteins are not functional. Therefore, it is rational to phosphate), Etoposide, Etoposide Phosphate. Folex (methotr target CDK function to prevent unregulated proliferation of exate). Folex PFS (methotrexate), Hycamtin (topotecan US 2015/O 196543 A1 Jul. 16, 2015 48 hydrochloride), Methotrexate, Methotrexate LPF (methotr compound as a low-solubility, stable nanosuspension alone, exate), Mexate (methotrexate), Mexate-AQ (methotrexate), as co-crystal/co-precipitate complexes, and/or as mixtures Toposar (etoposide), Topotecan Hydrochloride, and VePesid with low solubility lipids such as solid-lipid nanoparticles), a (etoposide). dry powder (e.g., dry powder pirfenidone or pyridone analog 0312 Aerosol administration directly to one or more compound alone or in co-crystal/co-precipitate/spray-dried desired regions of the respiratory tract, which includes the complex or mixture with low solubility excipients/salts or upper respiratory tract (e.g., nasal, sinus, and pharyngeal readily soluble blends such as lactose), or an organic soluble compartments), the respiratory airways (e.g., laryngeal, tra or organic Suspension Solution, for packaging and adminis cheal, and bronchial compartments) and the lungs or pulmo tration using an inhalation device such as a metered-dose nary compartments (e.g., respiratory bronchioles, alveolar inhalation device. ducts, alveoli), may be effected (e.g., “pulmonary delivery”) 0315 Selection of a particular pirfenidone or pyridone in certain preferred embodiments through intra-nasal or oral analog compound formulation or pirfenidone or pyridone inhalation to obtain high and titrated concentration of drug, analog compound formulation composition as provided pro-drug active or Sustained-release delivery to a site of res herein according to certain preferred embodiments may be piratory pathology. Aerosol administration Such as by intra influenced by the desired product packaging. Factors to be nasal or oral inhalation may also be used to provide drug, considered in selecting packaging may include, for example, pro-drug active or Sustained-release delivery through the pull intrinsic product stability, whether the formulation may be monary vasculature (e.g., further to pulmonary delivery) to Subject to lyophilization, device selection (e.g., liquid nebu reach other tissues or organs, by non-limiting example, the lizer, dry-powder inhaler, meter-dose inhaler), and/or pack heart, brain, liver central nervous system and/or kidney, with aging form (e.g., simple liquid or complex liquid formulation, decreased risk of extra-respiratory toxicity associated with whether provided in a vial as a liquid or as a lyophilisate to be non-respiratory routes of drug delivery. Accordingly, because dissolved prior to or upon insertion into the device; complex the efficacy of a particular pyridone compound (e.g., pirfeni Suspension formulation whether provided in a vial as a liquid done) therapeutic composition may vary depending on the or as a lyophilisate, and with or without a soluble salt/excipi formulation and delivery parameters, certain embodiments ent component to be dissolved prior to or upon insertion into described herein reflect re-formulations of compositions and the device, or separate packaging of liquid and solid compo novel delivery methods for recognized active drug com nents; dry powder formulations in a vial, capsule or blister pounds. Other embodiments contemplate topical pathologies pack; and other formulations packaged as readily soluble or and/or infections that may also benefit from the discoveries low-solubility solid agents in separate containers alone or described herein, for example, through direct exposure of a together with readily soluble or low-solubility solid agents. pirfenidone or pyridone analog compound formulation as 0316 Packaged agents may be manufactured in Such a provided herein to diseased skin, rectum, vagina, urethra, way as to be provide a pirfenidone or pyridone analog com urinary bladder, eye, and/or ear, including aerosol delivery to pound formulation composition for pulmonary delivery that a burn wound to prevent Scarring. comprises a solution which is provided as a pirfenidone or 0313. In addition to the clinical and pharmacological cri pyridone analog compound aqueous Solution having a pH teria according to which any composition intended for thera from about 3.0 to about 11.0, more preferably from about pH peutic administration (such as the herein described pirfeni 4 to about pH 8, at a concentration of at least 0.1 mg/mL to done or pyridone analog compound formulations) may be about 50 mg/mL, and having a total osmolality at least 50 characterized, those familiar with the art will be aware of a mOsmol/kg to about 1000 mOsmol/kg, more preferably 200 number of physicochemical factors unique to a given drug to about 500 mOsmol/kg. composition. These include, but are not limited to aqueous 0317. In some embodiments, the present invention relates solubility, Viscosity, partitioning coefficient (Log P), pre to the aerosol and/or topical delivery of a pyridone analog dicted Stability in various formulations, osmolality, Surface compound (e.g., pirfenidone). Pirfenidone has favorable tension, pH, pKa, pKb, dissolution rate, sputum permeability, solubility characteristics enabling dosing of clinically-desir sputum binding/inactivation, taste, throat irritability and able levels by aerosol (e.g., through liquid nebulization, dry acute tolerability. powder dispersion or meter-dose administration) or topically 0314. Other factors to consider when selecting the particu (e.g., aqueous Suspension, oily preparation or the like or as a lar product form include physical chemistry of the formula drip, spray, Suppository, Salve, oran ointment or the like), and tion (e.g., a pirfenidone or pyridone analog compound for can be used in methods for acute or prophylactic treatment of mulation), the intended disease indication(s) for which the a Subject having pulmonary fibrosis, or of a subject at risk for formulation is to be used, clinical acceptance, and patient having pulmonary fibrosis. Clinical criteria for determining compliance. As non-limiting examples, a desired pirfenidone when pulmonary fibrosis is present, or when a Subject is at or pyridone analog compound formulation for aerosol deliv risk for having pulmonary fibrosis, are known to the art. ery (e.g., by oral and/or intra-nasal inhalation of a mist Such as Pulmonary delivery via inhalation permits direct and titrated a nebulized Suspension of liquid particles, a dispersion of a dosing directly to the clinically-desired site with reduced dry powder formulation or aerosol generated by meter-dose systemic exposure. propellant), may be provided in the form of a simple liquid 0318. In a preferred embodiment, the method treats or Such as an aqueous liquid (e.g., soluble pirfenidone or pyri serves as prophylaxis against interstitial lung disease (ILD) done analog compound with non-encapsulating soluble by administering a pirfenidone or pyridone analog compound excipients/salts), a complex liquid Such as an aqueous liquid formulation as an aerosol (e.g., a suspension of liquid par (e.g., pirfenidone or pyridone analog compound encapsulated ticles in air or another gas) to a subject having or Suspected to or complexed with soluble excipients such as lipids, lipo have interstitial lung disease. Interstitial lung disease includes Somes, cyclodextrins, microencapsulations, and emulsions), those conditions of idiopathic interstitial pneumonias as a complex Suspension (e.g., pirfenidone or pyridone analog defined by American Thoracic Society/European Respiratory US 2015/O 196543 A1 Jul. 16, 2015 49

Society international multidisciplinary concensus classifica Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuber tion of the idiopathic interstitial pneumonias, AM. J. Respir. culosis, Yersinia intermedia, Bordetella pertussis, Bordetella Crit. Care Med. 165, 277-304 (2002). These include ILD of parapertuSSis, Bordetella bronchiseptica, Haemophilus known cause or association with connective tissue diseases, influenzae, Haemophilus parainfluenzae, Haemophilus occupational causes or drug side effect, idiopathic interstitial haemolyticus, Haemophilus parahaemolyticus, Haemophi pneumonias (e.g. idiopathic pulmonary fibrosis, non-specific lus ducreyi, Pasteurella multocida, Pasteurella haemolytica, interstitial pneumonia, desquamative interstitial pneumonia, Branhamella catarrhalis, Helicobacter pylori, Campylo respiratory bronchiolitis-ILD, cryptogenic organizing pneu bacter fetus, Campylobacter jejuni, Campylobacter coli, monia, acute interstitial pneumonia and lyphocytic interstitial Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyti pneumonia), granulomatous lung disease (e.g., sarcodosis, cus, Legionella pneumophila, Listeria monocytogenes, Neis hypersensitity pneumonitis and infection), and otherforms of seria gonorrhoeae, Neisseria meningitidis, Kingella, ILD (e.g., lymphangioleiomyomatosis, pulmonary Langer Moraxella, Gardnerella vaginalis, Bacteroides fragilis, hans cell histocytosis, eosinophilic pneumonia and pulmo Bacteroides distasonis, Bacteroides 3452A homology group, nary alveolar proteinosis). Bacteroides vulgatus, Bacteroides Ovalus, Bacteroides 0319. The therapeutic method may also include a diagnos thetaiotaomicron, Bacteroides uniformis, Bacteroides egger tic step, such as identifying a Subject with or Suspected of thii, and Bacteroides splanchnicus. In some embodiments of having ILD. In some embodiments, the method further sub the methods described above, the bacteria are gram-negative classifies into idiopathic pulmonary fibrosis. In some anaerobic bacteria, by non-limiting example these include embodiments, the delivered amount of aerosol pirfenidone or Bacteroides fragilis, Bacteroides distasonis, Bacteroides pyridone analog compound (or salt thereof) formulation is 3452A homology group, Bacteroides vulgatus, Bacteroides Sufficient to provide acute, Sub-acute, or chronic symptomatic Ovalus, Bacteroides thetaiotaomicron, Bacteroides unifor relief, slowing of fibrosis progression, halting fibrosis pro mis, Bacteroides eggerthii, and Bacteroides splanchnicus. In gression, reversing fibrotic damage, and/or Subsequent some embodiments of the methods described above, the bac increase in Survival and/or improved quality of life. teria are gram-positive bacteria, by non-limiting example 0320. The therapeutic method may also include a diagnos these include: Corynebacterium diphtheriae, Corynebacte tic step, such as identifying a Subject with or Suspected of rium ulcerans, Streptococcus pneumoniae, Streptococcus having fibrosis in other tissues, by non-limiting example in agalactiae, Streptococcus pyogenes, Streptococcus milleri, the heart, liver, kidney or skin. In some embodiments, the Streptococcus (Group G); Streptococcus (Group C/F); delivered amount of liquid nebulized, dry powder or metered Enterococcus faecalis, Enterococcus faecium, Staphylococ dose aerosol pirfenidone or pyridone analog compound (or cus aureus, Staphylococcus epidermidis, Staphylococcus salt thereof) formulation is sufficient to provide acute, sub Saprophyticus, Staphylococcus intermedius, Staphylococcus acute, or chronic symptomatic relief, slowing of fibrosis pro hyicus Subsp. hyicus, Staphylococcus haemolyticus, Staphy gression, halting fibrosis progression, reversing fibrotic dam lococcus hominis, and Staphylococcus saccharolyticus. In age, and/or Subsequent increase in Survival and/or improved some embodiments of the methods described above, the bac quality of life. teria are gram-positive anaerobic bacteria, by non-limiting 0321. The therapeutic method may also include a diagnos example these include Clostridium difficile, Clostridium per tic step, such as identifying a Subject with or Suspected of fringens, Clostridium tetini, and Clostridium botulinum. In having multiple Sclerosis. In some embodiments, the deliv some embodiments of the methods described above, the bac ered amount of liquid nebulized, dry powder or metered-dose teria are acid-fast bacteria, by non-limiting example these aerosol pirfenidone or pyridone analog compound (or salt include Mycobacterium tuberculosis, Mycobacterium avium, thereof) formulation is sufficient to provide acute, sub-acute, Mycobacterium intracellulare, and Mycobacterium leprae. or chronic symptomatic relief, slowing of demylination pro In some embodiments of the methods described above, the gression, halting demylination progression, reversing bacteria are atypical bacteria, by non-limiting example these demylinated damage, and/or Subsequent increase in Survival include Chlamydia pneumoniae and Mycoplasma pneumo and/or improved quality of life. Cé. 0322. In another embodiment, liquid nebulized, dry pow 0323. As a non-limiting example, in a preferred embodi der or metered-dose aerosol pirfenidone or pyridone analog ment, a pyridone analog compound as provided herein (e.g., compound (or salt thereof) may be co-administered, admin pirfenidone) formulated to permit mist, gas-liquid Suspension istered sequentially or prepared in a fixed-combination with or liquid nebulized, dry powder and/or metered-dose inhaled antimicrobial agents to also provide therapy for a co-existing aerosol administration to Supply effective concentrations or bacterial infection. By non-limiting example the bacteria may amounts to produce and maintain threshold drug concentra be a gram-negative bacteria Such as Pseudomonas aerugi tions in the lung and/or targeted downstream tissue, which nosa, Pseudomonas fluorescens, Pseudomonas acidovorans, may be measured as drug levels in epithelial lining fluid Pseudomonas alcaligenes, Pseudomonasputida, Stenotroph (ELF), sputum, lung tissue, bronchial lavage fluid (BAL), or Omonas maltophilia, Burkholderia cepacia, Aeromonas by deconvolution of blood concentrations through pharma hydrophilia, Escherichia coli, Citrobacter freundii, Salmo cokinetic analysis. One embodiment includes the use of aero nella typhimurium, Salmonella typhi, Salmonella paratyphi, Sol administration, delivering high or titrated concentration Salmonella enteritidis, Shigella dysenteriae, Shigella flex drug exposure directly to the affected tissue for treatment of neri, Shigella Sonnei, Enterobacter cloacae, Enterobacter pulmonary fibrosis and inflammation associated with ILD aerogenes, Klebsiella pneumoniae, Klebsiella Oxytoca, Ser (including idiopathic pulmonary fibrosis), COPD and asthma ratia marcescens, Francisella tularensis, Morganella morga in animals and humans. In one such embodiment, the peak nii, Proteus mirabilis, Proteus vulgaris, Providencia alcali lung ELF levels achieved following aerosol administration to faciens, Providencia rettgeri, Providencia Stuartii, the lung will be between 0.1 mg/mL and about 50 mg/mL Acinetobacter calcoaceticus, Acinetobacter haemolyticus, pirfenidone or pyridone analog. In another embodiment, the US 2015/O 196543 A1 Jul. 16, 2015 50 peak lung wettissue levels achieved following aerosol admin equal to about 3 microns. In another embodiment, the particle istration to the lung will be between 0.004 mcg/gram lung size is 2 microns to about 5 microns mass median aerody tissue and about 500 mcg/gram lung tissue pirfenidone or namic diameter and a particle size geometric standard devia pyridone analog. tion of less than or equal to about 3 microns. In one embodi 0324. As a non-limiting example, in a preferred embodi ment, the particle size geometric standard deviation is less ment, a pyridone analog compound as provided herein (e.g., than or equal to about 2 microns. pirfenidone) formulated to permit mist, gas-liquid Suspension 0328. As a non-limiting example, in a preferred embodi or liquid nebulized, dry powder and/or metered-dose inhaled ment, a pyridone analog compound as provided herein (e.g., aerosol administration to supply effective concentrations or pirfenidone) remains at the therapeutically effective concen amounts to produce and maintain threshold drug concentra tration at the site of pulmonary pathology, Suspected pulmo tions in the blood and/or lung, which may be measured as nary pathology, and/or site of pulmonary absorption into the drug levels in epithelial lining fluid (ELF), sputum, lung pulmonary vasculature for at least about 1 minute, at least tissue, bronchial lavage fluid (BAL), or by deconvolution of about a 5 minute period, at least about a 10 min period, at least blood concentrations through pharmacokinetic analysis that about a 20 min period, at least about a 30 min period, at least absorb to the pulmonary vasculature producing drug levels about a 1 hour period, at least a 2 hour period, at least about a Sufficient for extra-pulmonary therapeutics, maintenance or 4 hour period, at least an 8 hour period, at least a 12 hour prophylaxis. One embodiment includes the use of aerosol period, at least a 24 hour period, at least a 48 hour period, at administration, delivering high concentration drug exposure least a 72 hour period, or at least one week. The effective in the pulmonary vasculature and Subsequent tissues and pirfenidone or pyridone analog concentration is sufficient to associated vasculature for treatment, maintenance and/or pro cause a therapeutic effect and the effect may be localized or phylaxis of, but not limited to cardiac fibrosis, kidney fibrosis, broad-acting to or from the site of pulmonary pathology. hepatic fibrosis, heart or kidney toxicity, or multiple Sclerosis. 0329. As a non-limiting example, in a preferred embodi In one such embodiment, the peak tissue-specific plasma ment, a pyridone analog compound as provided herein (e.g., levels (e.g., heart, kidney and liver) or cerebral spinal fluid pirfenidone or salt thereof) following inhalation administra levels (e.g. central nervous system) achieved following aero tion remains at the therapeutically effective concentration at Sol administration to the lung following oral inhalation or to the site of cardiac fibrosis, kidney fibrosis, hepatic fibrosis, the lung or nasal cavity following intra-nasal administration heart or kidney toxicity, or multiple Sclerosis demylination will be between 0.1 mcg/mL and about 50 mcg/mL pirfeni for at least about 1 minute, at least about a 5 minute period, at done or pyridone analog. In another embodiment, the peak least about a 10 min period, at least about a 20 min period, at lung wet tissue levels achieved following aerosol administra least about a 30 min period, at least about a 1 hour period, at tion to the lung will be between 0.004 mcg/gram lung tissue least a 2 hour period, at least about a 4 hour period, at least an and about 500mcg/gram lung tissue pirfenidone or pyridone 8 hour period, at least a 12 hour period, at least a 24 hour analog. period, at least a 48 hour period, at least a 72 hour period, or 0325 In another embodiment, a method is provided for at least one week. The effective pirfenidone or pyridone ana acute or prophylactic treatment of a patient through non-oral log concentration is sufficient to cause a therapeutic effect or non-nasal topical administration of pirfenidone or pyri and the effect may be localized or broad-acting to or from the done analog (or a salt thereof) compound formulation to site of extrapulmonary pathology. produce and maintain threshold drug concentrations at a burn 0330. In some embodiments, delivery sites such as a pull site. One embodiment includes the use of aerosol administra monary site, the apirfenidone or pyridone analog compound tion, delivering high concentration drug exposure directly to formulation as provided herein is administered in one or more the affected tissue for treatment or prevention of scarring in administrations so as to achieve a respirable delivered dose skin. For example according to these and related embodi daily of pirfenidone or pyridone analog of at least about 0.1 ments, the term aerosol may include a spray, mist, or other mg to about 50 mg, including all integral values therein Such nucleated liquid or dry powder form. as 0.1, 0.2,0.4,0.8, 1, 2, 4, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50 0326 In another embodiment, a method is provided for milligrams. In some embodiments, a pirfenidone or pyridone acute or prophylactic treatment of a patient through non-oral analog compound formulation as provided herein is admin or non-nasal topical administration of pirfenidone or pyri istered in one or more administrations so as to achieve a done analog (or a salt thereof) compound formulation to respirable delivered dose daily of pirfenidone or pyridone produce and maintain threshold drug concentrations in the analog of at least about 0.1 mg to about 300 mg, including all eye. One embodiment includes the use of aerosol administra integral values therein such as 0.1, 0.2,0.4,0.8, 1, 2, 4, 6, 10. tion or formulation drops to deliver high concentration drug 15, 20, 25, 30,35, 40, 45,50,55, 60, 65,70, 75,80, 85,90, 95, exposure directly to the affected tissue for treatment or pre 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, vention of scarring following Surgical glaucoma Surgery (e.g., 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, bleb fibrosis). For example according to these and related 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, embodiments, the term aerosol may include a spray, mist, or 275, 280, 285,290, 295,300 milligrams. The pirfenidone or other nucleated liquid or dry powder form. A drop may be pyridone analog formulation is administered in the described simple liquid or Suspension formulation. respirable delivered dose in less than 60 minutes, less than 50 0327. In another embodiment, a pyridone analog com minutes, less than 40 minutes, less than 30 minutes, less than pound as provided herein (e.g., pirfenidone) formulation by 20 minutes, less than 15 minutes, less than 10 minutes, less inhalation, wherein the inhaled liquid aerosol (e.g., following than 7 minutes, less than 5 minutes, in less than 3 minutes, in liquid nebulization or metered-dose administration) or dry less than 2 minutes, in less than 1 minute, 10 inhalation powder aerosol has a mean particle size from about 1 micron breaths, 8 inhalation breaths, 6 inhalation breaths, 4 inhala to 10 microns mass median aerodynamic diameter and a tion breaths, 3 inhalation breaths, 2 inhalation breaths or 1 particle size geometric standard deviation of less than or inhalation breath. In some embodiments, pirfenidone or pyri US 2015/O 196543 A1 Jul. 16, 2015

done analog formulation is administered in the described cardiac fibrosis therapy. In some embodiments of the methods respirable delivered dose using a breathing pattern of 1 sec describe above, the human Subject may be mechanically ven ondinhalation and 2 seconds exhalation, 2 seconds inhalation tilated. and 2 seconds exhalation, 3 seconds inhalation and 2 seconds 0335. In some embodiments of the methods described exhalation, 4 seconds inhalation and 2 seconds exhalation, 5 above, the Subject is a human. In some embodiments of the seconds inhalation and 2 seconds exhalation, 6 seconds inha methods described above, the Subject is a human requiring lation and 2 seconds exhalation, 7 seconds inhalation and 2 kidney fibrosis therapy. In some embodiments of the methods seconds exhalation, and 8 seconds inhalation and 2 seconds describe above, the human Subject may be mechanically ven exhalation. tilated. 0331. In some embodiments, delivery sites such as the 0336. In some embodiments of the methods described nasal cavity or sinus, pirfenidone or pyridone analog (or salt above, the Subject is a human. In some embodiments of the thereof) compound formulation is administered in one or methods described above, the Subject is a human requiring more administrations so as to achieve a nasal cavity or sinus hepatic fibrosis therapy. In some embodiments of the methods deposited dose daily of pirfenidone or pyridone analog of at describe above, the human Subject may be mechanically ven least about 0.1 mg to about 50 mg, including all integral tilated. values therein such as 0.1, 0.2,0.4,0.8, 1, 2, 4, 6, 10, 15, 20, 0337. In some embodiments of the methods described 25, 30, 35, 40, 45, 50 milligrams. In some embodiments, above, the Subject is a human. In some embodiments of the delivery sites such as the nasal cavity or sinus, pirfenidone or methods described above, the Subject is a human requiring pyridone analog (or salt thereof) compound formulation is cardiac or kidney toxicity therapy. In some embodiments of administered in one or more administrations so as to achieve the methods describe above, the human subject may be a nasal cavity or sinus deposited dose daily of pirfenidone or mechanically ventilated. pyridone analog of at least about 0.1 mg to about 300 mg. 0338. In some embodiments of the methods described including all integral values therein such as 0.1, 0.2,0.4,0.8. above, the Subject is a human. In some embodiments of the 1, 2, 4, 6, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,70, 75, methods described above, the Subject is a human requiring 80, 85,90,95,95, 100,105,110, 115, 120, 125, 130, 135,140, COPD therapy. In some embodiments of the methods 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, describe above, the human Subject may be mechanically ven 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, tilated. 265, 270,275, 280, 285,290, 295,300 milligrams. The pir 0339. In some embodiments of the methods described fenidone or pyridone analog formulation is administered in above, the subject is a human. In some embodiments of the the described nasal or sinus deposited dose in less than 20 methods described above, the Subject is a human requiring minutes, less than 15 minutes, less than 10 minutes, less than asthma therapy. In some embodiments of the methods 7 minutes, less than 5 minutes, in less than 3 minutes, in less describe above, the human Subject may be mechanically ven than 2 minutes, in less than 1 minute, 10 intranasal inhalation tilated. breaths, 8 intranasal inhalation breaths, 6 intranasal inhala 0340. In some embodiments of the methods described tion breaths, 4 intranasal inhalation breaths, 3 intranasal inha above, the Subject is a human. In some embodiments of the lation breaths, 2 intranasal inhalation breaths or 1 intranasal methods described above, the Subject is a human requiring inhalation breath. In some embodiments, pirfenidone or pyri multiple Sclerosis therapy. In some embodiments of the meth done analog formulation is administered in the described ods describe above, the human Subject may be mechanically respirable delivered dose using a breathing pattern of 1 sec ventilated. ondinhalation and 2 seconds exhalation, 2 seconds inhalation 0341. In another embodiment, a pharmaceutical composi and 2 seconds exhalation, 3 seconds inhalation and 2 seconds tion is provided that includes a simple liquid pirfenidone or exhalation, 4 seconds inhalation and 2 seconds exhalation, 5 pyridone analog (or salt thereof) compound formulation with seconds inhalation and 2 seconds exhalation, 6 seconds inha non-encapsulating water soluble excipients as described lation and 2 seconds exhalation, 7 seconds inhalation and 2 above having an osmolality from about 50 mOsmol/kg to seconds exhalation, and 8 seconds inhalation and 2 seconds about 6000 mOsmol/kg. In one embodiment, the osmolality exhalation. is from about 50 mOsmol/kg to about 1000 mOsmol/kg. In 0332. In some embodiments of the methods described one embodiment, the osmolality is from about 400 mOsmol/ above, the Subject is a human. In some embodiments of the kg to about 5000 mOsmol/kg. In other embodiments the methods described above, the subject is a human with ILD. In osmolality is from about 50, 100, 150, 200, 250, 300, 350, some embodiments, the method further sub-classifies into 400, 450, 500 mOsmol/kg to about 1000, 1100, 1200, 1300, idiopathic pulmonary fibrosis. In some embodiments of the 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200,2400, 2600, methods describe above, the human Subject may be mechani 2800, 3000, 3200,3400, 3600, 3800, 4000, 4200,4400, 4600, cally ventilated. 4800 m 5000, 5200, 5400, 5600, 5800 and 6000 mOsmol/kg. With respect to osmolality, and also elsewhere in the present 0333. In embodiments where a human is mechanically application, “about when used to refer to a quantitative value ventilated, aerosol administration would be performed using means that a specified quantity may be greater than or less an in-line device (by non-limiting example, the Nektar than the indicated amount by 1, 2,3,4,5,6,7,8,9, 10, 11, 12, Aeroneb Pro) or similar adaptor with device for liquid nebu 13, 14, 15, 16, 17, 18, 19 or 20 percent of the stated numerical lization. Aerosol administration could also be performed value. using an in-line adaptor for dry powder or metered-dose 0342. In another embodiment, a pharmaceutical composi aerosol generation and delivery. tion is provided that includes a simple liquid pirfenidone or 0334. In some embodiments of the methods described pyridone analog (or salt thereof) compound formulation hav above, the Subject is a human. In some embodiments of the ing a permeant ion concentration between from about 30 mM methods described above, the Subject is a human requiring to about 300 mM and preferably between from about 50 mM US 2015/O 196543 A1 Jul. 16, 2015 52 to 200 mM. In one such embodiment, one or more permeant to one magnesium ions, and two pirfenidone or pyridone ions in the composition are selected from the group consisting analog compounds to two magnesium ions. of chloride and bromide. 0349. In another embodiment, a pharmaceutical composi 0343. In another embodiment, a pharmaceutical composi tion is provided that includes a complex liquid pirfenidone or tion is provided that includes a complex liquid pirfenidone or pyridone analog (or salt thereof) compound formulation as a pyridone analog (or salt thereof) compound formulation low water-soluble stable nanosuspension alone or in co-crys encapsulated or complexed with water soluble excipients tal/co-precipitate complexes, or mixtures with low solubility Such as lipids, liposomes, cyclodextrins, microencapsula lipids, such as lipid nanosuspensions) as described above tions, and emulsions) as described above having a solution having a solution osmolality from about 50 mCSmol/kg to osmolality from about 50 mOsmol/kg to about 6000 mOs about 6000 mOsmol/kg. In one embodiment, the osmolality mol/kg. In one embodiment, the osmolality is from about 50 is from about 100 mOsmol/kg to about 500 mOsmol/kg. In mOsmol/kg to about 1000 mOsmol/kg. In one embodiment, one embodiment, the osmolality is from about 400 mOsmol/ the osmolality is from about 100 mOsmol/kg to about 500 kg to about 5000 mOsmol/kg. mOsmol/kg. In one embodiment, the osmolality is from about 0350. In another embodiment, a pharmaceutical composi 400 mOsmol/kg to about 5000 mOsmol/kg. tion is provided that includes a complex Suspension of a 0344. In another embodiment, a pharmaceutical composi pirfenidone or pyridone analog (or salt thereof) compound tion is provided that includes a complex liquid pirfenidone or formulation having a permeantion concentration from about pyridone analog (or salt thereof) compound formulation hav 30 mM to about 300 mM. In one such embodiment, one or ing a permeant ion concentration from about 30 mM to about more permeant ions in the composition are selected from the 300 mM. In one such embodiment, one or more permeantions group consisting of chloride and bromide. in the composition are selected from the group consisting of 0351. In another embodiment, a pharmaceutical composi chloride and bromide. tion is provided that includes a complex Suspension of a 0345. In another embodiment, a pharmaceutical composi pirfenidone or pyridone analog (or salt thereof) compound tion is provided that includes a complex liquid pirfenidone or formulation having a permeantion concentration from about pyridone analog (or salt thereof) compound formulation hav 50 mM to about 200 mM. In one such embodiment, one or ing a permeant ion concentration from about 50 mM to about more permeant ions in the composition are selected from the 200 mM. In one such embodiment, one or more permeantions group consisting of chloride and bromide. in the composition are selected from the group consisting of 0352. In another embodiment, a pharmaceutical composi chloride and bromide. tion is provided that includes a complex suspension of pir 0346. In another embodiment, a pharmaceutical composi fenidone or pyridone analog (or salt thereof) compound for tion is provided that includes a simple liquid formulation of mulation having a pirfenidone or pyridone analog to pirfenidone or pyridone analog (or salt thereof) compound multivalent cation positive charge molar ratio between about formulation having a prifenidone or pyridone analog to mul one pirfenidone or pyridone analog compounds to about 0.1 tivalent cation positive charge molar ratio between about two to about 4 multivalent cation positive charges. By non-limit pirfenidone or pyridone analog compounds to about 0.1 to ing example, two pirfenidone or pyridone analog compounds about 4 multivalent cation positive charges. By non-limiting to one magnesium ion (two cation positive charges), three example, two pirfenidone or pyridone analog compounds to prifenidone or pyridone analog compounds to one magne one magnesium ion (two cation positive charges), three sium ions, four pirfenidone or pyridone analog compounds to prifenidone or pyridone analog compounds to one magne one magnesium ions, and two pirfenidone or pyridone analog sium ions, four pirfenidone or pyridone analog compounds to compounds to two magnesium ions. one magnesium ions, and two pirfenidone or pyridone analog 0353. In other embodiments, a pirfenidone or pyridone compounds to two magnesium ions. analog (or salt thereof) compound formulation as provided 0347 An unexpected finding was that divalent cations, by herein, or a pharmaceutical composition, is provided that non-limiting example magnesium, reduced pirfenidone dis includes a taste-masking agent. As non-limiting examples, a Solution time and increased pirfenidone aqueous solubility in taste-masking agent may include a Sugar, Saccharin (e.g., a molar ratio-dependent manner. This increased Saturation Sodium saccharin), Sweetener or other compound or agent solubility is enabling to deliverpredicted-sufficient quantities that beneficially affects taste, after-taste, perceived unpleas of inhaled liquid-nebulized pirfenidone to the lung. By ant saltiness, Sourness or bitterness, or that reduces the ten example, one pirfenidone molecules to three magnesium dency of an oral or inhaled formulation to irritate a recipient molecules exhibited a slower dissolution time and reduced (e.g., by causing coughing or Sore throat or other undesired saturation solubility than one pirfenidone molecule to one side effect, such as may reduce the delivered dose or magnesium molecule. Moreover, one pirfenidone molecules adversely influence patient compliance with a prescribed to one magnesium molecule exhibited a faster dissolution therapeutic regimen). Certaintaste-masking agents may form time and greater aqueous solubility than an equal-molar ratio complexes with a pirfenidone or pyridone analog (or salt of pirfenidone to sodium. thereof) compound. 0348. In another embodiment, a pharmaceutical composi 0354. In certain preferred embodiments that relate to the tion is provided that includes a complex liquid formulation of pirfenidone or pyridone analog (or salt thereof) compound pirfenidone or pyridone analog (or salt thereof) compound formulations disclosed herein, the formulation comprises a formulation having aprifenidone or pyridone analog to about pirfenidone or pyridone analog (or salt thereof) compound 0.1 to about 4 multivalent cation positive charges. By non and a taste-masking agent and may be optimized with respect limiting example, two pirfenidone or pyridone analog com to a desired osmolality, and/or an optimized permeant ion pounds to one magnesium ion (two cation positive charges), concentration. In certain such embodiments, the taste-mask three prifenidone or pyridone analog compounds to one mag ing agent comprises saccharin (e.g., Sodium saccharin). nesium ions, four pirfenidone or pyridone analog compounds which according to non-limiting theory affords certain advan US 2015/O 196543 A1 Jul. 16, 2015 tages associated with the ability of this taste-masking agent to citrate is replaced with phosphate (e.g., Sodium phosphate) in provide desirable taste effects even when present in extremely an aqueous Solution containing from about 0.0 mM to about low concentrations, such as may have little or no effect on the 100 mM phosphate. detectable osmolality of a solution, thereby permitting the 0355. In another embodiment, while the inclusion of the herein described formulations to deliver aqueous Solutions, correct molar ratio of magnesium to pirfenidone reduces dis organic or dry powder formulations in a well-tolerated man Solution time and increases saturation solubility to a level ner. In certain such embodiments, the taste-masking agent required for sufficient liquid nebulization delivery to the lung, comprises a chelating agent (e.g., EDTA or divalent cation an unexpected finding was that this formulation additionally Such as magnesium), which according to non-limiting theory requires a taste masking agent for acute tolerability upon affords certain advantages associated with the ability of this inhalation of a nebulized solution. To this end, between 0.1 taste-masking agent to provide desirable taste effects by and 1.0 micromolar saccharin enables the use of this solubil masking taste-stimulating chemical moieties on pirfenidone ity-enabling formulation. of pyridone analog. With divalent cations, inclusion as a 0356. In another embodiment, a pharmaceutical composi taste-masking agent may also substitute as an osmolality tion may be protected from light to avoid photodegradation. adjusting agent, and pending the salt form may also provide By non-limiting example, this may occur by light-protected vials, ampoules, blisters, capsules, or other colored or light the permeant ion (e.g. magnesium chloride), thereby permit protected primary packaging. By another non-limiting ting the herein described formulations to deliver aqueous example, this may occur by use of secondary packaging Such Solutions, organic or dry powder formulations in a well-tol as an aluminum or other light-protected over-pouch, box or erated manner. Non-limiting examples of these and related other secondary packaging. embodiments include a pirfenidone or pyridone analog (or 0357. In another embodiment, a pharmaceutical composi salt thereof) compound formulation for pulmonary delivery tion may be protected from oxygen to protect from oxidation. as described herein that comprises an aqueous solution hav By non-limiting example, in Solution this may occur by ing a pH of from about 4 to about 8 and an osmolality of from removing oxygen from Solution prior to or during compound about 50 to about 1000 mOsmol/kg (e.g., adjusted with ing (e.g., sparging), and or controlled the primary packaging Sodium chloride), the solution comprising pirfenidone or head-space gas (e.g. using of inert gas such as argon or nitro pyridone analog (or salt thereof) compound and sodium sac gen in the head space). Similarly, by another non-limiting charin where the aqueous Solution contains from about 0.1 example, controlling the included secondary packaging gas mM to about 2.0 mM saccharin. A related non-limiting (e.g. with inert gas) may also be required. For powder formu example further comprises citrate (e.g., citric acid) in an lations this may be controlled by use of insert gas in primary aqueous solution containing from about 1 mM to about 100 and/or secondary packaging. Meter-dose inhaled products mM citrate. A related non-limiting example further comprises may benefit by the same means as described above for solu or replace citrate with phosphate (e.g., Sodium phosphate) in tion products. an aqueous Solution containing from about 0.0 mM to about 0358. In another embodiment, pirfenidone or pyridone 100 mM phosphate. Another related non-limiting example analog present in a pharmaceutical composition may be pro further comprises or replace citrate with phosphate (e.g., tected from hydrolysis by inclusion of a cationic metal ion. Sodium phosphate) in an aqueous Solution containing from By non-limiting example, acid hydrolysis of amide bonds about 0.5 mM to about 100 mM phosphate. By another non decreases with an increased salt concentration. Specifically, limiting examples, these and related embodiments include a hydration number is important for this rate decrease, as elec pirfenidone or pyridone analog (or salt thereof) compound trolyte hydration decreases the availability of free water for formulation for pulmonary delivery as described herein that the reaction. Thus, the rate decreases with increased salt and increased hydration number. The order of increasing hydra comprises an aqueous Solution having a pH of from about 4 to tion number: potassium-sodium-lithium-magnesium. The about 8 and an osmolality of from about 50 to about 5000 rate decrease also nearly parallels ionic strength. By non mOsmol/kg (e.g., adjusted with magnesium chloride), the limiting example, the addition of magnesium will stabilize Solution comprising pirfenidone or pyridone analog (or salt the 2-pyridone structure of pirfenidone. It is known that pir thereof) compound, wherein a divalent cation (e.g., berilium, fenidone chelates Fe(III) at a ratio of 3 pirfenidone molecules magnesium, or calcium) serves both to adjust osmolality and to 1 Fe(III). From this it follows that pirfenidone will chelate as a taste-masking agent. Where included as a taste-masking magnesium at 2 pirfenidone molecules to 1 magnesium-2 agent, divalent cation (e.g., magnesium) is added Stoichio charge. Therefore, for this purpose the addition of magnesium metrically with pirfenidone or pyridone analog. By example, or other cationic metal ion may be stoichiometric to the 1 mol divalention to 2 mols pirfenidone or pyridone analog, amount of pirfenidone or pyridone analog. By non-limiting 1.5 mols divalention to 2 mols pirfenidone or pyridone ana example, 2 pirfenidone molecules to 0.1 magnesium mol log, 2 mols divalent ion to 2 mols pirfenidone or pyridone ecules, 2 pirfenidone molecules to 0.25 magnesium mol analog, 3 mols divalention to 2 molspirfenidone or pyridone ecules, 2 pirfenidone molecules to 0.5 magnesium molecules, analog, or 4 mols divalention to 2 mols pirfenidone or pyri 2 pirfenidone molecules to 0.75 magnesium molecules, 2 done analog. Where osmolality required further increase pirfenidone molecules to 1 magnesium molecules, 2 pirfeni sodium chloride or additional divalent salt may be used. A done molecules to 1.5 magnesium molecules, 2 pirfenidone related non-limiting example further comprises citrate (e.g., molecules to 2 magnesium molecules, 2 pirfenidone mol citric acid) in an aqueous solution containing from about 1 ecules to 3 magnesium molecules, 2 pirfenidone molecules to mM to about 100 mM citrate. A related non-limiting example 4 magnesium molecules, 2 pirfenidone molecules to 5 mag citrate is replaced with phosphate (e.g., sodium phosphate) in nesium molecules, 2 pirfenidone molecules to 6 magnesium an aqueous Solution containing from about 0.0 mM to about molecules, 2 pirfenidone molecules to 7 magnesium mol 100 mM phosphate. In another related non-limiting example ecules, 2 pirfenidone molecules to 8 magnesium molecules, 2 US 2015/O 196543 A1 Jul. 16, 2015 54 pirfenidone molecules to 9 magnesium molecules, 2 pirfeni pirfenidone molecules to 6 magnesium molecules, 2 pirfeni done molecules to 10 magnesium molecules, 2 pirfenidone done molecules to 7 magnesium molecules, 2 pirfenidone molecules to 12 magnesium molecules, 2 pirfenidone mol molecules to 8 magnesium molecules, 2 pirfenidone mol ecules to 14 magnesium molecules, 2 pirfenidone molecules ecules to 9 magnesium molecules, 2 pirfenidone molecules to to 16 magnesium molecules, 2 pirfenidone molecules to 18 10 magnesium molecules, 2 pirfenidone molecules to 12 magnesium molecules, or 2 pirfenidone molecules to 20 mag magnesium molecules, 2 pirfenidone molecules to 14 mag nesium molecules. Potassium, Sodium, lithium or iron may nesium molecules, 2 pirfenidone molecules to 16 magnesium Substitute for magnesium in these ratios and pharmaceutical molecules, 2 pirfenidone molecules to 18 magnesium mol composition. Included in the above pharmaceutical compo ecules, or 2 pirfenidone molecules to 20 magnesium mol sition is the maintenance of the buffers described herein, at a ecules. Potassium, Sodium, lithium or iron may substitute for pH from about 4.0 to about 8.0, and include MgCl2 or cat magnesium in these ratios and pharmaceutical composition. ionic salt thereof at a level that provides an osmolality of 300 Included in the above pharmaceutical composition is the mOsmo/kg and 600 mOsmo/kg. While 300 mOsmo?kg is maintenance of the buffers described herein, at a pH from discussed in the literature as important for acute tolerability about 4.0 to about 8.0, and include MgCl, or cationic salt upon inhalation of this in a nebulized solution, 600 mOsmo/ thereof at a level that provides an osmolality of 300 mOsmo/ kg has been shown in unpublished studies to be well tolerated kg and 600 mOsmo?kg. While 300 mOsmo?kg is discussed in with other drug solutions. However, a final Solution osmola the literature as important for acute tolerability upon inhala lity up to 6000 mOsmo/kg is contemplated. Unexpectantly, tion of this in a nebulized solution, 600 mOsmo?kg has been formulations described herein demonstrate good tolerability shown in unpublished studies to be well tolerated with other at high osmolalities. drug Solutions. However, a final Solution osmolality up to 0359. In another embodiment, a pharmaceutical composi 5000 mOsmo/kg is contemplated. tion of liquid pirfenidone or pyridone analog may contain a 0362. In some embodiments, described herein is a phar solubility enhancing agent or co-solvent. By non-limiting maceutical composition that includes: pirfenidone; water; example, these may include ethanol, cetylpridinium chloride, phosphate buffer or citrate buffer; and optionally sodium glycerin, lecithin, propylene glycol, polysorbate (including chloride or magnesium chloride. In other embodiments, polysorbate 20, 40, 60, 80 and 85), sorbitan triolate, and the described herein is a pharmaceutical composition that like. By further example, cetylpridinium chloride may be includes: pirfenidone; water; a buffer; and at least one addi used from about 0.01 mg/mL to about 4 mg/mL pharmaceu tional ingredient selected from Sodium chloride, magnesium tical composition. Similarly, by another non-limiting chloride, ethanol, propylene glycol, glycerol, polysorbate 80, example, ethanol may be used from about 0.01% to about and cetylpyridinium bromide (or chloride). In some embodi 30% pharmaceutical composition. Similarly, by another non ments, the buffer is phosphate buffer. In other embodiments, limiting example, glycerin may be used from about 0.01% to the buffer is citrate buffer. In some embodiments, the phar about 25% pharmaceutical composition. Similarly, by maceutical composition includes 1 mg to 500 mg of pirfeni another non-limiting example, lecithin may be used from done, for example, 5 mg, 10 mg, 15 mg, 25 mg, 37.5 mg, 75 about 0.01% to about 4% pharmaceutical composition. Simi mg, 100 mg, 115 mg, 150 mg, 190 mg, 220 mg. or 500 mg. In larly, by another non-limiting example, propylene glycol may Some embodiments, the osmolality of the pharmaceutical be used from about 0.01% to about 30% pharmaceutical composition described herein is between about 50 mOsmo?kg composition. Similarly, by another non-limiting example, to 6000 mOsmo/kg. In some embodiments, the pharmaceu polysorbates may also be used from about 0.01% to about tical composition optionally includes saccharin (e.g. sodium 10% pharmaceutical composition. Similarly, by another non salt). Non-limiting examples of pharmaceutical compositions limiting example, Sorbitan triolate may be used from about described herein include any one of the pharmaceutical com 0.01% to about 20% pharmaceutical composition. positions described in Tables 1-1 to Table 1-11 of Example 1. 0360. In another embodiment, a pharmaceutical composi 0363 Solutions of pirfenidone should remain protected tion of liquid or dry powder pirfenidone or pyridone analog from light as the API in solution is subject to degradation may contain a chelated metalion to assist in Solubility and/or 0364. In another embodiment, a pharmaceutical composi dissolution of pirfenidone or pyridone analog. By non-limit tion is provided that includes a simple dry powderpirfenidone ing example, these may include iron, magnesium, or calcium. or pyridone analog (or salt thereof) compound alone in dry 0361. In another embodiment, a pharmaceutical composi powderform with or without a blending agent such as lactose. tion of liquid or dry powder pirfenidone or pyridone analog 0365. In another embodiment, the pharmaceutical compo may contain a chelated metal ion to assist in Scavenging sition used in a liquid, dry powder or meter-dose inhalation reactive oxygen species. By non-limiting example, these may device is provided Such that pirfenidone or pyridone analog is include iron, magnesium, or calcium. By non-limiting not in a salt form. example, for this purpose the addition of magnesium or other 0366. In another embodiment, a pharmaceutical composi cationic metal ion may be stoichiometric to the amount of tion is provided that includes a complex dry powder pirfeni pirfenidone or pyridone analog. By non-limiting example, 2 done or pyridone analog (or salt thereof) compound formu pirfenidone molecules to 0.1 magnesium molecules, 2 pir lation in co-crystal/co-precipitate/spray dried complex or fenidone molecules to 0.25 magnesium molecules, 2 pirfeni mixture with low water soluble excipients/salts in dry powder done molecules to 0.5 magnesium molecules, 2 pirfenidone form with or without a blending agent Such as lactose. molecules to 0.75 magnesium molecules, 2 pirfenidone mol 0367. In another embodiment, a system is provided for ecules to 1 magnesium molecules, 2 pirfenidone molecules to administering a pirfenidone or pyridone analog (or salt 1.5 magnesium molecules, 2 pirfenidone molecules to 2 mag thereof) compound that includes a container comprising a nesium molecules, 2 pirfenidone molecules to 3 magnesium Solution of a pirfenidone or pyridone analog (or salt thereof) molecules, 2 pirfenidone molecules to 4 magnesium mol compound formulation and a nebulizer physically coupled or ecules, 2 pirfenidone molecules to 5 magnesium molecules, 2 co-packaged with the container and adapted to produce an US 2015/O 196543 A1 Jul. 16, 2015

aerosol of the solution having a particle size from about 1 0376. The term “microM refers to micromolar. microns to about 5 microns mean mass aerodynamic diam 0377 The term “QD” refers to once a day dosing. eter, volumetric mean diameter (VMD) or mass median diam 0378. The term “BID” refers to twice a day dosing. eter (MMD) and a particle size geometric standard deviation 0379 The term “TID” refers to three times a day dosing. of less than or equal to about 2.5 microns mean mass aero (0380. The term “QID” refers to four times a day dosing. dynamic diameter. In one embodiment, the particle size geo 0381. As used herein, the term “about is used synony metric standard deviation is less than or equal to about 3.0 mously with the term “approximately.” Illustratively, the use microns. In one embodiment, the particle size geometric stan of the term “about with regard to a certain therapeutically dard deviation is less than or equal to about 2.0 microns. effective pharmaceutical dose indicates that values slightly 0368. In another embodiment, a system is provided for outside the cited values, e.g., plus or minus 0.1% to 10%, administering a pirfenidone or pyridone analog (or salt which are also effective and safe. thereof) compound that includes a container comprising a dry 0382. As used herein, the terms “comprising,” “includ powder of a pirfenidone or pyridone analog (or salt thereof) ing,” “such as and “for example' are used in their open, compound and a dry powder inhaler coupled to the container non-limiting sense. and adapted to produce a dispersed dry powder aerosol hav 0383. The terms “administration' or “administering and ing a particle size from about 1 microns to about 5 microns “delivery' or “delivery” refer to a method of giving to a mean mass aerodynamic and a particle size standard devia mammal a dosage of a therapeutic or prophylactic formula tion of less than or equal to about 3.0 microns. In one embodi tion, Such as apirfenidone or pyridone analog (or salt thereof) ment, the particle size standard deviation is less than or equal compound formulation described herein, for example as an to about 2.5 microns. In one embodiment, the particle size anti-inflammatory, anti-fibrotic and/or anti-demylination standard deviation is less than or equal to about 2.0 microns. pharmaceutical composition, or for other purposes. The pre 0369. In another embodiment, a kit is provided that ferred delivery method or method of administration can vary includes a container comprising a pharmaceutical formula depending on various factors, e.g., the components of the tion comprising a pirfenidone or pyridone analog (or salt pharmaceutical composition, the desired site at which the thereof) compound and an aerosolizer adapted to aerosolize formulation is to be introduced, delivered or administered, the the pharmaceutical formulation (e.g., in certain preferred site where therapeutic benefit is sought, or the proximity of embodiments, a liquid nebulizer) and deliver it to the lower the initial delivery site to the downstream diseased organ respiratory tract, for instance, to a pulmonary compartment (e.g., aerosol delivery to the lung for absorption and second Such as alveoli, alveolar ducts and/or bronchioles, following ary delivery to the heart, kidney, liver, central nervous system intraoral administration. The formulation may also be deliv or other diseased destination). In some embodiments, phar ered as a dry powder or through a metered-dose inhaler. maceutical compositions described herein are administered 0370. In another embodiment, a kit is provided that by pulmonary administration. includes a container comprising a pharmaceutical formula 0384 The terms “pulmonary administration” or “inhala tion comprising a pirfenidone or pyridone analog (or salt tion” or “pulmonary delivery' or “oral inhalation” or “intra thereof) compound and an aerosolizer adapted to aerosolize nasal inhalation' and other related terms refer to a method of the pharmaceutical formulation (e.g., in certain preferred giving to a mammal a dosage of a therapeutic or prophylactic embodiments, a liquid nebulizer) and deliver it to a nasal formulation, such as a pirfenidone or pyridone analog (or salt cavity following intranasal administration. The formulation thereof) compound formulation described herein, by a route may also be delivered as a dry powder or through a metered Such that the desired therapeutic or prophylactic agent is dose inhaler. delivered to the lungs of a mammal. Such delivery to the lung 0371. It should be understood that many carriers and may occur by intranasal administration, oral inhalation excipients may serve several functions, even within the same administration. Each of these routes of administration may formulation. occur as inhalation of an aerosol of formulations described 0372 Contemplated pharmaceutical compositions pro herein. In some embodiments, pulmonary administration vide a therapeutically effective amount of pirfendione orpyri occurs by passively delivering an aerosol described herein by done analog compound enabling, for example, once-a-day, mechanical ventilation. twice-a-day, three times a day, etc. administration. In some embodiments, pharmaceutical compositions for inhaled 0385. The terms “intranasal inhalation administration” delivery provide an effective amount of pirfendione or pyri and “intranasal inhalation delivery” refer to a method of giv done analog compound enabling once-a-day dosing. In some ing to a mammala dosage of a pirfenidone or pyridone analog embodiments, pharmaceutical compositions for inhaled (or salt thereof) compound formulation described herein, by a delivery provide an effective amount of pirfendione or pyri route Such that the formulation is targeting delivery and done analog compound enabling twice-a-day dosing. In some absorption of the therapeutic formulation directly in the lungs embodiments, pharmaceutical compositions for inhaled of the mammal through the nasal cavity. In some embodi delivery provide an effective amount of pirfendione or pyri ments, intranasal inhalation administration is performed with done analog compound enabling three times-a-day dosing. a nebulizer. 0386 The terms “intranasal administration' and “intrana 0373. It is to be understood that both the foregoing general sal delivery refer to a method of giving to a mammal a description and the following detailed description are exem dosage of a therapeutic or prophylactic formulation, Such as a plary and explanatory only and are not restrictive of the inven pirfenidone or pyridone analog (or salt thereof) compound tion, as claimed. formulation described herein, by a route such that the desired Certain Terminology therapeutic or prophylactic agent is delivered to the nasal cavity or diseased organs downstream (e.g., aerosol delivery 0374 The term “mg” refers to milligram. to the nasal cavity for absorption and secondary delivery to 0375 The term “mcg” refers to microgram. the central nervous system or other diseased destination). US 2015/O 196543 A1 Jul. 16, 2015 56

Such delivery to the nasal cavity may occur by intranasal man et al. (Eds.) (1990); Goodman and Gilman's: The Phar administration, wherein this route of administration may macological Basis of Therapeutics, 8th Ed., Pergamon Press. occur as inhalation of an aerosol of formulations described 0394. A "diagnostic' as used herein is a compound, herein, injection of an aerosol of formulations described method, system, or device that assists in the identification and herein, gavage of a formulation described herein, or passively characterization of a health or disease state. The diagnostic delivered by mechanical ventilation. can be used in Standard assays as is known in the art. 0387. The terms “intraoccular administration' and 0395 “Patient” or “subject” are used interchangeably and “intraoccular delivery” refer to a method of giving to a mam refer to a mammal. mal a dosage of a therapeutic or prophylactic formulation, 0396 The term “mammal’ is used in its usual biological Such as a pirfenidone or pyridone analog (or salt thereof) sense. In some embodiments, a mammal is a human. compound formulation described herein, by a route such that 0397) The term “ex vivo” refers to experimentation or the desired therapeutic or prophylactic agent is delivered to manipulation done in or on living tissue in an artificial envi the eye. Such delivery to the eye may occur by direct admin ronment outside the organism. istration to the eye. This route of administration may occuras 0398. The term “pharmaceutically acceptable carrier' or spray of an aerosol of formulations described herein, injec “pharmaceutically acceptable excipient includes any and all tion of an aerosol of formulations described herein, or drops Solvents, dispersion media, coatings, antibacterial and anti of a formulation described herein. fungal agents, isotonic and absorption delaying agents and 0388 “Oral administration” or “orally” or “oral” is a route the like. The use of Such media and agents for pharmaceuti of administration where a substance (e.g. a pharmaceutical cally active substances is well known in the art. Exceptinsofar composition) is taken through the mouth. In some embodi as any conventional media or agent is incompatible with the ments, when it is used without any further descriptors, it active ingredient, its use in the therapeutic compositions is refers to administration of a substance through the mouth and contemplated. Supplementary active ingredients can also be directly into the gastrointestinal tract. Oral administration incorporated into the compositions. generally includes a number of forms, such as tablets, pills, 0399. The term “pharmaceutically acceptable salt” refers capsules, and solutions. to salts that retain the biological effectiveness and properties 0389. The terms “oral inhalation administration” or "oral of the compounds of this invention and, which are not bio inhalation delivery' or “oral inhalation” refer to a method of logically or otherwise undesirable. In many cases, the com giving to a mammal a dosage of a pirfenidone or pyridone pounds of this invention are capable of forming acid and/or analog (or salt thereof) compound formulation described base salts by virtue of the presence of amino and/or carboxyl herein, through the mouth for delivery and absorption of the groups or groups similar thereto. Pharmaceutically accept formulation directly to the lungs of the mammal. In some able acid addition salts can be formed with inorganic acids embodiments, oral inhalation administration is carried out by and organic acids. Inorganic acids from which salts can be the use of a nebulizer. derived include, for example, hydrochloric acid, hydrobro 0390 The term “abnormal liver function may manifestas mic acid, Sulfuric acid, nitric acid, phosphoric acid, and the abnormalities in levels of biomarkers of liver function, like. Organic acids from which salts can be derived include, including alanine transaminase, aspartate transaminase, for example, acetic acid, propionic acid, naphtoic acid, oleic bilirubin, and/or alkaline phosphatase, and may be an indica acid, palmitic acid, pamoic (emboic) acid, Stearic acid, gly tor of drug-induced liver injury. See FDA Draft Guidance for colic acid, pyruvic acid, oxalic acid, maleic acid, malonic Industry. Drug-Induced Liver Injury: Premarketing Clinical acid, Succinic acid, fumaric acid, tartaric acid, citric acid, Evaluation, October 2007. ascorbic acid, glucoheptonic acid, glucuronic acid, lactic 0391 "Grade 2 liver function abnormalities include acid, lactobioic acid, tartaric acid, benzoic acid, cinnamic elevations in alanine transaminase (ALT), aspartate transami acid, mandelic acid, methanesulfonic acid, ethanesulfonic nase (AST), alkaline phosphatase (ALP), orgamma-glutamyl acid, p-toluenesulfonic acid, Salicylic acid, and the like. Phar transferase (GGT) greater than 2.5-times and less than or maceutically acceptable base addition salts can be formed equal to 5-times the upper limit of normal (ULN). Grade 2 withinorganic and organic bases. Inorganic bases from which liver function abnormalities also include elevations of biliru salts can be derived include, for example, Sodium, potassium, bin levels greater than 1.5-times and less than or equal to lithium, ammonium, calcium, magnesium, iron, Zinc, copper, 3-times the ULN. manganese, aluminum, and the like; particularly preferred are 0392 "Gastrointestinal adverse events’ include but are the ammonium, potassium, sodium, calcium and magnesium not limited to any one or more of the following: dyspepsia, salts. Organic bases from which salts can be derived include, nausea, diarrhea, gastroesophageal reflux disease (GERD) for example, primary, secondary, and tertiary amines, Substi and Vomiting. tuted amines including naturally occurring Substituted 0393 A“carrier' or “excipient' is a compound or material amines, cyclic amines, basic ion exchange resins, and the like, used to facilitate administration of the compound, for specifically Such as isopropylamine, trimethylamine, diethy example, to increase the solubility of the compound. Solid lamine, triethylamine, tripropylamine, histidine, arginine, carriers include, e.g., starch, lactose, dicalcium phosphate, lysine, benethamine, N-methyl-glucamine, and ethanola Sucrose, and kaolin. Liquid carriers include, e.g., Sterile mine. Other acids include dodecylsulfuric acid, naphthalene water, Saline, buffers, non-ionic Surfactants, and edible oils 1.5-disulfonic acid, naphthalene-2-sulfonic acid, and saccha Such as oil, peanut and sesame oils. In addition, various adju rin. vants such as are commonly used in the art may be included. 0400. The term “pH-reducing acid refers to acids that These and other such compounds are described in the litera retain the biological effectiveness and properties of the com ture, e.g., in the Merck Index, Merck & Company, Rahway, pounds of this invention and, which are not biologically or N.J. Considerations for the inclusion of various components otherwise undesirable. Pharmaceutically acceptable pH-re in pharmaceutical compositions are described, e.g., in Gil ducing acids include, for example, inorganic acids such as, US 2015/O 196543 A1 Jul. 16, 2015 57 e.g., hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric desired biological or pharmacological activity of a pirfeni acid, phosphoric acid, and the like. Also by nonlimiting done or pyridone analog compound, based on the disclosure example, pH-reducing acids may also include organic acids herein. Suitable buffers may include those in Table 1 or Such as citric acid, acetic acid, propionic acid, naphtoic acid, known to the art (see, e.g., CalbiochemR Biochemicals & oleic acid, palmitic acid, pamoic (emboic) acid, Stearic acid, Immunochemicals Catalog 2004/2005, pp. 68-69 and catalog glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic pages cited therein, EMD Biosciences, La Jolla, Calif.). acid, Succinic acid, fumaric acid, tartaric acid, citric acid, 04.05 Non-limiting examples of buffers that may be used ascorbic acid, glucoheptonic acid, glucuronic acid, lactic according to certain embodiments disclosed herein, include acid, lactobioic acid, tartaric acid, benzoic acid, cinnamic but are not limited to formate (pKa 3.77), Citric acid (pKa2 acid, mandelic acid, methanesulfonic acid, ethanesulfonic 4.76), Malate (pKa2 5.13), Pyridine (pKa 5.23), Piperazine acid, p-toluenesulfonic acid, salicylic acid, and the like. ((pKa1) 5.33). Succinate ((pKa2) 5.64). Histidine (pKa 6.04), 04.01. According to certain herein disclosed embodiments Maleate ((pKa2) 6.24), Citric acid (pKa3) 6.40), Bis-Tris a pirfenidone or a pyridone analog compound formulation (pKa 6.46), Pyrophosphate ((pKa3) 6.70), PIPES (pKa 6.76), may comprise an "acidic excipient’ that is typically present as ACES (pKa 6.78), Histidine (pKa 6.80), MES (pKa 6.15), an acidic excipient aqueous solution. Examples of may Cacodylic acid (pKa 6.27), H2CO3/NaHCO3 (pKa1) (6.37), include acid salts such as phosphate, Sulphate, nitrate, acetate, ADA (N-(2-Acetamido)-2-iminodiacetic acid) (pKa 6.60). In formate, citrate, tartrate, propionate and Sorbate, organic Some embodiments, pharmaceutical compositions disclosed acids such as carboxylic acids, Sulfonic acids, phosphonic herein include a citrate buffer or a phosphate buffer. In some acids, phosphinic acids, phosphoric monoesters, and phos embodiments, pharmaceutical compositions disclosed herein phoric diesters, and/or other organic acids that contain from 1 include a citrate buffer. In some embodiments, pharmaceuti to 12 carbon atoms, citric acid, acetic acid, formic acid, pro cal compositions disclosed herein include a phosphate buffer. pionic acid, butyric acid, benzoic acid, mono-, di-, and (0406. “Solvate” refers to the compound formed by the trichloroacetic acid, salicylic acid, trifluoroacetic acid, ben interaction of a solvent and pirfenidone or a pyridone analog Zenesulfonic acid, toluenesulfonic acid, methylphosphonic compound, a metabolite, or salt thereof. Suitable solvates are acid, methylphosphinic acid, dimethylphosphinic acid, and pharmaceutically acceptable Solvates including hydrates. phosphonic acid monobutyl ester. 0407. By “therapeutically effective amount’ or “pharma 0402. A "buffer refers to a compound that functions to ceutically effective amount' is meant pirfenidone or a pyri regulate pH. In certain related embodiments the pH buffer is done analog compound, as disclosed for this invention, which present under conditions and in Sufficient quantity to maintain has a therapeutic effect. The doses of pirfenidone or a pyri a pH that is “about a recited pH value. About such a pH done analog compound which are useful in treatment are refers to the functional presence of that buffer, which, as is therapeutically effective amounts. Thus, as used herein, a known in the art, may be a consequence of a variety of factors therapeutically effective amount means those amounts of pir including pKa value(s) of the buffer, buffer concentration, fenidone or a pyridone analog compound which produce the working temperature, effects of other components of the desired therapeutic effect as judged by clinical trial results composition on pKa (i.e., the pH at which the buffer is at and/or model animal pulmonary fibrosis, cardiac fibrosis, equilibrium between protonated and deprotonated forms, kidney fibrosis, hepatic fibrosis, heart or kidney toxicity, mul typically the center of the effective buffering range of pH tiple sclerosis, COPD or asthma. In particular embodiments, values), and other factors. the pirfenidone or pyridone analog compounds are adminis 0403. Hence, “about in the context of pH may be under tered in a pre-determined dose, and thus a therapeutically stood to represent a quantitative variation in pH that may be effective amount would be an amount of the dose adminis more or less than the recited value by no more than 0.5 pH tered. This amount and the amount of the pirfenidone or units, more preferably no more than 0.4 pH units, more pref pyridone analog compound can be routinely determined by erably no more than 0.3 pH units, still more preferably no one of skill in the art, and will vary, depending on several more than 0.2 pH units, and most preferably no more than factors, such as the therapeutic or prophylactic effect for 0.1-0.15 pH units. As also noted above, in certain embodi fibrotic, inflammatory or demylination injury occurs, and ments a Substantially constant pH (e.g., a pH that is main how distant that disease site is from the initial respiratory tained within the recited range for an extended time period) location receiving the initial inhaled aerosol dose. This may be from about pH 4.0 to about pH 8.0, from about pH 4.0 amount can further depend upon the patient's height, weight, to about pH 7.0, or from about pH 4.0 to about pH 6.8, or any sex, age and medical history. For prophylactic treatments, a other pH or pH range as described herein, which in preferred therapeutically effective amount is that amount which would embodiments may be from about pH 4.0 to about pH 8.0 for be effective to prevent a fibrotic, inflammatory or demylina apirfenidone or pyridone analog compound formulation, and tion injury. greater than about pH 8.0 for a pirfenidone or pyridone analog 0408. A “therapeutic effect” relieves, to some extent, one compound aqueous solution. or more of the symptoms associated with inflammation, fibro 04.04 Therefore the pH buffer typically may comprise a sis and/or demylination. This includes slowing the progres composition that, when present under appropriate conditions sion of, or preventing or reducing additional inflammation, and in Sufficient quantity, is capable of maintaining a desired fibrosis and/or demylination. For IPF, a “therapeutic effect” is pH level as may be selected by those familiar with the art, for defined as a patient-reported improvement in quality of life example, buffers comprising citrate, formate, malate, for and/or a statistically significant increase in or stabilization of mate, pyridine, piperazine, Succinate, histidine, maleate, bis exercise tolerance and associated blood-oxygen saturation, Tris, pyrophosphate, PIPES, ACES, histidine, MES, reduced decline in baseline forced vital capacity, decreased cacodylic acid, H2CO3/NaHCO3 and N-(2-Acetamido)-2- incidence inacute exacerbations, increase in progression-free iminodiacetic acid (ADA) or other buffers for maintaining, Survival, increased time-to-death or disease progression, and/ preserving, enhancing, protecting or otherwise promoting or reduced lung fibrosis. For cardiac fibrosis, a “therapeutic US 2015/O 196543 A1 Jul. 16, 2015 effect” is defined as a patient-reported improvement in qual disease. Thus, in preferred embodiments, treating is the ity of life and/or a statistically significant improvement in administration to a mammal (either fortherapeutic or prophy cardiac function, reduced fibrosis, reduced cardiac stiffness, lactic purposes) of therapeutically effective amounts of pir reduced or reversed valvular stenosis, reduced incidence of arrhythmias and/or reduced atrial or ventricular remodeling. fenidone or a pyridone analog compound. For kidney fibrosis, a “therapeutic effect” is defined as a 0411. The term “dosing interval refers to the time patient-reported improvement in quality of life and/or a sta between administrations of the two sequential doses of a tistically significant improvement in glomular filtration rate pharmaceuticals during multiple dosing regimens. and associated markers. For hepatic fibrosis, a “therapeutic effect” is defined as a patient-reported improvement in qual 0412. The “respirable delivered dose” is the amount of ity of life and/or a statistically significant lowering of elevated aerosolized pirfenidone or a pyridone analog compound par aminotransferases (e.g., AST and ALT), alkaline phos ticles inhaled during the inspiratory phase of the breath simu phatases, gamma-glutamyl transferase, bilirubin, prothrom lator that is equal to or less than 5 microns. bintime, globulins, as well as reversal of thromobocytopenia, leukopenai and neutropenia and coagulation defects. Further 0413 “Lung Deposition” as used herein, refers to the frac a potential reversal of imaging, endoscopic or other patho tion of the nominal dose of an active pharmaceutical ingredi logical findings. For COPD, a “therapeutic effect” is defined ent (API) that is deposited on the inner surface of the lungs. as a patient-reported improvement in quality of life and/or a 0414 “Nominal dose, or “loaded dose” refers to the statistically significant improved exercise capacity and asso amount of drug that is placed in the nebuluZerprior to admin ciated blood-oxygen saturation, FEV1 and/or FVC, a slowed istration to a mammal. The Volume of solution containing the or halted progression in the same, progression-free Survival, nominal dose is referred to as the “fill volume.” increased time-to-death or disease progression, and/or reduced incidence or acute exacerbation. For asthma, a 0415 “Enhanced pharmacokinetic profile” means an “therapeutic effect” is defined as a patient-reported improve improvement in some pharmacokinetic parameter. Pharma ment in quality of life and/or a statistically significantly cokinetic parameters that may be improved include, AUClast, improved exercise capacity, improved FEV 1 and/or FVC, AUC(O-Oo) Tmax, and optionally a Cmax. In some embodi and/or reduced incidence or acute exacerbation. For multiple ments, the enhanced pharmacokinetic profile may be mea sclerosis, a “therapeutic effect” is defined as a patient-re Sured quantitatively by comparing a pharmacokinetic param ported improvement in quality of life and/or a statistically eter obtained for a nominal dose of an active pharmaceutical significantly improved Scripps Neurological Rating Scale ingredient (API) administered with one type of inhalation score, improvement in bladder dysfunction, improved Dis device with the same pharmacokinetic parameter obtained ability Status Socres, MRI lesion count, and/oran slowed or with oral administration of a composition of the same active halted progression of disease. pharmaceutical ingredient (API). 04.09 “Treat,” “treatment,” or “treating,” as used herein refers to administering a pharmaceutical composition for 0416) “Blood plasma concentration” refers to the concen therapeutic purposes. In some embodiments, treating refers to tration of an active pharmaceutical ingredient (API) in the alleviating, abating or ameliorating at least one symptom of a plasma component of blood of a Subject or patient population. disease or condition, preventing any additional symptoms 0417 "Respiratory condition, as used herein, refers to a from arising, arresting the progression of at least one current disease or condition that is physically manifested in the res symptom of the disease or condition, relieving at least one of piratory tract, including, but not limited to, pulmonary fibro the symptoms of a disease or condition, causing regression of sis, chronic obstructive pulmonary disease (COPD), bronchi the disease or condition, relieving a condition caused by the tis, chronic bronchitis, emphysema, or asthma. disease or condition, or stopping the symptoms of the disease or condition. In some embodiments, the compositions 0418 “Nebulizer, as used herein, refers to a device that described herein are used for prophylactic treatment. The turns medications, compositions, formulations, Suspensions, term “prophylactic treatment” refers to treating a patient who and mixtures, etc. into a fine mist or aerosol for delivery to the is not yet diseased but who is susceptible to, or otherwise at lungs. Nebulizers may also be referred to as atomizers. risk of a particular disease, or who is diseased but whose 0419 “Drug absorption” or simply “absorption' typically condition does not worsen while being treated with the phar maceutical compositions described herein. The term “thera refers to the process of movement of drug from site of deliv peutic treatment” refers to administering treatment to a ery of a drug across a barrier into a blood vessel or the site of patient already Suffering from a disease. Thus, in preferred action, e.g., a drug being absorbed in the pulmonary capillary embodiments, treating is the administration to a mammal beds of the alveoli. (either for therapeutic or prophylactic purposes) of therapeu tically effective amounts of pirfenidone or a pyridone analog Pirfenidone and Pyridone Analog Compounds compound. 0420. As also noted elsewhere herein, in preferred 0410. “Treat,” “treatment or “treating, as used herein embodiments the pyridone compound for use in a pyridone refers to administering a pharmaceutical composition for pro compound formulation as described herein comprises pir phylactic and/or therapeutic purposes. The term “prophylac fenidone (5-methyl-1-phenyl-2-(1H)-pyridone) or a salt tic treatment” refers to treating a patient who is not yet dis thereof. Although various embodiments are described with eased, but who is susceptible to, or otherwise at risk of, a the use of pirfenidone, it is noted that other pyridone analog particular disease. The term “therapeutic treatment” refers to compounds, or salts thereof, may be used in place of pirfeni administering treatment to a patient already suffering from a done.

US 2015/O 196543 A1 Jul. 16, 2015 cyanophenyl)-6-methyl-2-oxo-1H-pyridine-3-carbonitrile, ies. Similarly, in the case of treating CNS disorder (e.g., 3.3-diethyl-1-(piperazin-1-ylamino)methylpyridine-2,4- multiple Sclerosis), deposition of drug in the respiratory tract dione, 5-ethyl-3-(5-ethyl-2-methoxy-6-methylpyridin-3-yl) (as defined above) or nasal cavity, more specifically the methylamino-6-methyl-1H-pyridin-2-one and pharmaceuti absorption from the nasal cavity to the nasal capillary beds for cally acceptable salts thereof. immediate access to the brain and CNS. This direct delivery 0429. In some embodiments, the pirfendione or pyridone will permit direct dosing of high concentration pirfenidone or analog compound is used in compositions and methods a pyridone analog compound in the absence of unnecessary described herein in free-base or free-acid form. In other systemic exposure. Similarly, this route permits titration of embodiments, the pirfendione or pyridone analog compound the dose to a level that may be critical for these indications. is used as pharmaceutically acceptable salts. In some embodi 0432 Pharmaceutical Compositions ments, pharmaceutically acceptable salts are obtained by 0433 For purposes of the method described herein, a pyri reacting the compound with an acid or with a base. The type done analog compound, most preferably pirfenidone may be of pharmaceutical acceptable salts, include, but are not lim administered using a liquid nebulization, dry powder or ited to: (1) acid addition salts, formed by reacting the free base metered-dose inhaler. In some embodiments, pirfenidone or a form of the compound with a pharmaceutically acceptable: pyridone analog compound disclosed herein is produced as a (1) acid such as, for example, hydrochloric acid, hydrobromic pharmaceutical composition Suitable for aerosol formation, acid, Sulfuric acid, phosphoric acid, metaphosphoric acid, dose for indication, deposition location, pulmonary or intra acetic acid, propionic acid, hexanoic acid, cyclopentanepro nasal delivery for pulmonary, intranasal/sinus, or extra-respi pionic acid, glycolic acid, pyruvic acid, lactic acid, malonic ratory therapeutic action, good taste, manufacturing and Stor acid, Succinic acid, malic acid, maleic acid, fumaric acid, age Stability, and patient safety and tolerability. trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 0434. In some embodiments, the isoform content of the 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic manufactured pyridone analog compound, most preferably acid, methanesulfonic acid, ethanesulfonic acid, 1.2- pirfenidone may be optimized for drug Substance and drug ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benze product stability, dissolution (in the case of dry powder or nesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic Suspension formulations) in the nose and/or lung, tolerability, acid, 4-methylbicyclo-2.2.2]oct-2-ene-1-carboxylic acid, and site of action (be that lung, nasal/sinus, or regional tis glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1- Sue). carboxylic acid), 3-phenylpropionic acid, trimethylacetic 0435. Manufacture acid, tertiary butylacetic acid, lauryl Sulfuric acid, gluconic 0436. In some embodiments, pirfenidone drug product acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, (DP) includes pirfenidone at a concentration of about 1 Stearic acid, muconic acid, butyric acid, phenylacetic acid, mg/mL to about 100 mg/mL in aqueous buffer (citrate or phenylbutyric acid, valproic acid, and the like; or (2) base, phosphate pH-4 to 8), plus optional added salts (NaCl and/or where an acidic proton present in the parent compound is MgCl, and/or MgSO). In some embodiments, the pirfeni replaced by a metalion, e.g., an alkali metalion (e.g. lithium, done drug product also includes co-solvent(s) (by non-limit Sodium, potassium), an alkaline earth ion (e.g. magnesium, or ing example ethanol, propylene glycol, and glycerin) and/or calcium), or an aluminum ion. In some cases, the pirfendione orpyridone analog compound is reacted with an organic base, surfactant(s) (by non-limiting example Tween 80, Tween 60, Such as, but not limited to, ethanolamine, diethanolamine, lecithin, Cetylpyridinium, and Tween 20). In some embodi triethanolamine, tromethamine, N-methylglucamine, dicy ments, the formulation also includes a taste-masking agent clohexylamine, tris(hydroxymethyl)methylamine or with an (by non-limiting example sodium saccharin). 0437. To achieve pirfenidone concentrations above 3 amino acid Such as, but not limited to, arginine, lysine, and the mg/mL, manufacturing process are described. In one embodi like. ment, the manufacturing process includes high temperature Advantages of Inhaled Aerosol and Topical (Non-Oral) Drug pirfenidone aqueous dissolution, followed by co-solvent and/ Delivery or Surfactant and/or salt addition, and Subsequent cooling to ambient temperature. In this process, added co-solvent and/or 0430. Inhalation therapy of aerosolized pirfenidone or a Surfactant and/or salt stabilize the high-temperature-dis pyridone analog compound enables direct deposition of the Solved pirfenidone during the cooling process and provide a Sustained-release or active Substance in the respiratory tract stable, high-concentration, ambient-temperature formulation (be that intra-nasal or pulmonary) for therapeutic action at of pirfenidone. In some embodiments, the processing tem that site of deposition or systemic absorption to regions perature is 30° C., 35° C., 40° C., 45° C., 50° C., 55° C., 60° immediately down stream of the vascular absorption site. In C., 650 C., 70° C., 75° C., 80° C. 850 C., 90° C., 95°C., 100° the case of central nervous system (CNS) deposition, intra C. or other pressure-enabled increased temperature. In some nasal inhalation aerosol delivery deposits pirfenidone or a embodiments, the process includes addition of Surfactant pyridone analog compound directly upstream of the CNS and/or co-solvent and/or salt at the highest temperature or compartment. incrementally-lower temperature as the solution is cooled. In 0431 Similar to the intra-nasal and pulmonary applica Some embodiments, addition of Surfactant and/or co-solvent tions described above, treatment or prevention of organs out and/or salt occurs all at once or incrementally during a main side the respiratory tract requires absorption to the systemic tained temperature or as the solution is cooled. The time by vascular department for transport to these extra-respiratory which the Solution is maintained at the highest temperature is sites. In the case of treating or preventing fibrotic or inflam from 0 minutes to 24 hours. The time by which the solution is matory diseases associated with the heart, liver and kidney, cooled from the highest temperature is from 0 minutes to 24 deposition of drug in the respiratory tract, more specifically hours. In some embodiments, the solution is protected from the deep lung will enable direct access to these organs through light. In some embodiments, the Solution is sparged to remove the left atrium to either the carotid arteries or coronary arter or lower the oxygen concentration. In some embodiments, the US 2015/O 196543 A1 Jul. 16, 2015 64 head space of the reaction container includes an inert gas or the prescribing physician; for example, a likely dose range for mixture of inert gases. Inert gases include, but are not limited aerosol administration of pirfenidone in preferred embodi to, nitrogen and argon. In some embodiments, the pirfenidone ments, or in other embodiments of pyridone analog com drug product includes co-solvent(s) in the concentration pound, would be about 0.28 to 1852 mg per day. range of 0% to 100% in otherwise buffered aqueous solution. 0441 Another unexpected observation is that inhalation In some embodiments, the pirfenidone drug product includes delivery of aerosol pirfenidone to the lung exhibits less co-solvent(s) at a concentration of about 1% to about 25%. metabolism of pirfenidone observed with oral administration. Co-solvents include, but are not limited to, ethanol, glycerin Thus, oral or intranasal inhalation of pirfenidone or pyridone or propylene glycol. In some embodiments, the pirfenidone analog will permit maximum levels of active Substance to the drug product includes Surfactant(s) in the concentration range pulmonary tissue in the absence of Substantial metabolism to of 0% to 100% in otherwise buffered aqueous solution. In inactive agents. Some embodiments, the pirfenidone drug product includes 0442. Inhibitors of CYP enzymes reduce pirfenidone surfactant(s) at a concentration of about 0.1% to about 10%. metabolism resulting in elevated blood levels and associated Surfactants include, but are not limited to Tween 20, Tween toxicity. As many products effecting CYPenzymes are useful 60. Tween 80, Cetylpyridinium Bromide, or Lecithin. In to fibrosis patients, permitting their use would be beneficial. Some embodiments, the pirfenidone drug product includes a While the oral route is already at the maximum permissible buffer. In some embodiments, the buffer includes salt and/or dose (which provides only moderate efficacy), any inhibition acid forms of agents such as citrate, phosphate or formate at of the enzymes described above elevates pirfenidone blood a concentration between 0 mM to 1000 mM. In some embodi levels and increases the rate and severity of the toxic events ments, the buffer includes salt and/or acid forms of agents described herein. Because oral and intranasal inhalation Such as citrate, phosphate or formate at a concentration delivery of pirfenidone or pyridone analogs can achieve between about 1 mM and about 50 mM. In some embodi effective tissue levels with much less drug than that required ments, the pirfenidone drug product includes a salt. In some by the oral product, resulting blood levels are significantly embodiments, the salt is present at a concentration between lower and consequences associated with CYP enzyme inhibi 0% to 100%. In some embodiments, the salt is present at a tory properties described herein are removed. Thus, permit concentration between about 0.1% and about 5%. In some ting use of these CYP inhibitory enzyme products currently embodiments, the Salt is sodium chloride, magnesium chlo contraindicated with the oral medicine. ride, magnesium Sulfate or barium chloride. In some embodi 0443) The primary metabolite of pirfenidone is 5-carboxy ments, a Sweetening agent is added to the pirfenidone drug pirfenidone. Following oral or intravenous administration, product. In some embodiments, the Sweetening agent is sac this metabolite appears quickly at at high concetrations in charin or a salt thereof. In some embodiments, the Sweetening blood. 5-carboxy-pirfenidone does not appear to have anti agent is present at a concentration between about 0.01 mM fibrotic or anti-inflammatory activity, its high blood levels and about 10 mM. In some embodiments, the pH of the occur at the loss of pirfenidone blood concentrations. Thus, buffered solution will be between about 2.0 and about 10.0. while the oral product is dosed at the highest possible level, 0438. In another embodiment, the manufacturing process once pirfenidone enters the blood it is rapidly metabolized to includes excess co-solvent and/or Surfactant and/or cation a non-active species further reducing the drugs potential to addition to a Super-saturated pirfenidone aqueous solution. achieve sufficient lung levels required for substantital effi Upon dissolution in the excess co-solvent and/or surfactant cacy. Because oral and intranasal inhalation delivery of pir and/or cation aqueous solution, the formulation is diluted to fenidone or pyridone analogs can achieve effective lung tis reduce co-solvent and/or surfactant and/or cation concentra Sue levels directly extra-lung metabolism is not a factor. tions to within the concentration range generally-recognized 0444 Administration of the pyridone analog compound, as safe and/or non-toxic and/or non-irritable. most preferably pirfenidone as disclosed herein, such as a 0439. In some embodiments, the manufacturing process is pharmaceutically acceptable salt thereof, can be via any of the as described in Example 5. accepted modes of administration for agents that serve simi lar utilities including, but not limited to, aerosol inhalation Administration Such as nasal and/or oral inhalation of a mist or spray con 0440 The pyridone analog compound, most preferably taining liquid particles, for example, as delivered by a nebu pirfenidone as disclosed herein can be administered at a lizer. therapeutically effective dosage, e.g., a dosage sufficient to 0445 Pharmaceutically acceptable compositions thus provide treatment for the disease states previously described. may include Solid, semi-solid, liquid and aerosol dosage Generally, for example, a daily aerosol dose of pirfenidone in forms, such as, e.g., powders, liquids, Suspensions, complex a pirfenidone compound formulation may be from about ations, liposomes, particulates, or the like. Preferably, the 0.001 mg to about 6.6 mg pirfenidone/kg of body weigh per compositions are provided in unit dosage forms suitable for dose. Thus, for administration to a 70 kg person, the dosage single administration of a precise dose. The unit dosage form range would be about 0.07 mg to about 463 mg pirfenidone can also be assembled and packaged together to provide a per dose or up to about 0.280 mg to about 1852 mg pirfeni patient with a weekly or monthly Supply and can also incor done day. The amount of active compound administered will, porate other compounds Such as Saline, taste masking agents, of course, be dependent on the Subject and disease state being pharmaceutical excipients, and other active ingredients or treated, the severity of the affliction, the manner and schedule carriers. of administration, the location of the disease (e.g., whether it 0446. The pyridone analog compound, most preferably is desired to effect intra-nasal or upper airway delivery, pha pirfenidone as disclosed herein, Such as a pharmaceutically ryngeal or laryngeal delivery, bronchial delivery, pulmonary acceptable salt thereof, can be administered either alone or delivery and/or pulmonary delivery with Subsequent systemic more typically in combination with a conventional pharma or central nervous system absorption), and the judgment of ceutical carrier, excipient or the like (e.g., mannitol, lactose, US 2015/O 196543 A1 Jul. 16, 2015

starch, magnesium Stearate, sodium saccharin, talcum, cellu of pirfenidone or pyridone analog compound alone or with lose, Sodium crosscarmellose, glucose, gelatin, Sucrose, mag either water soluble or organic soluble non-encapsulating nesium carbonate, magnesium chloride, magnesium Sulfate, excipients with or without a blending agent such as lactose. calcium chloride, lactose, Sucrose, glucose and the like). If Complex formulations can be further separated into five desired, the pharmaceutical composition can also contain groups. 1. Complex formulations may include water-based minor amounts of nontoxic auxiliary Substances Such as wet liquid formulations for nebulization. By non-limiting ting agents, emulsifying agents, Solubilizing agents, pH buff example water-based liquid complex formulations may con ering agents and the like (e.g., citric acid, ascorbic acid, sist of pirfenidone or pyridone analog compound encapsu Sodium phosphate, potassium phosphate, Sodium acetate, lated or complexed with water-soluble excipients such as Sodium citrate, cyclodextrin derivatives, Sorbitan monolau lipids, liposomes, cyclodextrins, microencapsulations, and rate, triethanolamine acetate, triethanolamine oleate, and the emulsions. 2. Complex formulations may also include like). Generally, depending on the intended mode of admin organic-based liquid formulations for nebulization or meter istration, the pharmaceutical formulation will contain about dose inhaler. By non-limiting example organic-based liquid 0.005% to 95%, preferably about 0.1% to 50% by weight of complex formulations may consist ofpirfenidone or pyridone a compound of the invention. Actual methods of preparing analog compound encapsulated or complexed with organic Such dosage forms are known, or will be apparent, to those soluble excipients such as lipids, microencapsulations, and skilled in this art; for example, see Remington’s Pharmaceu reverse-phase water-based emulsions. 3. Complex formula tical Sciences, Mack Publishing Company, Easton, Pa. tions may also include low-solubility, water-based liquid for 0447. In one preferred embodiment, the compositions will mulations for nebulization. By non-limiting example low take the form of a unit dosage form Such as vial containing a solubility, water-based liquid complex formulations may liquid, Solid to be suspended, dry powder, lyophilisate, or consist of pirfenidone or pyridone analog compound as a other composition and thus the composition may contain, low-water soluble, stable nanosuspension alone or in co along with the active ingredient, a diluent Such as lactose, crystal/co-precipitate excipient complexes, or mixtures with Sucrose, dicalcium phosphate, or the like; a lubricant such as low solubility lipids, such as lipid nanosuspensions. 4. Com magnesium Stearate or the like; and a binder Such as starch, plex formulations may also include low-solubility, organic gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellu based liquid formulations for nebulization or meter-dose lose derivatives or the like. inhaler. By non-limiting example low-solubility, organic 0448. Liquid pharmaceutically administrable composi based liquid complex formulations may consist of pirfeni tions can, for example, be prepared by dissolving, dispersing, done or pyridone analog compound as a low-organic Soluble, etc. an active compound as defined above and optional phar stable nanosuspension alone or in co-crystal/co-precipitate maceutical adjuvants in a carrier (e.g., water, saline, aqueous excipient complexes, or mixtures with low solubility lipids, dextrose, glycerol, glycols, ethanol or the like) to form a Such as lipid nanosuspensions. 5. Complex formulations may Solution or Suspension. Solutions to be aerosolized can be also include dry powder formulations for administration prepared in conventional forms, either as liquid solutions or using a dry powder inhaler. By non-limiting example, com Suspensions, as emulsions, or in Solid forms suitable for dis plex dry powder formulations may consist of pirfenidone or Solution or Suspension in liquid prior to aerosol production pyridone analog compound in co-crystal/co-precipitate/spray and inhalation. The percentage of active compound contained dried complex or mixture with low-water soluble excipients/ in Such aerosol compositions is highly dependent on the spe salts in dry powder form with or without a blending agent cific nature thereof, as well as the activity of the compound Such as lactose. Specific methods for simple and complex and the needs of the Subject. However, percentages of active formulation preparation are described herein. ingredient of 0.01% to 90% in solution are employable, and will be higher if the composition is a solid, which will be Aerosol Delivery Subsequently diluted to the above percentages. In some embodiments, the composition will comprise 0.25%-50.0% 0450 Pirfenidone or pyridone analog compounds as of the active agent in Solution. described herein are preferably directly administered as an 0449 Pirfenidone or pyridone analog compound formula aerosol to a site of pulmonary pathology including pulmonary tions can be separated into two groups; those of simple for fibrosis, COPD or asthma. The aerosol may also be delivered mulation and complex formulations providing taste-masking to the pulmonary compartment for absorption into the pull for improved tolerability, pH-optimized for stability and tol monary vasculature for therapy or prophylaxis of extra-pull erability, immediate or Sustained-release, and/or area-under monary pathologies such as fibrosis and inflammatory dis the-curve (AUC) shape-enhancing properties. Simple formu eases of the heart, kidney and liver, or pulmonary or intra lations can be further separated into three groups. 1. Simple nasal delivery for extra-pulmonary or extra-nasal cavity formulations may include water-based liquid formulations demylination diseases associated with the central nervous for nebulization. By non-limiting example water-based liquid system. formulations may consist of pirfenidone or pyridone analog 0451. Several device technologies exist to deliver either compound alone or with non-encapsulating water soluble dry powder or liquid aerosolized products. Dry powder for excipients. 2. Simple formulations may also include organic mulations generally require less time for drug administration, based liquid formulations for nebulization or meter-dose yet longer and more expensive development efforts. Con inhaler. By non-limiting example organic-based liquid for versely, liquid formulations have historically suffered from mulations may consist of pirfenidone or pyridone analog longer administration times, yet have the advantage of shorter compound or with non-encapsulating organic soluble excipi and less expensive development efforts. Pirfenidone or pyri ents. 3. Simple formulations may also include dry powder done analog compounds disclosed herein range in Solubility, formulations for administration with a dry powder inhaler. By are generally stable and have a range of tastes. In one Such non-limiting example dry powder formulations may consist embodiment, pirfenidone or pyridone analog compounds are US 2015/O 196543 A1 Jul. 16, 2015 66 water soluble at pH 4 to pH 8, are stable in aqueous solution VMD, MMD and MMAD measurements are considered to be and have limited to no taste. Such a pyridone includes pir under standard conditions such that descriptions of VMD, fenidone. MMD and MMAD will be comparable. Similarly, dry powder 0452. Accordingly, in one embodiment, a particular for particle size determinations in MMD and MMAD are also mulation of the pirfenidone or pyridone analog compound considered comparable. disclosed herein is combined with a particular aerosolizing 0457. In some embodiments, the particle size of the aero device to provide an aerosol for inhalation that is optimized Sol is optimized to maximize the pirfenidone or pyridone for maximum drug deposition at a site of infection, pulmo analog compound deposition at the site of pulmonary pathol nary arterial hypertension, pulmonary or intra-nasal site for ogy and/or extra-pulmonary, systemic or central nervous sys systemic absorption for extra-nasal and/or extra-pulmonary tem distribution, and to maximize tolerability (or in the later indications, and maximal tolerability. Factors that can be case, systemic absorption). Aerosol particle size may be optimized include Solution or Solid particle formulation, rate expressed interms of the mass medianaerodynamic diameter of delivery, and particle size and distribution produced by the (MMAD). Large particles (e.g., MMAD-5 um) may deposit aerosolizing device. in the upper airway because they are too large to navigate the curvature of the upper airway. Small particles (e.g., Particle Size and Distribution MMAD-2 um) may be poorly deposited in the lower airways 0453 The distribution of aerosol particle/droplet size can and thus become exhaled, providing additional opportunity be expressed interms of either: the mass medianaerodynamic for upper airway deposition. Hence, intolerability (e.g., diameter (MMAD)—the droplet size at which half of the cough and bronchospasm) may occur from upper airway mass of the aerosol is contained in Smaller droplets and halfin deposition from both inhalation impaction of large particles larger droplets; and settling of small particles during repeated inhalation and volumetric mean diameter (VMD); expiration. Thus, in one embodiment, an optimum particle mass median diameter (MMD); size is used (e.g., MMAD=2-5 um) in order to maximize the fine particle fraction (FPF)—the percentage of particles deposition at a mid-lung and to minimize intolerability asso that are <5 um in diameter. ciated with upper airway deposition. Moreover, generation of 0454. These measures have been used for comparisons of a defined particle size with limited geometric standard devia the in vitro performance of different inhaler device and drug tion (GSD) may optimize deposition and tolerability. Narrow combinations. In general, the higher the fine particle fraction, GSD limits the number of particles outside the desired the higher the proportion of the emitted dose that is likely to MMAD size range. In one embodiment, an aerosol contain deposit the lung. ing one or more compounds disclosed herein is provided 0455 Generally, inhaled particles are subject to deposi having a MMAD from about 2 microns to about 5 microns tion by one of two mechanisms: impaction, which usually with a GSD of less than or equal to about 2.5 microns. In predominates for larger particles, and sedimentation, which is another embodiment, an aerosol having an MMAD from prevalent for Smaller particles. Impaction occurs when the about 2.8 microns to about 4.3 microns with a GSD less than momentum of an inhaled particle is large enough that the or equal to 2 microns is provided. In another embodiment, an particle does not follow the air stream and encounters a physi aerosol having an MMAD from about 2.5 microns to about ological Surface. In contrast, sedimentation occurs primarily 4.5 microns with a GSD less than or equal to 1.8 microns is in the deep lung when very small particles which have trav provided. eled with the inhaled air stream encounter physiological Sur 0458 In some embodiments, the pirfenidone or pyridone faces as a result of random diffusion within the air stream. analog compound that is intended for respiratory delivery (for 0456. For pulmonary administration, the upper airways either systemic or local distribution) can be administered as are avoided in favor of the middle and lower airways. Pulmo aqueous formulations, as Suspensions or solutions in haloge nary drug delivery may be accomplished by inhalation of an nated hydrocarbon propellants, or as dry powders. Aqueous aerosol through the mouth and throat. Particles having a mass formulations may be aerosolized by liquid nebulizers median aerodynamic diameter (MMAD) of greater than employing either hydraulic or ultrasonic atomization. Propel about 5 microns generally do not reach the lung; instead, they lant-based systems may use Suitable pressurized metered tend to impact the back of the throat and are swallowed and dose inhalers (pMDIs). Dry powders may use dry powder possibly orally absorbed. Particles having diameters of about inhaler devices (DPIs), which are capable of dispersing the 1 to about 5 microns are Small enough to reach the upper- to drug substance effectively. A desired particle size and distri mid-pulmonary region (conducting airways), but are too bution may be obtained by choosing an appropriate device. large to reach the alveoli. Smaller particles, i.e., about 0.5 to 0459 Lung Deposition as used herein, refers to the frac about 2 microns, are capable of reaching the alveolar region. tion of the nominal dose of an active pharmaceutical ingredi Particles having diameters smaller than about 0.5 microns can ent (API) that is bioavailable at a specific site of pharmaco also be deposited in the alveolar region by sedimentation, logic activity upon administration of the agent to a patient via although very small particles may be exhaled. Measures of a specific delivery route. For example, a lung deposition of particle size can be referred to as Volumetric mean diameter 30% means 30% of the active ingredient in the inhalation (VMD), mass median diameter (MMD), or MMAD. These device just prior to administration is deposited in the lung. measurements may be made by impaction (MMD and Likewise, a lung deposition of 60% means 60% of the active MMAD) or by laser (VMD). For liquid particles, VMD, ingredient in the inhalation device just prior to administration MMD and MMAD may be the same if environmental condi is deposited in the lung, and so forth. Lung deposition can be tions are maintained, e.g., standard humidity. However, if determined using methods of Scintigraphy or deconvolution. humidity is not maintained, MMD and MMAD determina In some embodiments, the present invention provides for tions will be smaller than VMD due to dehydration during methods and inhalation systems for the treatment or prophy impator measurements. For the purposes of this description, laxis of a respiratory condition in a patient, comprising US 2015/O 196543 A1 Jul. 16, 2015 67 administering to the patient a nominal dose of pirfenidone or deposit on the Surface epithelium of the patients lung. The a pyridone analog compound with a liquid nebulizer. In some RDD is determined by multiplying the DD by the FPF. embodiments, the liquid nebulizer is a high efficiency liquid 0465. In one embodiment, described herein an aqueous nebulizer. In some embodiments a lung deposition of pirfeni droplet containing pirfenidone or pyridone analog com done or a pyridone analog compound of at least about 7%, at pound, wherein the aqueous droplet has a diameter less than least about 10%, at least about 15%, at least about 20%, at about 5.0Lum. In some embodiments, the aqueous droplet has least about 25%, at least about 30%, at least about 35%, at a diameter less than about 5.0 Lim, less than about 4.5um, less least about 40%, at least about 45%, at least about 50%, at than about 4.0 um, less than about 3.5um, less than about 3.0 least about 55%, at least about 60%, at least about 65%, at um, less than about 2.5um, less than about 2.0 um, less than least about 70%, at least about 75%, at least about 80%, or at about 1.5 um, or less than about 1.0 Lum. In some embodi least about 85%, based on the nominal dose of pirfenidone or ments, the aqueous droplet further comprises one or more a pyridone analog compound is achieved. colsolvents. In some embodiments, the one or more cosol 0460. There are two main methods used to measure aero vents are selected from ethanol and propylene glycol. In some Sol deposition in the lungs. First, Y-scintigraphy is performed embodiments, the aqueous droplet further comprises a buffer. by radiolabeling the drug with a substance like 99m-techne In some embodiments, the buffer is a citrate buffer or a phos tium, and scanning the Subject after inhalation of the drug. phate buffer. In some embodiments, the dioplet was produced This technique has the advantage of being able to quantify the from a liquid nebulizer and an aqueous solution of pirfeni proportion of aerosol inhaled by the patient, as well as done or pyridone analog compound as described herein. In regional distribution in the upper airway and lungs. Second, Some embodiments, the aqueous droplet was produced from since most of the drug deposited in the lower airways will be an aqueous Solution that has concentration of pirfenidone or absorbed into the bloodstream, pharmacokinetic techniques pyridone analog compound between about 0.1 mg/mL and are used to measure lung deposition. This technique can about 60 mg/mL and an osmolality from about 50 mOsmol/ assess the total amount of ICSs that interacts with the airway kg to about 6000 mOsmol/kg. In some embodiments, the epithelium and is absorbed systemically, but will miss the osmolality is greater than about 100 mOsmol/kg. In some small portion that may be expectorated or swallowed after embodiments, the osmolality is greater than about 400 mOs mucociliary clearance, and cannot tell us about regional dis mol/kg. In some embodiments, the osmolality is greater than tribution. Therefore, y-scintigraphy and pharmacokinetic about 1000 mOsmol/kg. In some embodiments, the osmola studies are in many cases considered complementary. lity is greater than about 2000 mOsmol/kg. In some embodi 0461. In some embodiments, administration of the pirfeni ments, the osmolality is greater than about 3000 mOsmol/kg. done or pyridone analog compound with a liquid nebulizer In some embodiments, the osmolality is greater than about provides a GSD of emitted droplet size distribution of about 4000 mOsmol/kg. In some embodiments, the osmolality is 1.0Lm to about 2.5um, about 1.2 Lum to about 2.0 um, or about greater than about 5000 mOsmol/kg. 1.0 Lum to about 2.0 Lum. In some embodiments, the MMAD is 0466 Also described are aqueous aerosols comprising a about 0.5um to about 5um, or about 1 to about 4 um or less plurality of aqueous droplets of pirfenidone or pyridone ana than about 5um. In some embodiments, the VMD is about 0.5 log compound as described herein. In some embodiments, the um to about 5um, or about 1 to about 4 um or less than about at least about 30% of the aqueous droplets in the aerosol have 5um. a diameter less than about 5 Lim. In some embodiments, at 0462 Fine Particle Fraction (FPF) describes the efficiency least about 35%, at least about 40%, at least about 45%, at of a nebulizer inhalation device. FPF represents the percent least about 50%, at least about 55%, at least about 60%, at age of the delivered aerosol dose, or inhaled mass, with drop least about 65%, at least about 70%, at least about 75%, at lets of diameter less than 5.0Lum. Droplets of less than 5.0 um least about 80%, at least about 85%, or at least about 90% of in diameter are considered to penetrate to the lung. In some the aqueous droplets in the aerosol have a diameter less than embodiments, administration of an aqueous inhalation pir about 5um. In some embodiments, the aqueous aerosols are fenidone or pyridone analog Solution with a liquid nebulizer produced with a liquid nebulizer. In some embodiments, the provides a RDD of at least about 30%, at least about 35%, at aqueous aerosols are produced with a high efficiency liquid least about 40%, at least about 45%, at least about 50%, at nebulizer. least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%. Liquid Nebulizer 0463. The Delivered Dose (DD) of drug to a patient is the 0467. In one embodiment, a nebulizer is selected on the certain portion of volume of liquid filled into the nebulizer, basis of allowing the formation of an aerosol of a pirfenidone i.e. the fill volume, which is emitted from the mouthpiece of or pyridone analog compound disclosed herein having an the device. The difference between the nominal dose and the MMAD predominantly between about 1 to about 5 microns. DD is the amount of volume lost primarily to residues, i.e. the In one embodiment, the delivered amount of pirfenidone or amount of fill volume remaining in the nebulizer after admin pyridone analog compound provides a therapeutic effect for istration, or is lost in aerosol form during expiration of air pulmonary pathology and/or extra-pulmonary, systemic, tis from the patient and therefore not deposited in the patients Sue or central nervous system distribution. body. In some embodiments, the DD of the nebulized formu 0468 Previously, two types of nebulizers, jet and ultra lations described herein is at least about 30%, at least about sonic, have been shown to be able to produce and deliver 35%, at least about 40%, at least about 45%, at least about aerosol particles having sizes between 2 and 4 micron. These 50%, at least about 55%, at least about 60%, at least about particle sizes have been shown as being optimal for middle 65%, at least about 70%, or at least about 80%. airway deposition. However, unless a specially formulated 0464. The Respirable Delivered Dose (RDD) is an expres Solution is used, these nebulizers typically need larger Vol sion of the delivered mass of drug contained within emitted umes to administer Sufficient amount of drug to obtain a droplets from a nebulizer that are Small enough to reach and therapeutic effect. A jet nebulizer utilizes air pressure break US 2015/O 196543 A1 Jul. 16, 2015

age of an aqueous Solution into aerosol droplets. An ultra described respirable delivered dose in less than about 20 min, Sonic nebulizer utilizes shearing of the aqueous Solution by a less than about 15 min, less than about 10 min, less than about piezoelectric crystal. Typically, however, the jet nebulizers 7 min, less than about 5 min, less thanabout 3 min, or less than are only about 10% efficient under clinical conditions, while about 2 min. the ultrasonic nebulizer is only about 5% efficient. The 0473 By non-limiting example, a nebulized pirfenidone amount of pharmaceutical deposited and absorbed in the or pyridone analog compound may be administered in the lungs is thus afraction of the 10% in spite of the large amounts described respirable delivered dose using a breath-actuated of the drug placed in the nebulizer. The amount of drug that is nebulizer in less than about 20 min, less than about 10 min, placed in the nebuluZerprior to administration to the mammal less than about 7 min, less than about 5 min, less than about 3 is generally referred to the “nominal dose.” or “loaded dose.” min, or less than about 2 min. The Volume of Solution containing the nominal dose is 0474 By non-limiting example, in other circumstances, a referred to as the “fill volume.” Smaller particle sizes or slow nebulized pirfenidone or pyridone analog compound may inhalation rates permit deep lung deposition. In addition to achieve improved tolerability and/or exhibit an area-under slow inhalation, devices such as the Philips Ineb Adaptive the-curve (AUC) shape-enhancing characteristic when Aerosol Delivery (AAD) System and the Activaero Flow And administered over longer periods of time. Under these con Volume Regulated Inhalation Technology (FAVORITE) use ditions, the described respirable delivered dose in more than controlled device features to assist inspiratory flow to maxi about 2 min, preferably more than about 3 min, more prefer mize delivery efficiency, peripheral deposition and improve ably more than about 5 min, more preferably more than about dose reproducibility while reducing side effects. Both 7 min, more preferably more than about 10 min, and in some middle-lung and alveolar deposition may be desired for this cases most preferable from about 10 to about 20 min. invention depending on the indication, e.g., middle and/or 0475. As disclosed herein, there is provided a pyridone alveolar deposition for pulmonary fibrosis and systemic analog compound formulation composition comprising a pir delivery. Exemplary disclosure of compositions and methods fenidone compound aqueous solution having a pH from about for formulation delivery using nebulizers can be found in, 4.0 to about pH 8.0 where the pirfenidone compound is e.g., US 2006/0276483, including descriptions oftechniques, present at a concentration from about 34 mcg/mL to about protocols and characterization of aerosolized mist delivery 463 mg/mL pirfenidone. In certain other embodiments the using a vibrating mesh nebulizer. pirfenidone compound formulation is provided as an aqueous 0469 Accordingly, in one embodiment, a vibrating mesh solution having a pH of from about 4.0 to about 8.0, the nebulizer is used to deliver in preferred embodiments an Solution comprising a pirfenidone compound at a concentra aerosol of the pirfenidone compound as disclosed herein, or tion of from about 34 mcg/mL to about 463 mg/mL pirfeni in other embodiments, a pyridone analog compound as dis done; and citrate buffer orphosphate buffer at a concentration closed herein. A vibrating mesh nebulizer comprises a liquid offrom about 0mMto about 50 mM. In certain other embodi storage container in fluid contact with a diaphragm and inha ments the pirfenidone compound formulation is provided as lation and exhalation valves. In one embodiment, about 1 to an aqueous Solution having a pH of from about 4.0 to about about 6 ml of the pirfenidone compound formulation (or in 8.0, the Solution comprising a pirfenidone compound at a another related embodiment, of a pyridone analog compound concentration of from about 34 mcg/mL to about 463 mg/mL formulation) is placed in the storage container and the aerosol pirfenidone; and a buffer that has a pKa between 4.7 and 6.8 generator is engaged producing atomized aerosol of particle and that is present at a concentration Sufficient to maintain or sizes selectively between about 1 and about 5 micron. In one maintain after titration with acid or base a pH from about 4.0 embodiment, about 1 to about 10 mL of the pirfenidone to about 8.0 for a time period sufficient to enable marketable compound formulation (or in another related embodiment, of product shelf-life storage. a pyridone analog compound formulation) is placed in the 0476. In some embodiments, described herein is a phar storage container and the aerosol generator is engaged pro maceutical composition that includes: pirfenidone; water; ducing atomized aerosol of particle sizes selectively between phosphate buffer or citrate buffer; and optionally sodium about 1 and about 5 micron. In one embodiment, about the chloride or magnesium chloride. In other embodiments, volume of the pirfenidone compound formulation (or in described herein is a pharmaceutical composition that another related embodiment, of a pyridone analog compound includes: pirfenidone; water; a buffer; and at least one addi formulation) that is originally placed in the storage container tional ingredient selected from Sodium chloride, magnesium and the aerosol generator is replaced to increase the admin chloride, ethanol, propylene glycol, glycerol, polysorbate 80, istered dose size. and cetylpyridinium bromide (or chloride). In some embodi 0470. In some embodiments a pirfenidone or pyridone ments, the buffer is phosphate buffer. In other embodiments, analog compound formulation as disclosed herein, is placed the buffer is citrate buffer. In some embodiments, the phar in a liquid nebulization inhaler and prepared in dosages to maceutical composition includes 1 mg to 500 mg of pirfeni deliver from about 34 mcg to about 463 mg from a dosing done, for example, 5 mg, 10 mg, 15 mg, 25 mg, 37.5 mg, 75 solution of about 0.5 to about 6 ml with MMAD particles mg, 100 mg, 115 mg, 150 mg, 190 mg, 220 mg. or 500 mg. In sizes between about 1 to about 5 micron being produced. Some embodiments, the osmolality of the pharmaceutical 0471. In some embodiments a pirfenidone or pyridone composition described herein is between about 50 mOsmo?kg analog compound formulation as disclosed herein, is placed to 6000 mOsmo/kg. In some embodiments, the osmolality of in a liquid nebulization inhaler and prepared in dosages to the pharmaceutical composition described herein is between deliver from about 34 mcg to about 463 mg from a dosing about 50 mOsmo/kg to 5000 mOsmo/kg. In some embodi solution of about 0.5 to about 7 ml with MMAD particles ments, the pharmaceutical composition optionally includes sizes between about 1 to about 5 micron being produced. saccharin (e.g. sodium salt). In some embodiments, such a 0472. By non-limiting example, a nebulized pirfenidone pharmaceutical composition is placed in a liquid nebulization or pyridone analog compound may be administered in the inhaler to deliver from about 1 mg to about 500 mg from a US 2015/O 196543 A1 Jul. 16, 2015 69 dosing solution of about 0.5 to about 6 mL with MMAD Hospitak, Inc. Ultrasonic nebulizers rely on mechanical particles sizes between about 1 to about 5 micron being pro energy in the form of vibration of a piezoelectric crystal to duced. In some embodiments, such a pharmaceutical compo generate respirable liquid droplets and are commercially sition is placed in a liquid nebulization inhaler to deliver from available from, for example, Omron Heathcare, Inc., Boe about 1 mg to about 500 mg from a dosing solution of about hiringer Ingelheim, and DeVilbiss Health Care, Inc. Vibrating 0.5 to about 7 mL with MMAD particles sizes between about mesh nebulizers rely upon either piezoelectric or mechanical 1 to about 5 micron being produced. In some embodiments pulses to respirable liquid droplets generate. Other examples Such a nebulized pharmaceutical composition may deliver of nebulizers for use with pirfenidone or pyridone analogs between about 0.0001 mg and about 25 mg pirfenidone or described herein are described in U.S. Pat. Nos. 4,268,460; pryridone analog in aerosol particles with a MMAD between 4,253,468; 4,046,146; 3,826,255; 4,649,911; 4,510,929: 1 and 5 microns in each inhaled breath. In some embodi 4,624,251; 5,164,740: 5,586,550; 5,758,637; 6,644,304: ments, 1 mg pirfenidone or pyridone analog delivered in 10 6,338,443; 5,906,202; 5,934,272; 5,960,792; 5,971,951: breaths over 1 minute, whereby 50% of the inhaled particles 6,070,575; 6,192,876; 6,230,706; 6,349,719; 6,367.470; are between 1 and 5 microns, 0.05 mg pirfenidone or pyridine 6,543,442: 6,584,971; 6,601,581; 4,263,907; 5,709,202: analog will be delivered in each breath. In some embodi 5,823, 179; 6, 192,876; 6,644,304: 5,549,102: 6,083,922: ments, 1 mg pirfenidone or pyridone analog delivered in 15 6,161,536; 6,264,922: 6,557,549; and 6,612,303 all of which breaths per minute over 10 minutes, whereby 50% of the are hereby incorporated by reference in their entirety. inhaled particles are between 1 and 5 microns, 0.0033 mg 0479. Any known inhalation nebulizer suitable to provide pirfenidone or pyridone analog will be delivered in each delivery of a medicament as described herein may be used in breath. In some embodiments, 1 mg pirfenidone or pyridone the various embodiments and methods described herein. Such analog delivered in 20 breaths per minute over 20 minutes, nebulizers include, e.g., jet nebulizers, ultrasonic nebulizers, whereby 50% of the inhaled particles are between 1 and 5 pulsating membrane nebulizers, nebulizers with a vibrating microns, 0.00125 mg pirfenidone or pyridone analog will be mesh or plate with multiple apertures, and nebulizers com delivered in each breath. In some embodiments, 200 mg pir prising a vibration generator and an aqueous chamber (e.g., fenidone or pyridone analog delivered in 10 breaths over 1 ParieFlow(R). Commercially available nebulizers suitable for minute, whereby 50% of the inhaled particles are between 1 use in the present invention can include the AeronebR), and 5 microns, 10 mg pirfenidone or pyridone analog will be MicroAirR), AeronebR Pro, and AeronebR. Go, AeronebR) delivered in each breath. In some embodiments, 200 mg pir Solo, AeronebR Solo/Idehaler combination, AeronebR Solo fenidone or pyridone analog delivered in 15 breaths per or Go Idehaler-Pocket(R) combination, PARILC-Plus(R), PARI minute over 10 minutes, whereby 50% of the inhaled particles LC-Star R, PARI Sprint(R), eFlow and eFlow Rapid R, Pari are between 1 and 5 microns, 0.67 mg pirfenidone or pyridone Boy R N and Pari Duraneb.R. (PARI, GmbH), MicroAir R analog will be delivered in each breath. By another non (Omron Healthcare, Inc.), Halolite(R) (Profile Therapeutics limiting example. In some embodiments, 200 mg pirfenidone Inc.), Respimat(R) (Boehringer Ingelheim), Aerodose(R) or pyridone analog delivered in 20 breaths per minute over 20 (Aerogen, Inc, Mountain View, Calif.), Omron Elite(R) (Om minutes, whereby 50% of the inhaled particles are between 1 ron Healthcare, Inc.), Omron Microair(R) (Omron Healthcare, and 5 microns, 0.25 mg pirfenidone or pyridone analog will Inc.), Mabismist IIR (Mabis Healthcare, Inc.), Lumiscope(R) be delivered in each breath. In some embodiments, 500 mg 6610. (The Lumiscope Company, Inc.), Airsep Mystique(R), pirfenidone or pyridine analog delivered in 10 breaths over 1 (AirSep Corporation), Acorn-1 and Acorn-II (Vital Signs, minute, whereby 50% of the inhaled particles are between 1 Inc.), AquatowerR (Medical Industries America), Ava-Neb(R) and 5 microns, 25 mg pirfenidone or pyridone analog will be (Hudson Respiratory Care Incorporated), Cirrus(R (Intersur delivered in each breath. In some embodiments, 500 mg pir gical Incorporated), Dart(R) (Professional Medical Products), fenidone or pyridone analog delivered in 15 breaths per Devilbiss(R) Pulmo Aide (DeVilbiss Corp.), Downdraft(R) minute over 10 minutes, whereby 50% of the inhaled particles (Marquest), Fan JetR) (Marquest), MB-5 (Mefar), Misty are between 1 and 5 microns, 1.67 mg pirfenidone or pyridone Neb.R. (Baxter), Salter 8900 (Salter Labs), Sidestream(R) analog will be delivered in each breath. In some embodi (Medic-Aid), Updraft-IIR (Hudson Respiratory Care). Whis ments, 500 mg pirfenidone orpyridone analog delivered in 20 per JetR) (Marquest Medical Products), Aiolos(R (Aiolos breaths per minute over 20 minutes, whereby 50% of the Medicnnsk Teknik), Inspiron(R) (Intertech Resources, Inc.), inhaled particles are between 1 and 5 microns, 0.625 mg Optimist(R) (Unomedical Inc.), Prodomo(R), Spira.R. (Respira pirfenidone or pyridone analog will be delivered in each tory Care Center), AERX(R) and AERX EssenceTM (Aradigm), breath. Respirgard IIR, Sonik R. LDI Nebulizer (Evit Labs), Swirler 0477. In some embodiments, a nebulized pirfenidone or W Radioaerosol System (AMICI, Inc.), Maquet SUN 145 pyridone analog compound may be administered in the ultrasonic, Schill untrasonic, compare and compare Elite described respirable delivered dose in less than about 20 min, from Omron, Monoghan AeroEclipse BAN, Transneb, DeV less than about 10 min, less than about 7 min, less than about ilbiss 800, AerovectRX, Porta-Neb.R., Freeway FreedomTM, 5 min, less than about 3 min, or less than about 2 min. Sidestream, Ventstream and I-neb produced by Philips, Inc. 0478 For aqueous and other non-pressurized liquid sys By further non-limiting example, U.S. Pat. No. 6,196.219, is tems, a variety of nebulizers (including Small Volume nebu hereby incorporated by reference in its entirety. lizers) are available to aerosolize the formulations. Compres 0480. Any of these and other known nebulizers suitable to sor-driven nebulizers incorporate jet technology and use provide delivery of a aqueous inhalation medicament as compressed air to generate the liquid aerosol. Such devices described herein may be used in the various embodiments and are commercially available from, for example, Healthdyne methods described herein. In some embodiments, the nebu Technologies, Inc., Invacare, Inc.; Mountain Medical Equip lizers are available from, e.g., Pari GmbH (Starnberg, Ger ment, Inc.; Pari Respiratory, Inc.; Mada Medical, Inc.; Puri many), DeVilbiss Healthcare (Heston, Middlesex, UK), tan-Bennet; Schuco, Inc., DeVilbiss Health Care, Inc.; and Healthdyne, Vital Signs, Baxter, Allied Health Care, Invac US 2015/O 196543 A1 Jul. 16, 2015 70 are, Hudson, Omron, Bremed, AirSep. Luminscope, In this case, the Solution is mixed upon activation of the Medisana, Siemens, Aerogen, Mountain Medical, Aerosol nebulizer, such as described in U.S. Pat. No. 6,427,682 and Medical Ltd. (Colchester, Essex, UK), AFP Medical (Rugby, PCT Publication No. WO 03/035030, both of which are Warwickshire, UK), Bard Ltd. (Sunderland, UK), Carri-Med hereby incorporated by reference in their entirety. In these Ltd. (Dorking, UK), Plaem Nuiva (Brescia, Italy), Henleys nebulizers, the solid drug, optionally combined with excipi Medical Supplies (London, UK), Intersurgical (Berkshire, ents to form a solid composition, is stored in a separate UK), Lifecare Hospital Supplies (Leies, UK), Medic-Aid compartment from a liquid solvent. Ltd. (West Sussex, UK), Medix Ltd. (Essex, UK), Sinclair 0486 The liquid solvent is capable of dissolving the solid Medical Ltd. (Surrey, UK), and many others. composition to form a liquid composition, which can be 0481 Other nebulizers suitable for use in the methods and aerosolized and inhaled. Such capability is, among other fac systems describe herein can include, but are not limited to, jet tors, a function of the selected amount and, potentially, the nebulizers (optionally sold with compressors), ultrasonic composition of the liquid. To allow easy handling and repro nebulizers, and others. Exemplary jet nebulizers for use ducible dosing, the sterile aqueous liquid may be able to herein can include Pari LC plus/ProNeb, Pari LC plus/ dissolve the solid composition within a short period of time, ProNeb Turbo, Pari LCPlus/Dura Neb 1000 & 2000 Pari LC possibly under gentle shaking. In some embodiments, the plus/Walkhaler, Pari LC plus/Pari Master, Pari LC star, final liquid is ready to use after no longer than about 30 Omron Compair XL Portable Nebulizer System (NE-C18 seconds. In some cases, the Solid composition is dissolved and JetAir Disposable nebulizer), Omron compare Elite within about 20 seconds, and advantageously, within about 10 Compressor Nebulizer System (NE-C21 and Elite Air Reus seconds. As used herein, the terms “dissolve(d)”, “dissolv able Nebulizer, Pari LC Plus or Pari LC Star nebulizer with ing, and “dissolution” refer to the disintegration of the solid Proneb Ultra compressor, Pulomo-aide, Pulmo-aide LT, composition and the release, i.e., the dissolution, of the active Pulmo-aide traveler, Invacare Passport, Inspiration Health compound. As a result of dissolving the solid composition dyne 626, Pulmo-Neb Traveler, DeVilbiss 646, WhisperJet, with the liquid solvent a liquid composition is formed in AcornII, Misty-Neb, Allied aerosol, Schuco Home Care, which the active compound is contained in the dissolved state. Lexan Plasic Pocet Neb, SideStream Hand Held Neb, Mobil As used herein, the active compound is in the dissolved State Mist, Up-Draft, Up-DraftII, TUp-Draft, ISO-NEB, Ava-Neb, when at least about 90 wt.-% are dissolved, and more prefer Micro Mist, and PulmoMate. ably when at least about 95 wt.-% are dissolved. 0482 Exemplary ultrasonic nebulizers suitable to provide 0487. With regard to basic separated-compartment nebu delivery of a medicament as described herein can include lizer design, it primarily depends on the specific application MicroAir, Ultra Air, Siemens Ultra Nebulizer 145, Comp Air, whether it is more useful to accommodate the aqueous liquid Pulmosonic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic and the solid composition within separate chambers of the Neb. 5004 Desk Ultrasonic Nebulizer, Mystique Ultrasonic, same container or primary package, or whether they should Lumiscope's Ultrasonic Nebulizer, Medisana Ultrasonic be provided in separate containers. If separate containers are Nebulizer, Microstat Ultrasonic Nebulizer, and Mabismist used, these are provided as a set within the same secondary Hand Held Ultrasonic Nebulizer. Other nebulizers for use package. The use of separate containers is especially pre herein include 5000 Electromagnetic Neb. 5001 Electromag ferred for nebulizers containing two or more doses of the netic Neb 5002 Rotary Piston Neb, Lumineb I Piston Nebu active compound. There is no limit to the total number of lizer 5500, Aeroneb Portable Nebulizer System, Aerodose containers provided in a multi-dose kit. In one embodiment, Inhaler, and AeroEclipse Breath Actuated Nebulizer. Exem the Solid composition is provided as unit doses within mul plary nebulizers comprising a vibrating mesh or plate with tiple containers or within multiple chambers of a container, multiple apertures are described by R. Dhand in New Nebu whereas the liquid solvent is provided within one chamber or liser Technology—Aerosol Generation by Using a Vibrating container. In this case, a favorable design provides the liquid Mesh or Plate with Multiple Apertures, Long-Term Health in a metered-dose dispenser, which may consist of a glass or care Strategies 2003, (July 2003), p. 1-4 and Respiratory plastic bottle closed with a dispensing device. Such as a Care, 47: 1406-1416 (2002), the entire disclosure of each of mechanical pump for metering the liquid. For instance, one which is hereby incorporated by reference. actuation of the pumping mechanism may dispense the exact 0483. Additional nebulizers suitable for use in the pres amount of liquid for dissolving one dose unit of the Solid ently described invention include nebulizers comprising a composition. vibration generator and an aqueous chamber. Such nebulizers 0488. In another embodiment for multiple-dose sepa are sold commercially as, e.g., ParieFlow, and are described rated-compartment nebulizers, both the solid composition in U.S. Pat. Nos. 6,962,151, 5,518,179, 5,261,601, and 5,152, and the liquid solvent are provided as matched unit doses 456, each of which is specifically incorporated by reference within multiple containers or within multiple chambers of a herein. container. For instance, two-chambered containers can be 0484 The parameters used in nebulization, such as flow used to hold one unit of the solid composition in one of the rate, mesh membrane size, aerosol inhalation chamber size, chambers and one unit of liquid in the other. As used herein, mask size and materials, valves, and power Source may be one unit is defined by the amount of drug present in the Solid varied as applicable to provide delivery of a medicament as composition, which is one unit dose. Such two-chambered described herein to maximize their use with different types containers may, however, also be used advantageously for and aqueous inhalation mixtures. nebulizers containing only one single drug dose. 0485. In some embodiments, the drug solution is formed 0489. In one embodiment of a separated-compartment prior to use of the nebulizer by a patient. In other embodi nebulizer, a blister pack having two blisters is used, the blis ments, the drug is stored in the nebulizer in liquid form, which ters representing the chambers for containing the Solid com may include a suspension, Solution, or the like. In other position and the liquid solvent in matched quantities for pre embodiments, the drug is store in the nebulizer in solid form. paring a dose unit of the final liquid composition. As used US 2015/O 196543 A1 Jul. 16, 2015 herein, a blister pack represents a thermoformed or pressure cochemical properties of the drug, the desired dissolution formed primary packaging unit, most likely comprising a rate, cost considerations, and other criteria. In one of the polymeric packaging material that optionally includes a embodiments, the Solid composition is a single unit. This metal foil. Such as aluminum. The blister pack may be shaped implies that one unit dose of the drug is comprised in a single, to allow easy dispensing of the contents. For instance, one physically shaped solid form or article. In other words, the side of the pack may be tapered or have a tapered portion or Solid composition is coherent, which is in contrast to a mul region through which the content is dispensable into another tiple unit dosage form, in which the units are incoherent. vessel upon opening the blister pack at the tapered end. The 0495 Examples of single units which may be used as tapered end may represent a tip. dosage forms for the Solid composition include tablets, such 0490. In some embodiments, the two chambers of the blis as compressed tablets, film-like units, foil-like units, wafers, ter pack are connected by a channel, the channel being lyophilized matrix units, and the like. In a preferred embodi adapted to direct fluid from the blister containing the liquid ment, the Solid composition is a highly porous lyophilized Solvent to the blister containing the Solid composition. During form. Such lyophilizates, sometimes also called wafers or storage, the channel is closed with a seal. In this sense, a seal lyophilized tablets, are particularly useful for their rapid dis is any structure that prevents the liquid solvent from contact integration, which also enables the rapid dissolution of the ing the solid composition. The seal is preferably breakable or active compound. removable; breaking or removing the seal when the nebulizer 0496. On the other hand, for some applications the solid is to be used will allow the liquid solvent to enter the other composition may also be formed as a multiple unit dosage chamber and dissolve the solid composition. The dissolution form as defined above. Examples of multiple units are pow process may be improved by shaking the blister pack. Thus, ders, granules, microparticles, pellets, beads, lyophilized the final liquid composition for inhalation is obtained, the powders, and the like. In one embodiment, the Solid compo liquid being present in one or both of the chambers of the pack sition is a lyophilized powder. Such a dispersed lyophilized connected by the channel, depending on how the pack is held. system comprises a multitude of powderparticles, and due to 0491. According to another embodiment, one of the cham the lyophilization process used in the formation of the pow bers, preferably the one that is closer to the tapered portion of der, each particle has an irregular, porous microstructure the blister pack communicates with a second channel, the through which the powder is capable of absorbing water very channel extending from the chamber to a distal position of the rapidly, resulting in quick dissolution. tapered portion. During storage, this second channel does not 0497 Another type of multiparticulate system which is communicate with the outside of the pack but is closed in an also capable of achieving rapid drug dissolution is that of air-tight fashion. Optionally, the distal end of the second powders, granules, or pellets from water-soluble excipients channel is closed by a breakable or removable cap or closure, which are coated with the drug, so that the drug is located at which may e.g., be a twist-off cap, a break-off cap, or a cut-off the outer surface of the individual particles. In this type of Cap. system, the water-soluble low molecular weight excipient is 0492. In one embodiment, a vial or container having two useful for preparing the cores of such coated particles, which compartments is used, the compartment representing the can be Subsequently coated with a coating composition com chambers for containing the solid composition and the liquid prising the drug and, preferably, one or more additional Solvent in matched quantities for preparing a dose unit of the excipients. Such as a binder, a pore former, a saccharide, a final liquid composition. The liquid composition and a second Sugar alcohol, a film-forming polymer, a plasticizer, or other liquid solvent may be contained in matched quantities for excipients used in pharmaceutical coating compositions. preparing a dose unit of the final liquid composition (by 0498. In another embodiment, the solid composition non-limiting example in cases where two soluble excipients resembles a coating layer that is coated on multiple units or the pirfenidone or pyridone analog compound and excipi made of insoluble material. Examples of insoluble units ent are unstable for storage, yet desired in the same mixture include beads made of glass, polymers, metals, and mineral for administration. salts. Again, the desired effect is primarily rapid disintegra 0493. In some embodiments, the two compartments are tion of the coating layer and quick drug dissolution, which is physically separated but in fluid communication Such as when achieved by providing the Solid composition in a physical so the vial or container are connected by a channel or break form that has a particularly high Surface-to-volume ratio. able barrier, the channel or breakable barrier being adapted to Typically, the coating composition will, in addition to the direct fluid between the two compartments to enable mixing drug and the water-soluble low molecular weight excipient, prior to administration. During storage, the channel is closed comprise one or more excipients, such as those mentioned with a seal or the breakable barrier intact. In this sense, a seal above for coating Soluble particles, or any other excipient is any structure that prevents mixing of contents in the two known to be useful in pharmaceutical coating compositions. compartments. The seal is preferably breakable or remov 0499. To achieve the desired effects, it may be useful to able; breaking or removing the seal when the nebulizer is to be incorporate more than one water-soluble low molecular used will allow the liquid solvent to enter the other chamber weight excipient into the Solid composition. For instance, one and dissolve the solid composition or in the case of two excipient may be selected for its drug carrier and diluent liquids permit mixing. The dissolution or mixing process may capability, while another excipient may be selected to adjust be improved by shaking the container. Thus, the final liquid the pH. If the final liquid composition needs to be buffered, composition for inhalation is obtained, the liquid being two excipients that together form a buffer system may be present in one or both of the chambers of the pack connected selected. by the channel or breakable barrier, depending on how the 0500. In one embodiment, the liquid to be used in a sepa pack is held. rated-compartment nebulizer is an aqueous liquid, which is 0494 The solid composition itself can be provided in vari herein defined as a liquid whose major component is water. ous different types of dosage forms, depending on the physi The liquid does not necessarily consist of water only; how US 2015/O 196543 A1 Jul. 16, 2015 72 ever, in one embodiment it is purified water. In another 0504 Some embodiments the high efficiency liquid nebu embodiment, the liquid contains other components or Sub lizers use passive nozzle membranes and a separate piezo stances, preferably other liquid components, but possibly also electric transducer that are in contact with the solution. In dissolved solids. Liquid components other than water which contrast, Some high efficiency liquid nebulizers employ an may be useful include propylene glycol, glycerol, and poly active nozzle membrane, which use the acoustic pressure in ethylene glycol. One of the reasons to incorporate a solid the nebulizer to generate very fine droplets of solution via the compound as a solute is that such a compound is desirable in high frequency vibration of the nozzle membrane. the final liquid composition, but is incompatible with the solid 0505 Some high efficiency liquid nebulizers contain a composition or with a component thereof. Such as the active resonant system. In some such high efficiency liquid nebuliz ingredient. ers, the membrane is driven by a frequency for which the 0501. Another desirable characteristic for the liquid sol amplitude of the vibrational movement at the center of the vent is that it is sterile. An aqueous liquid would be subject to membrane is particularly large, resulting in a focused acous the risk of considerable microbiological contamination and tic pressure in the vicinity of the nozzle; the resonant fre growth if no measures were taken to ensure sterility. In order quency may be about 100 kHz. A flexible mounting is used to to provide a substantially sterile liquid, an effective amount of keep unwanted loss of vibrational energy to the mechanical an acceptable antimicrobial agent or preservative can be Surroundings of the atomizing head to a minimum. In some incorporated or the liquid can be sterilized prior to providing embodiments, the vibrating membrane of the high efficiency it and to seal it with an air-tight seal. In one embodiment, the liquid nebulizer may be made of a nickel-palladium alloy by liquid is a sterilized liquid free of preservatives and provided electroforming. in an appropriate air-tight container. However, according to 0506. In some embodiments, the high efficiency liquid another embodiment in which the nebulizer contains multiple nebulizer (i) achieves lung deposition of at least about 5%, at doses of the active compound, the liquid may be Supplied in a least about 6%, at least about 7%, at least about 8%, at least multiple-dose container, Such as a metered-dose dispenser, about 9%, at least about 10%, at least about 15%, at least and may require a preservative to prevent microbial contami about 20%, at least about 25%, at least about 30%, at least nation after the first use. about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least High Efficiency Liquid Nebulizers about 65%, at least about 70%, at least about 75%, at least about 80%, or at least about 85%, based on the nominal dose 0502. High efficiency liquid nebulizers are inhalation of the pirfenidone or pyridone analog compound adminis devices that are adapted to deliver a large fraction of a loaded tered to the mammal. dose to a patient. Some high efficiency liquid nebulizers uti 0507. In some embodiments, the high efficiency liquid lize microperforated membranes. In some embodiments, the nebulizer (ii) provides a Geometric Standard Deviation high efficiency liquid nebulizer also utilizes one or more (GSD) of emitted droplet size distribution of the solution actively or passively vibrating microperforated membranes. administered with the high efficiency liquid nebulizer of In some embodiments, the high efficiency liquid nebulizer about 1.0 um to about 2.5 Lim, about 1.2 Lum to about 2.5um, contains one or more oscillating membranes. In some about 1.3 um to about 2.0 um, at least about 1.4 um to about embodiments, the high efficiency liquid nebulizer contains a 1.9 Lim, at least about 1.5um to about 1.9 um, about 1.5um, vibrating mesh or plate with multiple apertures and optionally about 1.7 um, or about 1.9 um. a vibration generator with an aerosol mixing chamber. In 0508. In some embodiments, the high efficiency liquid Some such embodiments, the mixing chamber functions to nebulizer (iii) provides a mass median aerodynamic diameter collect (or stage) the aerosol from the aerosol generator. In (MMAD) of droplet size of the solution emitted with the high Some embodiments, an inhalation valve is also used to allow efficiency liquid nebulizer of about 1 um to about 5um, about an inflow of ambient air into the mixing chamber during an 2 to about 4 Lim, or about 2.5 to about 4.0 um. In some inhalation phase and is closed to prevent escape of the aerosol embodiments, the high efficiency liquid nebulizer (iii) pro from the mixing chamber during an exhalation phase. In some vides a volumetric mean diameter (VMD) 1 um to about 5um, Such embodiments, the exhalation valve is arranged at a about 2 to about 4 um, or about 2.5 to about 4.0 Lim. In some mouthpiece which is removably mounted at the mixing cham embodiments, the high efficiency liquid nebulizer (iii) pro ber and through which the patient inhales the aerosol from the vides a mass median diameter (MMD) 1 um to about 5 um, mixing chamber. In yet some other embodiments, the high about 2 to about 4 Lum, or about 2.5 to about 4.0 um. efficiency liquid nebulizer contains a pulsating membrane. In 0509. In some embodiments, the high efficiency liquid Some embodiments, the high efficiency liquid nebulizer is nebulizer (iv) provides a fine particle fraction (FPF=%s5 continuously operating. microns) of droplets emitted from the high efficiency nebu 0503. In some embodiments, the high efficiency liquid lizer of at least about 60%, at least about 65%, at least about nebulizer contains a vibrating microperforated membrane of 70%, at least about 75%, at least about 80%, at least about tapered nozzles againstabulk liquid will generate a plume of 85%, or at least about 90%. droplets without the need for compressed gas. In these 0510. In some embodiments, the high efficiency liquid embodiments, a solution in the microperforated membrane nebulizer (v) provides an output rate of at least 0.1 mL/min, at nebulizer is in contact with a membrane, the opposite side of least 0.2 mL/min, at least 0.3 mL/min, at least 0.4 mL/min, at which is open to the air. The membrane is perforated by a least 0.5 mL/min, at least 0.6 mL/min, at least 0.8 mL/min, or large number of nozzle orifices of an atomizing head. An at least 1.0 mL/min. aerosol is created when alternating acoustic pressure in the 0511. In some embodiments, the high efficiency liquid Solution is built up in the vicinity of the membrane causing the nebulizer (vi) delivers at least about 20%, at least about 25%, fluid on the liquid side of the membrane to be emitted through at least about 30%, at least about 35%, at least about 40%, at the nozzles as uniformly sized droplets. least about 45%, at least about 50%, at least about 55%, at US 2015/O 196543 A1 Jul. 16, 2015

least about 60%, at least about 65%, at least about 70%, at example ethanol), Soluble in the propellant plus an additional least about 75%, or at least about 80% of the fill volume to the moiety promoting increased solubility (by non-limiting mammal. example glycerol orphospholipid), or as a stable Suspension 0512. In some embodiments, the high efficiency liquid or micronized, spray-dried or nanosuspension. nebulizer provides an RDD of at least about 5%, at least about 0519. By non-limiting example, a metered-dose pirfeni 6%, at least about 7%, at least about 8%, at least about 9%, at done or pyridone analog compound may be administered in least about 10%, at least about 15%, at least about 20%, at the described respirable delivered dose in 10 or fewer inha least about 25%, at least about 30%, at least about 35%, at lation breaths, more preferably in 8 or fewer inhalation least about 40%, at least about 45%, at least about 50%, at breaths, more preferably in 6 or fewer inhalation breaths, least about 55%, at least about 60%, at least about 65%, at more preferably in 8 or fewer inhalation breaths, more pref least about 70%, at least about 75%, at least about 80%, or at erably in 4 or fewer inhalation breaths, more preferably in 2 or least about 85%. fewer inhalation breaths. 0513. In some embodiments, the high efficiency liquid 0520. The propellants for use with the MDIs may be any nebulizer is characterized as providing one or more of (i), (ii), propellants known in the art. Examples of propellants include (iii) (iv), (v), or (vi). In some embodiments, the high effi chlorofluorocarbons (CFCs) such as dichlorodifluo ciency liquid nebulizer is characterized as providing at least romethane, trichlorofluorometbane, and dichlorotetrafluoro one, at least two, at least three, at least four, at least five, or all ethane; hydrofluoroalkanes (HFAs); and carbon dioxide. It six of (i), (ii), (iii) (iv), (v), or (vi). may be advantageous to use HFAs instead of CFCs due to the 0514. Additional features of a high efficiency liquid nebu environmental concerns associated with the use of CFCs. lizer with perforated membranes are disclosed in U.S. Pat. Examples of medicinal aerosol preparations containing HFAS Nos. 6,962,151, 5,152,456, 5,261,601, and 5,518,179, U.S. are presented in U.S. Pat. Nos. 6,585,958; 2,868,691 and Pat. No. 6,983,747, each of which is hereby incorporated by 3.014,844, all of which are hereby incorporated by reference reference in its entirety. Other embodiments of the high effi in their entirety. In some embodiments, a co-solvent is mixed ciency liquid nebulizers contain oscillatable membranes. with the propellant to facilitate dissolution or suspension of Features of these high efficiency liquid nebulizers are dis the drug Substance. closed in U.S. Pat. Nos. 7,252,085; 7,059,320; 6,983,747, 0521. In some embodiments, the propellant and active each of which is hereby incorporated by reference in its ingredient are contained in separate containers, such as entirety. described in U.S. Pat. No. 4,534,345, which is hereby incor 0515 Commercial high efficiency liquid nebulizers are porated by reference in its entirety. available from: PARI (Germany) under the trade name 0522. In some embodiments, the MDI used herein is acti eFlow(R); Nektar Therapeutics (San Carlos, Calif.) under the vated by a patient pushing a lever, button, or other actuator. In trade names AeroNeb(R) Go and AeroNebR Pro, and other embodiments, the release of the aerosol is breath acti AeroNeb(R) Solo, Respironics (Murrysville, Calif.) under the vated Such that, after initially arming the unit, the active trade names I-Neb(R), Omron (Bannockburn, Ill.) under the compound aerosol is released once the patient begins to trade name Micro-Air R, and Activaero (Germany) under the inhale, such as described in U.S. Pat. Nos. 6,672,304, 5,404, trade name Akita R. Commercial High Efficiency Nebulizers 871; 5,347,998: 5,284,133:5,217,004; 5,119,806; 5,060,643; are also available from Aerogen (Galaway, Ireland) utilizing 4,664,107; 4,648,393: 3,789,843: 3,732,864; 3,636,949; the OnOR) nebulizer technology. 3,598.294; 3,565,070; 3,456,646; 3,456,645; and 3,456,644, each of which is hereby incorporated by reference in its Meter Dose Inhaler (MDI) entirety. Such a system enables more of the active compound 0516 A propellant driven inhaler (pMDI) releases a to get into the lungs of the patient. Another mechanism to help metered dose of medicine upon each actuation. The medicine a patient get adequate dosage with the active ingredient may is formulated as a suspension or solution of a drug Substance include a valve mechanism that allows a patient to use more in a suitable propellant such as a halogenated hydrocarbon. than one breath to inhale the drug, such as described in U.S. pMDIs are described in, for example, Newman, S. P., Aero Pat. Nos. 4,470.412 and 5,385,140, both of which are hereby sols and the Lung, Clarke et al., eds., pp. 197-224 (Butter incorporated by reference in their entirety. worths, London, England, 1984). 0523) Additional examples of MDIs known in the art and 0517. In some embodiments, the particle size of the drug suitable for use herein include U.S. Pat. Nos. 6,435,177; Substance in an MDI may be optimally chosen. In some 6,585,958; 5,642,730; 6,223,746; 4,955,371; 5,404.871; embodiments, the particles of active ingredient have diam 5,364,838; and 6.523,536, all of which are hereby incorpo eters of less than about 50 microns. In some embodiments, the rated by reference in their entirety. particles have diameters of less than about 10 microns. In Some embodiments, the particles have diameters of from Dry Powder Inhaler (DPI) about 1 micronto about 5 microns. In some embodiments, the 0524. There are two major designs of dry powder inhalers. particles have diameters of less than about 1 micron. In one One design is the metering device in which a reservoir for the advantageous embodiment, the particles have diameters of drug is placed within the device and the patient adds a dose of from about 2 microns to about 5 microns. the drug into the inhalation chamber. The second is a factory 0518. By non-limiting example, metered-dose inhalers metered device in which each individual dose has been manu (MDI), the pirfenidone or pyridone analog compound dis factured in a separate container. Both systems depend upon closed herein are prepared in dosages to deliver from about 34 the formulation of drug into Small particles of mass median mcg to about 463 mg from a formulation meeting the require diameters from about 1 to about 5 micron, and usually involve ments of the MDI. The pirfenidone or pyridone analog com co-formulation with larger excipient particles (typically 100 pound disclosed herein may be soluble in the propellant, micron diameter lactose particles). Drug powder is placed soluble in the propellant plus a co-solvent (by non-limiting into the inhalation chamber (either by device metering or by US 2015/O 196543 A1 Jul. 16, 2015 74 breakage of a factory-metered dosage) and the inspiratory entirety. In a multiple unit dose DPI, a package containing flow of the patient accelerates the powder out of the device multiple single dose compartments is provided. For example, and into the oral cavity. Non-laminar flow characteristics of the package may comprise ablister pack, where each blister the powder path cause the excipient-drug aggregates to compartment contains one dose. Each dose can be dispensed decompose, and the mass of the large excipient particles upon breach of a blister compartment. Any of several arrange causes their impaction at the back of the throat, while the ments of compartments in the package can be used. For Smaller drug particles are deposited deep in the lungs. example, rotary or strip arrangements are common. Examples 0525. As with liquid nebulization and MDIs, particle size of multiple unit does DPIs are described in EPO Patent Appli of the pirfenidone or pyridone analog compound aerosol for cation Publication Nos. 0211595A2, 0455463A1, and mulation may be optimized. If the particle size is larger than 0467172A1, all of which are hereby incorporated by refer about 5 micron MMAD then the particles are deposited in ence in their entirety. In a multi-dose DPI, a single reservoir of upper airways. If the particle size of the aerosol is smaller than dry powder is used. Mechanisms are provided that measure about 1 micron then it is delivered into the alveoli and may get out single dose amounts from the reservoir to be aerosolized transferred into the systemic blood circulation. and inhaled, such as described in U.S. Pat. Nos. 5,829,434; 0526. By non-limiting example, in dry powder inhalers, 5,437,270; 2,587.215; 5,113,855; 5,840,279; 4,688,218; the pirfenidone or pyridone analog compound disclosed 4,667,668; 5,033,463; and 4,805,811 and PCT Publication herein are prepared in dosages to disperse and deliver from No. WO92/09322, all of which are hereby incorporated by about 34 mcg to about 463 mg from a dry powder formula reference in their entirety. tion. 0530. In some embodiments, auxiliary energy in addition 0527 By non-limiting example, a dry powder pirfenidone to or other than a patients inhalation may be provided to or pyridone analog compound may be administered in the facilitate operation of a DPI. For example, pressurized air described respirable delivered dose in 10 or fewer inhalation may be provided to aid in powder de-agglomeration, Such as breaths, more preferably in 8 or fewer inhalation breaths, described in U.S. Pat. Nos. 3,906,950; 5,113,855; 5,388,572: more preferably in 6 or fewer inhalation breaths, more pref 6,029,662 and PCT Publication Nos. WO 93/12831, WO erably in 8 or fewer inhalation breaths, more preferably in 4 or 90/07351, and WO99/62495, all of which are hereby incor fewer inhalation breaths, more preferably in 2 or fewer inha porated by reference in their entirety. Electrically driven lation breaths. impellers may also be provided, such as described in U.S. Pat. 0528. In some embodiments, a dry powder inhaler (DPI) is Nos. 3,948,264; 3,971,377; 4,147,166; 6,006,747 and PCT used to dispense the pirfenidone or pyridone analog com Publication No. WO98/03217, all of which are hereby incor pound described herein. DPIs contain the drug substance in porated by reference in their entirety. Another mechanism is fine dry particle form. Typically, inhalation by a patient an electrically powered tapping piston, Such as described in causes the dry particles to forman aerosol cloud that is drawn PCT Publication No. WO 90/13327, which is hereby incor into the patient's lungs. The fine dry drug particles may be porated by reference in its entirety. Other DPIs use a vibrator, produced by any technique known in the art. Some well such as described in U.S. Pat. Nos. 5,694,920 and 6,026,809, known techniques include use of a jet mill or other commi both of which are hereby incorporated by reference in their nution equipment, precipitation from Saturated or Super Satu entirety. Finally, a scraper system may be employed. Such as rated solutions, spray drying, in situ micronization described in PCT Publication No. WO 93/24165, which is (Hovione), or supercritical fluid methods. Typical powder hereby incorporated by reference in its entirety. formulations include production of spherical pellets or adhe 0531. Additional examples of DPIs for use herein are sive mixtures. In adhesive mixtures, the drug particles are described in U.S. Pat. Nos. 4,811,731; 5,113,855; 5,840,279; attached to larger carrier particles, such as lactose monohy 3,507,277; 3,669,113; 3,635,219; 3,991,761; 4,353,365; drate of size about 50 to about 100 microns in diameter. The 4,889,144, 4,907,538; 5,829,434; 6,681,768: 6,561,186: larger carrierparticles increase the aerodynamic forces on the 5,918,594; 6,003,512; 5,775,320; 5,740,794; and 6,626,173, carrier/drug agglomerates to improve aerosol formation. Tur all of which are hereby incorporated by reference in their bulence and/or mechanical devices break the agglomerates entirety. into their constituent parts. The Smaller drug particles are then 0532. In some embodiments, a spacer or chamber may be drawn into the lungs while the larger carrier particles deposit used with any of the inhalers described herein to increase the in the mouth or throat. Some examples of adhesive mixtures amount of drug Substance that gets absorbed by the patient, are described in U.S. Pat. No. 5,478,578 and PCT Publication such as is described in U.S. Pat. Nos. 4470.412; 4,790,305; Nos. WO95/11666, WO 87/05213, WO 96/23485, and WO 4,926,852; 5,012,803; 5,040,527: 5,024,467; 5,816,240; 97/03649, all of which are incorporated by reference in their 5,027,806; and 6,026,807, all of which are hereby incorpo entirety. Additional excipients may also be included with the rated by reference in their entirety. For example, a spacer may drug Substance. delay the time from aerosol production to the time when the 0529. There are three common types of DPIs, all of which aerosol enters a patient's mouth. Such a delay may improve may be used with the pirfenidone or pyridone analog com synchronization between the patients inhalation and the pounds described herein. In a single-dose DPI, a capsule aerosol production. A mask may also be incorporated for containing one dose of dry drug Substance/excipients is infants or other patients that have difficulty using the tradi loaded into the inhaler. Upon activation, the capsule is tional mouthpiece, such as is described in U.S. Pat. Nos. breached, allowing the dry powder to be dispersed and 4,809,692; 4,832,015; 5,012,804: 5,427,089: 5,645,049; and inhaled using a dry powder inhaler. To dispense additional 5.988,160, all of which are hereby incorporated by reference doses, the old capsule must be removed and an additional in their entirety. capsule loaded. Examples of single-dose DPIs are described 0533 Dry powder inhalers (DPIs), which involve in U.S. Pat. Nos. 3,807,400; 3,906,950; 3,991,761; and 4,013, deaggregation and aerosolization of dry powder particles, 075, all of which are hereby incorporated by reference in their normally rely upon a burst of inspired air that is drawn US 2015/O 196543 A1 Jul. 16, 2015 through the unit to deliver a drug dosage. Such devices are about 50 mg/mL, between about 20 mg/mL and about 50 described in, for example, U.S. Pat. No. 4,807,814, which is mg/mL, between about 25 mg/mL and about 50 mg/mL, or directed to a pneumatic powder ejector having a Suction stage between about 30 mg/mL and about 50 mg/mL. and an injection stage; SU 628930 (Abstract), describing a hand-held powder disperser having an axial airflow tube; Fox 0539. In some embodiments, the pH is between about pH et al., Powder and Bulk Engineering, pages 33-36 (March 4.0 and about pH 8.0. In some embodiments, the pH is 1988), describing a venturi eductor having an axial air inlet between about pH 5.0 and about pH 8.0. In some embodi tube upstream of a venturi restriction; EP347 779, describing ments, the pH is between about pH 6.0 and about pH 8.0. In a hand-held powder disperser having a collapsible expansion some embodiments, the pH is between about pH 6.5 and chamber, and U.S. Pat. No. 5,785,049, directed to dry powder about pH 8.0. delivery devices for drugs. 0540. In some embodiments, the aqueous pharmaceutical 0534 Commercial examples of dry powder inhalers that composition includes one or more co-solvents. In some can be used with the pirfenidone or pyridone analog com embodiments, the aqueous pharmaceutical composition pound formulations described herein include the Aerolizer, includes one or more co-solvents, where the total amount of Turohaler, Handihaler and Discus. co-solvents is from about 1% to about 50% w/v of the total Volume of the composition. In some embodiments, the aque Solution/Dispersion Formulations ous pharmaceutical composition includes one or more co solvents, where the total amount of co-solvents is from about 0535 In one embodiment, aqueous formulations contain 1% to about 50% v/v, from about 1% to about 40% w/v, from ing soluble or nanoparticulate drug particles are provided. For about 1% to about 30% w/v, or from about 1% to about 25% aqueous aerosol formulations, the drug may be present at a V/v, of the total volume of the composition. Co-solvents concentration from about 34 mcg/mL to about 463 mg/mL. In include, but are not limited to, ethanol, propylene glycol and Some embodiments the drug is present at a concentration glycerol. In some embodiments, the aqueous pharmaceutical from about 1 mg/mL to about 463 mg/mL, or about 1 mg/mL composition includes ethanol at about 1% V/v to about 25%. to about 400 mg/mL, or about 0.1 mg/mL to about 360 In some embodiments, the aqueous pharmaceutical compo mg/mL, or about 1 mg/mL to about 300 mg/mL, or about 1 sition includes ethanol at about 1% V/v to about 15%. In some mg/mL to about 200 mg/mL, about 1 mg/mL to about 100 embodiments, the aqueous pharmaceutical composition mg/mL, or about 1 mg/mL to about 50 mg/mL, or about 5 includes ethanol at about 1% w/v, 2% v/v, 3% V/v, 4% v/v, 5% mg/mL to about 50 mg/mL, or about 10 mg/mL to about 50 v/v, 6% v/v, 7% v/v, 8% v/v, 9% v?.v., 10% v/v, 11% v/v, 12% mg/mL, or about 15 mg/mL to about 50 mg/mL, or about 20 v/v, 13% v/v, 14% v?.v., 15% V/v, 16% v/v, 17% v/v, 18% v/v, mg/mL to about 50 mg/mL. Such formulations provide effec 19% v/v, 20% v/v, 21% v/v, 22% v/v, 23% V/V, 24% v/v, or tive delivery to appropriate areas of the lung, with the more 25% V/v. In some embodiments, the aqueous pharmaceutical concentrated aerosol formulations having the additional composition includes glycerol at about 1% V/v to about 25%. advantage of enabling large quantities of drug Substance to be In some embodiments, the aqueous pharmaceutical compo delivered to the lung in a very short period of time. In one sition includes glycerol at about 1% V/v to about 15%. In embodiment, a formulation is optimized to provide a well Some embodiments, the aqueous pharmaceutical composi tolerated formulation. Accordingly, in one embodiment, pir tion includes glycerol at about 1% V/V, 2% V/V, 3% V/V, 4% fenidone or pyridone analog compound disclosed herein are v/v, 5% v/v, 6% v/v, 7% v/v, 8% v/v, 9% v/v, 10% V/v, 11% formulated to have good taste, pH from about 4.0 to about 8.0, v/v, 12% v/v, 13% v/v, 14% v/v, 15% v/v, 16% w/v., 17% v/v, osmolarity from about 100 to about 5000 mOsmol/kg. In 18% v/v, 19% v/v, 20% w/v. 21% v/v, 22% v/v, 23%v/v, 24% some embodiments, the osmolarity is from about 100 to about V/V, or 25% V/v. In some embodiments, the aqueous pharma 1000 mOsmol/kg. In some embodiments, the osmolarity is ceutical composition includes propylene glycol at about 1% from about 200 to about 500 mOsmol/kg. In some embodi V/v to about 50%. In some embodiments, the aqueous phar ments, the permeant ion concentration is from about 30 to maceutical composition includes propylene glycol at about about 300 mM. 1% V/v to about 25%. In some embodiments, the aqueous 0536. In some embodiments, described herein is an aque pharmaceutical composition includes propylene glycol at ous pharmaceutical composition comprising pirfenidone or about 1% v?v, 2% v/v,3% w/v. 4% v/v, 5% v/v, 6% w/v.7% w/v, pyridone analog compound, water and one or more additional 8% v/v, 9% v?.v., 10% w/v. 11% v/v, 12% v/v, 13% v?.v., 14% ingredients selected from co-solvents, tonicity agents, Sweet v/v, 15% v/v, 16% w/v., 17% v/v, 18% v/v, 19% v/v, 20% v/v, eners, Surfactants, wetting agents, chelating agents, anti-oxi 21% v/v, 22% v/v, 23% v/v, 24% v/v, or 25% v/v. dants, salts, and buffers. It should be understood that many excipients may serve several functions, even within the same 0541. In some embodiments, the aqueous pharmaceutical formulation. composition includes ethanol at about 1% v/v to about 25% 0537. In some embodiments, pharmaceutical composi and propylene glycol at about 1% V/v to about 50%. In some tions described herein do not include any thickening agents. embodiments, the aqueous pharmaceutical composition 0538. In some embodiments, the concentration of pirfeni includes ethanol at about 1% V/v to about 15% and propylene done or pyridone analog compound in the aqueous pharma glycol at about 1% V/v to about 30%. In some embodiments, ceutical composition is between about 0.1 mg/mL and about the aqueous pharmaceutical composition includes ethanol at 100 mg/mL. In some embodiments, the concentration of pir about 1% V/v to about 8% and propylene glycol at about 1% fenidone or pyridone analog compound in the pharmaceutical V/v to about 16%. In some embodiments, the aqueous phar composition is between about 1 mg/mL and about 100 maceutical composition includes ethanol and twice as much mg/mL, between about 10 mg/mL and about 100 mg/mL propylene glycol, based on Volume. between about 20 mg/mL and about 100 mg/mL, between 0542. In some embodiments, the aqueous pharmaceutical about 25 mg/mL and about 100 mg/mL, between about 30 composition includes a buffer. In some embodiments, the mg/mL and about 100 mg/mL, between about 15 mg/mL and buffer is a citrate buffer or a phosphate buffer. In some US 2015/O 196543 A1 Jul. 16, 2015 76 embodiments, the buffer is a citrate buffer. In some embodi Some cases, a certain amount of chloride or another anion is ments, the buffer is a phosphate buffer. needed for successful and efficacious delivery of aerosolized 0543. In some embodiments, the aqueous pharmaceutical pirfenidone or pyridone analog compound. composition consists essentially of pirfenidone or pyridone 0550. In some embodiments, the osmolality of aqueous analog compound, water, ethanol and/or propylene glycol, a Solutions of the pirfenidone or pyridone analog compound buffer to maintain the pH at about 4 to 8 and optionally one or disclosed herein is greater than 100 mOsmol/kg. In some more ingredients selected from salts, Surfactants, and Sweet embodiments, the osmolality of aqueous solutions of the eners (taste-maksing agents). In some embodiments, the one pirfenidone or pyridone analog compound disclosed herein is or more salts are selected from tonicity agents. In some greater than 300 mOsmol/kg. In some embodiments, the embodiments, the one or more salts are selected from Sodium osmolality of aqueous Solutions of the pirfenidone or pyri chloride and magnesium chloride. done analog compound disclosed herein is greater than 1000 0544. In some embodiments, the aqueous pharmaceutical mOsmol/kg. In some embodiments, aerosol delivery of aque composition consists essentially of pirfenidone or pyridone ous solutions with high osmolality (i.e. greater than about 300 analog compound at a concentration of about 10 mg/mL to mOsmol/kg) have high incidence of bronchospastic, asth about 50 mg/mL, water, one or two coslovents (ethanol at a matic or other coughing incidents. In some embodiments, concentration of about 1% V/v to about 25% v/v and/or pro aerosol delivery of the aqueous solutions having high osmo pylene glycolata concentration of about 1% V/v to about 50% lality (i.e. greater than about 300 mOsmol/kg) as described do V/v), a buffer to maintain the pH at about 4 to 8 and optionally not increase the incidence of bronchospastic, asthmatic or one or more ingredients selected from salts, Surfactants, and other coughing incidents. Sweeteners (taste-maksing agents). 0551. In some embodiments, the osmolality of aqueous 0545. In one embodiment, the solution or diluent used for Solutions of the pirfenidone or pyridone analog compound preparation of aerosol formulations has a pH range from disclosed herein are are greater than 100 mOsmol/kg above about 4.0 to about 8.0. This pH range improves tolerability. by providing excipients. In some cases, a certain amount of When the aerosol is either acidic or basic, it can cause bron chloride or anotheranion is needed for successful and effica chospasm and cough. Although the safe range of pH is rela cious delivery of aerosolized pirfenidone or pyridone analog tive and some patients may tolerate a mildly acidic aerosol, compound while others will experience bronchospasm. Anyaerosol with 0552. In some embodiments, the formulation for an aero a pH of less than about 4.0 typically induces bronchospasm. Sol pirfenidone or pyridone analog compound may comprise Aerosols having pH greater than about 8.0 may have low from about 34 mcg to about 463 mg pirfenidone or pyridone tolerability because body tissues are generally unable to analog compound per about 1 to about 5 ml of dilute saline buffer alkaline aerosols. Aerosols with controlled pH below (between 1/10 to 2/1 normal saline). Accordingly, the con about 4.0 and over about 8.0 typically result in lung irritation centration of a pirfenidone or pyridone analog compound accompanied by severe bronchospasm cough and inflamma Solution may be greater than about 34 mcg/ml, greater than tory reactions. For these reasons as well as for the avoidance about 463 mcg/ml, greater than about 1 mg/ml, greater than of bronchospasm, cough or inflammation in patients, the opti about 2 mg/mL, greater than about 3.0 mg/mL, greater than mum pH for the aerosol formulation was determined to be about 3.7 mg/mL, greater than about 10 mg/mL, greater than between about pH 4.0 to about pH 8.0. about 37 mg/mL, greater than about 50 mg/ml, greater than 0546 By non-limiting example, compositions may also about 100 mg/mL, or greater than 463 mg/mL. include a buffer or a pH adjusting agent, typically a salt 0553. In some embodiments, solution osmolality is from prepared from an organic acid or base. Representative buffers about 100 mOsmol/kg to about 6000 mOsmol/kg. In some include organic acid salts of citric acid, ascorbic acid, glu embodiments, solution osmolality is from about 100 mOs conic acid, carbonic acid, tartaric acid, Succinic acid, acetic mol/kg to about 5000 mOsmol/kg. In some other embodi acid, or phthalic acid, Tris, tromethamine, hydrochloride, or ments, the solution osmolality is from about 400 mOsmol/kg phosphate buffers. to about 5000 mOsmol/kg. 0547. Many patients have increased sensitivity to various 0554. In one embodiments, permeant ion concentration is chemical tastes, including bitter, salt, Sweet, metallic sensa from about 25 mM to about 400 mM. In various other tions. To create well-tolerated drug products, by non-limiting embodiments, permeant ion concentration is from about 30 example taste masking may be accomplished through the mM to about 300 mM; from about 40 mM to about 200 mM; addition of taste-masking excipients, adjusted osmolality, and from about 50 mM to about 150 mM. and Sweeteners. 0548. Many patients have increased sensitivity to various Solid Particle Formulations chemical agents and have high incidence of bronchospastic, 0555. In some embodiments, solid drug nanoparticles are asthmatic or other coughing incidents. Their airways are par provided for use in generating dry aerosols or for generating ticularly sensitive to hypotonic or hypertonic and acidic or nanoparticles in liquid Suspension. Powders comprising alkaline conditions and to the presence of any permanention, nanoparticulate drug can be made by spray-drying aqueous Such as chloride. Any imbalance in these conditions or a dispersions of a nanoparticulate drug and a surface modifier presence of chloride above certain value leads to broncho to form a dry powder which consists of aggregated drug spastic or inflammatory events and/or cough which greatly nanoparticles. In one embodiment, the aggregates can have a impair treatment with inhalable formulations. Both these size of about 1 to about 2 microns which is suitable for deep conditions prevent efficient delivery of aerosolized drugs into lung delivery. The aggregate particle size can be increased to the endobronchial space. target alternative delivery sites, such as the upper bronchial 0549. In some embodiments, the osmolality of aqueous region or nasal mucosa by increasing the concentration of Solutions of the pirfenidone or pyridone analog compound drug in the spray-dried dispersion orby increasing the droplet disclosed herein are adjusted by providing excipients. In size generated by the spray dryer. US 2015/O 196543 A1 Jul. 16, 2015 77

0556 Alternatively, an aqueous dispersion of drug and particles by removing the water via spray-drying or lyo Surface modifier can contain a dissolved diluent Such as lac philization (freeze drying). Spray-drying is less time consum tose or mannitol which, when spray dried, forms respirable ing and less expensive than freeze-drying, and therefore more diluent particles, each of which contains at least one embed cost-effective. However, certain drugs, such as biologicals ded drug nanoparticle and Surface modifier. The diluent par benefit from lyophilization rather than spray-drying in mak ticles with embedded drug can have a particle size of about 1 ing dry powder formulations. to about 2 microns, suitable for deep lung delivery. In addi 0563 Conventional micronized drug particles used in dry tion, the diluent particle size can be increased to target alter powder aerosol delivery having particle diameters of from nate delivery sites, such as the upper bronchial region or nasal about 1 to about 5 microns MMAD are often difficult to meter mucosa by increasing the concentration of dissolved diluent and disperse in Small quantities because of the electrostatic in the aqueous dispersion prior to spray drying, or by increas cohesive forces inherent in such powders. These difficulties ing the droplet size generated by the spray dryer. can lead to loss of drug Substance to the delivery device as 0557. Spray-dried powders can be used in DPIs orpMDIs, well as incomplete powder dispersion and Sub-optimal deliv either alone or combined with freeze-dried nanoparticulate ery to the lung. Many drug compounds, particularly proteins powder. In addition, spray-dried powders containing drug and peptides, are intended for deep lung delivery and sys nanoparticles can be reconstituted and used in either jet or temic absorption. Since the average particle sizes of conven ultrasonic nebulizers to generate aqueous dispersions having tionally prepared dry powders are usually in the range of from respirable droplet sizes, where each droplet contains at least about 1 to about 5 microns MMAD, the fraction of material one drug nanoparticle. Concentrated nanoparticulate disper which actually reaches the alveolar region may be quite sions may also be used in these embodiments of the invention. small. Thus, delivery of micronized dry powders to the lung, 0558 Nanoparticulate drug dispersions can also be freeze especially the alveolar region, is generally very inefficient dried to obtain powders suitable for nasal or pulmonary deliv because of the properties of the powders themselves. ery. Such powders may contain aggregated nanoparticulate 0564. The dry powder aerosols which contain nanopar drug particles having a Surface modifier. Such aggregates may ticulate drugs can be made Smaller than comparable micron have sizes within a respirable range, e.g., about 1 to about 5 ized drug Substance and, therefore, are appropriate for effi microns MMAD. cient delivery to the deep lung. Moreover, aggregates of 0559 Freeze dried powders of the appropriate particle size nanoparticulate drugs are spherical in geometry and have can also be obtained by freeze drying aqueous dispersions of good flow properties, thereby aiding in dose metering and drug and surface modifier, which additionally contain a dis deposition of the administered composition in the lung or Solved diluent Such as lactose or mannitol. In these instances nasal cavities. the freeze dried powders consist of respirable particles of 0565 Dry nanoparticulate compositions can be used in diluent, each of which contains at least one embedded drug both DPIs and pMDIs. As used herein, “dry” refers to a nanoparticle. composition having less than about 5% water. 0560 Freeze-dried powders can be used in DPIs or 0566 In one embodiment, compositions are provided con pMDIs, either alone or combined with spray-dried nanopar taining nanoparticles which have an effective average particle ticulate powder. In addition, freeze-dried powders containing size of less than about 1000 nm, more preferably less than drug nanoparticles can be reconstituted and used in either jet about 400 nm, less thanabout 300 nm, less than about 250 nm, or ultrasonic nebulizers to generate aqueous dispersions that or less than about 200 nm, as measured by light-scattering have respirable droplet sizes, where each droplet contains at methods. By “an effective average particle size of less than least one drug nanoparticle. about 1000 nm it is meant that at least 50% of the drug 0561. One embodiment of the invention is directed to a particles have a weight average particle size of less than about process and composition for propellant-based systems com 1000 nm when measured by light scattering techniques. Pref prising nanoparticulate drug particles and a Surface modifier. erably, at least 70% of the drug particles have an average Such formulations may be prepared by wet milling the coarse particle size of less than about 1000 nm, more preferably at drug Substance and Surface modifier in liquid propellant, least 90% of the drug particles have an average particle size of either at ambient pressure or under high pressure conditions. less than about 1000 nm, and even more preferably at least Alternatively, dry powders containing drug nanoparticles about 95% of the particles have a weight average particle size may be prepared by spray-drying or freeze-drying aqueous of less than about 1000 nm. dispersions of drug nanoparticles and the resultant powders 0567 For aqueous aerosol formulations, the nanoparticu dispersed into Suitable propellants for use in conventional late pirfenidone or pyridone analog compound agent may be pMDIs. Such nanoparticulate pMDI formulations can be present at a concentration of about 34 mcg/mL up to about used for either nasal or pulmonary delivery. For pulmonary 463 mg/mL. For dry powder aerosol formulations, the nano administration, Such formulations afford increased delivery particulate agent may be present at a concentration of about to the deep lung regions because of the Small (e.g., about 1 to 34 mg/g up to about 463 mg/g, depending on the desired drug about 2 microns MMAD) particle sizes available from these dosage. Concentrated nanoparticulate aerosols, defined as methods. Concentrated aerosol formulations can also be containing a nanoparticulate drug at a concentration of about employed in pMDIs. 34 mcg/mL up to about 463 mg/mL for aqueous aerosol 0562 Another embodiment is directed to dry powders formulations, and about 34 mg/gup to about 463 mg/g for dry which contain nanoparticulate compositions for pulmonary powder aerosol formulations, are specifically provided. Such or nasal delivery. The powders may consist of respirable formulations provide effective delivery to appropriate areas aggregates of nanoparticulate drug particles, or of respirable of the lung or nasal cavities in short administration times, i.e., particles of a diluent which contains at least one embedded less than about 3-15 seconds per dose as compared to admin drug nanoparticle. Powders containing nanoparticulate drug istration times of up to 4 to 20 minutes as found in conven particles can be prepared from aqueous dispersions of nano tional pulmonary nebulizer therapies. US 2015/O 196543 A1 Jul. 16, 2015

0568 Nanoparticulate drug compositions for aerosol 0572 In a non-aqueous, pressurized milling system, a administration can be made by, for example, (1) nebulizing a non-aqueous liquid medium having a vapor pressure signifi dispersion of a nanoparticulate drug, obtained by either grind cantly greater than 1 atm at room temperature may be used in ing or precipitation; (2) aerosolizing a dry powder of aggre the milling process to make nanoparticulate drug composi gates of nanoparticulate drug and Surface modifier (the aero tions. If the milling medium is a suitable halogenated hydro Solized composition may additionally contain a diluent); or carbon propellant, the resultant dispersion may be filled (3) aerosolizing a suspension of nanoparticulate drug or drug directly into a suitable pMDI container. Alternately, the mill aggregates in a non-aqueous propellant. The aggregates of ing medium can be removed and recovered under vacuum or nanoparticulate drug and Surface modifier, which may addi heating to yield a dry nanoparticulate composition. This com tionally contain a diluent, can be made in a non-pressurized or position can then be filled into an appropriate container and a pressurized non-aqueous system. Concentrated aerosol for charged with a suitable propellant for use in a pMDI. mulations may also be made via Such methods. 0573 Spray drying is a process used to obtain a powder containing nanoparticulate drug particles following particle 0569 Milling of aqueous drug to obtain nanoparticulate size reduction of the drug in a liquid medium. In general, drug may be performed by dispersing drug particles in a spray-drying may be used when the liquid medium has a liquid dispersion medium and applying mechanical means in vapor pressure of less than about 1 atm at room temperature. the presence of grinding media to reduce the particle size of A spray-dryer is a device which allows for liquid evaporation the drug to the desired effective average particle size. The and drug powder collection. A liquid sample, either a solution particles can be reduced in size in the presence of one or more or Suspension, is fed into a spray noZZle. The nozzle generates Surface modifiers. Alternatively, the particles can be con droplets of the sample within a range of about 20 to about 100 tacted with one or more surface modifiers after attrition. micron in diameter which are then transported by a carrier gas Other compounds, such as a diluent, can be added to the into a drying chamber. The carrier gas temperature is typi drug/surface modifier composition during the size reduction cally from about 80 to about 200° C. The droplets are sub process. Dispersions can be manufactured continuously or in jected to rapid liquid evaporation, leaving behind dry par a batch mode. ticles which are collected in a special reservoir beneath a 0570 Another method of forming nanoparticle dispersion cyclone apparatus. Smaller particles in the range down about is by microprecipitation. This is a method of preparing stable 1 micron to about 5 microns are also possible. dispersions of drugs in the presence of one or more Surface 0574. If the liquid sample consists of an aqueous disper modifiers and one or more colloid stability enhancing surface sion of nanoparticles and surface modifier, the collected prod active agents free of any trace toxic solvents or solubilized uct will consist of spherical aggregates of the nanoparticulate heavy metal impurities. Such a method comprises, for drug particles. If the liquid sample consists of an aqueous example, (1) dissolving the drug in a suitable solvent with dispersion of nanoparticles in which an inert diluent material mixing; (2) adding the formulation from Step (1) with mixing was dissolved (such as lactose or mannitol), the collected to a solution comprising at least one Surface modifier to form product will consist of diluent (e.g., lactose or mannitol) a clear Solution; and (3) precipitating the formulation from particles which contain embedded nanoparticulate drug par step (2) with mixing using an appropriate nonsolvent. The ticles. The final size of the collected product can be controlled method can be followed by removal of any formed salt, if and depends on the concentration of nanoparticulate drug present, by dialysis or diafiltration and concentration of the and/or diluent in the liquid sample, as well as the droplet size dispersion by conventional means. The resultant nanoparticu produced by the spray-dryer nozzle. Collected products may late drug dispersion can be utilized in liquid nebulizers or be used in conventional DPIs for pulmonary or nasal delivery, processed to form a dry powder for use in a DPI or pMDI. dispersed in propellants for use in pMDIs, or the particles 0571. In a non-aqueous, non-pressurized milling system, a may be reconstituted in water for use in nebulizers. non-aqueous liquid having a vapor pressure of about 1 atm or 0575. In some instances it may be desirable to add an inert less at room temperature and in which the drug Substance is carrier to the spray-dried material to improve the metering essentially insoluble may be used as a wet milling medium to properties of the final product. This may especially be the case make a nanoparticulate drug composition. In such a process, when the spray dried powder is very small (less than about 5 a slurry of drug and surface modifier may be milled in the micron) or when the intended dose is extremely small, non-aqueous medium to generate nanoparticulate drug par whereby dose metering becomes difficult. In general. Such ticles. Examples of suitable non-aqueous media include etha carrier particles (also known as bulking agents) are too large nol, trichloromonofluoromethane, (CFC-11), and dichlo to be delivered to the lung and simply impact the mouth and rotetafluoroethane (CFC-114). An advantage of using CFC throat and are swallowed. Such carriers typically consist of 11 is that it can be handled at only marginally cool room Sugars such as lactose, mannitol, or trehalose. Other inert temperatures, whereas CFC-114 requires more controlled materials, including polysaccharides and cellulosics, may conditions to avoid evaporation. Upon completion of milling also be useful as carriers. the liquid medium may be removed and recovered under 0576 Spray-dried powders containing nanoparticulate vacuum or heating, resulting in a dry nanoparticulate compo drug particles may used in conventional DPIs, dispersed in sition. The dry composition may then be filled into a suitable propellants for use in pMDIs, or reconstituted in a liquid container and charged with a final propellant. Exemplary final medium for use with nebulizers. product propellants, which ideally do not contain chlorinated 0577 For compounds that are denatured or destabilized by hydrocarbons, include HFA-134a (tetrafluoroethane) and heat, such as compounds having a low melting point (i.e., HFA-227 (heptafluoropropane). While non-chlorinated pro about 70 to about 150° C.), or for example, biologics, subli pellants may be preferred for environmental reasons, chlori mation is preferred over evaporation to obtain a dry powder nated propellants may also be used in this embodiment of the nanoparticulate drug composition. This is because Sublima invention. tion avoids the high process temperatures associated with US 2015/O 196543 A1 Jul. 16, 2015 79 spray-drying. In addition, Sublimation, also known as freeze acids in the 2 and 3 of glycerol positions containing chains of drying or lyophilization, can increase the shelf stability of 12 to 26 carbon atoms and different head groups in the 1 drug compounds, particularly for biological products. position of glycerol that include choline, glycerol, inositol, Freeze-dried particles can also be reconstituted and used in serine, ethanolamine, as well as the corresponding phospha nebulizers. Aggregates of freeze-dried nanoparticulate drug tidic acids. The chains on these fatty acids can be saturated or particles can be blended with either dry powder intermediates unsaturated, and the phospholipid can be made up of fatty or used alone in DPIs and pMDIs for either nasal or pulmo acids of different chain lengths and different degrees of unsat nary delivery. uration. In particular, the compositions of the formulations 0578. Sublimation involves freezing the product and sub can include dipalmitoylphosphatidylcholine (DPPC), a major jecting the sample to strong vacuum conditions. This allows constituent of naturally-occurring lung Surfactant as well as for the formed ice to be transformed directly from a solid state dioleoylphosphatidylcholine (DOPC) and dioleoylphos to a vapor state. Such a process is highly efficient and, there phatidylglycerol (DOPG). Other examples include dimyris fore, provides greater yields than spray-drying. The resultant toylphosphatidycholine (DMPC) and dimyristoylphosphati freeze-dried product contains drug and modifier(s). The drug dylglycerol (DMPG) dipalmitoylphosphatidcholine (DPPC) is typically present in an aggregated State and can be used for and dipalmitoylphosphatidylglycerol (DPPG) dis inhalation alone (either pulmonary or nasal), in conjunction tearoylphosphatidylcholine (DSPC) and distearoylphos with diluent materials (lactose, mannitol, etc.), in DPIs or phatidylglycerol (DSPG), dioleylphosphatidylethanolamine pMDIs, or reconstituted for use in a nebulizer. (DOPE) and mixed phospholipids like palmitoyl stearoylphosphatidylcholine (PSPC) and palmitoyl Liposomal Compositions stearoylphosphatidylglycerol (PSPG), and single acylated 0579. In some embodiments, pirfenidone or pyridone ana phospholipids like mono-oleoyl-phosphatidylethanolamine log compounds disclosed herein may beformulated into lipo (MOPE). some particles, which can then be aerosolized for inhaled 0582. In a preferred embodiment, PEG-modified lipids are delivery. Lipids which are useful in the present invention can incorporated into the compositions of the present invention as be any of a variety of lipids including both neutral lipids and the aggregation-preventing agent. The use of a PEG-modified charged lipids. Carrier systems having desirable properties lipid positions bulky PEG groups on the surface of the lipo can be prepared using appropriate combinations of lipids, some or lipid carrier and prevents binding of DNA to the targeting groups and circulation enhancers. Additionally, the outside of the carrier (thereby inhibiting cross-linking and compositions provided herein can be in the form of liposomes aggregation of the lipid carrier). The use of a PEG-ceramide or lipid particles, preferably lipid particles. As used herein, is often preferred and has the additional advantages of stabi the term “lipid particle' refers to a lipid bilayer carrier which lizing membrane bilayers and lengthening circulation life "coats a nucleic acid and has little or no aqueous interior. times. Additionally, PEG-ceramides can be prepared with More particularly, the term is used to describe a self-assem different lipid tail lengths to control the lifetime of the PEG bling lipid bilayer carrier in which a portion of the interior ceramide in the lipid bilayer. In this manner, “programmable' layer comprises cationic lipids which form ionic bonds or release can be accomplished which results in the control of ion-pairs with negative charges on the nucleic acid (e.g., a lipid carrier fusion. For example, PEG-ceramides having plasmid phosphodiester backbone). The interior layer can C20-acyl groups attached to the ceramide moiety will diffuse also comprise neutral or fusogenic lipids and, in some out of a lipid bilayer carrier with a half-life of 22 hours. embodiments, negatively charged lipids. The outer layer of PEG-ceramides having C14- and C8-acyl groups will diffuse the particle will typically comprise mixtures of lipids oriented out of the same carrier with half-lives of 10 minutes and less in a tail-to-tail fashion (as in liposomes) with the hydrophobic than 1 minute, respectively. As a result, selection of lipid tail tails of the interior layer. The polar head groups present on the length provides a composition in which the bilayer becomes lipids of the outer layer will form the external surface of the destabilized (and thus fusogenic) at a known rate. Though less particle. preferred, other PEG-lipids or lipid-polyoxyethylene conju 0580 Liposomal bioactive agents can be designed to have gates are useful in the present compositions. Examples of a Sustained therapeutic effect or lower toxicity allowing less suitable PEG-modified lipids include PEG-modified phos frequent administration and an enhanced therapeutic index. phatidylethanolamine and phosphatidic acid, PEG-modified Liposomes are composed of bilayers that entrap the desired diacylglycerols and dialkylglycerols, PEG-modified dialky pharmaceutical. These can be configured as multilamellar lamines and PEG-modified 1,2-diacyloxypropan-3-amines. vesicles of concentric bilayers with the pharmaceutical Particularly preferred are PEG-ceramide conjugates (e.g., trapped within either the lipid of the different layers or the PEG-Cer-C8, PEG-Cer-C14 or PEG-Cer-C20) which are aqueous space between the layers. described in U.S. Pat. No. 5,820,873, incorporated herein by 0581. By non-limiting example, lipids used in the compo reference. sitions may be synthetic, semi-synthetic or naturally-occur 0583. The compositions of the present invention can be ring lipids, including phospholipids, tocopherols, steroids, prepared to provide liposome compositions which are about fatty acids, glycoproteins such as albumin, negatively 50 nm to about 400 nm in diameter. One with skill in the art charged lipids and cationic lipids. Phosholipids include egg will understand that the size of the compositions can be larger phosphatidylcholine (EPC), egg phosphatidylglycerol or Smaller depending upon the Volume which is encapsulated. (EPG), egg phosphatidylinositol (EPI), egg phosphati Thus, for larger volumes, the size distribution will typically dylserine (EPS), phosphatidylethanolamine (EPE), and egg be from about 80 nm to about 300 nm. phosphatidic acid (EPA); the Soya counterparts, soy phos phatidylcholine (SPC): SPG, SPS, SPI, SPE, and SPA; the Surface Modifiers hydrogenated egg and Soya counterparts (e.g., HEPC, 0584 Pirfenidone or pyridone analog compounds dis HSPC), other phospholipids made up of ester linkages offatty closed herein may be prepared in a pharmaceutical composi US 2015/O 196543 A1 Jul. 16, 2015

tion with suitable surface modifiers which may be selected cocamidopropyl betaine, cocamidopropylamine oxide, coca from known organic and inorganic pharmaceutical excipi mide MEA, DEA lauryl sulfate, di-stearyl phthalic acid ents. Such excipients include low molecular weight oligo amide, dicetyl dimethyl ammonium chloride, dipalmitoyl mers, polymers, Surfactants and natural products. Preferred ethyl hydroxethylmonium, disodium laureth SulfoSuccinate, Surface modifiers include nonionic and ionic Surfactants. Two di(hydrogenated) tallow phthalic acid, glyceryl dilaurate, or more Surface modifiers can be used in combination. glyceryl distearate, glyceryl oleate, glyceryl Stearate, isopro 0585 Representative examples of surface modifiers pyl myristate inf, isopropyl palmitate inf, lauramide DEA, include cetyl pyridinium chloride, gelatin, casein, lecithin lauramide MEA, lauramide oxide, myristamine oxide, octyl (phosphatides), dextran, glycerol, gum acacia, cholesterol, isononanoate, octyl palmitate, octyldodecyl neopentanoate, tragacanth, Stearic acid, benzalkonium chloride, calcium olealkonium chloride, PEG-2 stearate, PEG-32 glyceryl Stearate, glycerol monostearate, cetostearyl alcohol, caprylate/caprate, PEG-32 glyceryl Stearate, PEG-4 and cetomacrogol emulsifying wax, Sorbitan esters, polyoxyeth PEG-150 stearate & distearate, PEG-4 to PEG-150 laurate & ylene alkyl ethers (e.g., macrogol ethers such as cetomac dilaurate, PEG-4 to PEG-150 oleate & dioleate, PEG-7 glyc rogol 1000), polyoxyethylene castor oil derivatives, polyoxy eryl cocoate, PEG-8 beeswax, propylene glycol stearate, ethylene Sorbitan fatty acid esters (e.g., the commercially sodium C14-16 olefin sulfonate, sodium lauryl sulfoacetate, available TweensTM, such as e.g., Tween 20TM, and Tween Sodium lauryl Sulphate, sodium trideceth Sulfate, Stearalko 80TM, (ICISpecialty Chemicals)); polyethylene glycols (e.g., nium chloride, stearamide oxide, TEA-dodecylbenzene sul Carbowaxs 3350TM, and 1450TM, and Carbopol 934TM, fonate, TEA lauryl sulfate (Union Carbide)), dodecyl trimethyl ammonium bromide, 0587 Most of these surface modifiers are known pharma polyoxyethylenestearates, colloidal silicon dioxide, phos ceutical excipients and are described in detail in the Hand phates, Sodium dodecylsulfate, carboxymethylcellulose cal book of Pharmaceutical Excipients, published jointly by the cium, hydroxypropyl cellulose(HPC, HPC-SL, and HPC-L), American Pharmaceutical Association and The Pharmaceu hydroxypropyl methylcellulose (HPMC), carboxymethylcel tical Society of Great Britain (The Pharmaceutical Press, lulose sodium, methylcellulose, hydroxyethylcellulose, 1986), specifically incorporated by reference. The surface hydroxypropylcellulose, hydroxypropylmethyl-cellulose modifiers are commercially available and/or can be prepared phthalate, noncrystalline cellulose, magnesium aluminum by techniques known in the art. The relative amount of drug silicate, triethanolamine, polyvinyl alcohol (PVA), polyvi and Surface modifier can vary widely and the optimal amount nylpyrrolidone (PVP), 4-(1,1,3,3-tetaamethylbutyl)-phenol of the Surface modifier can depend upon, for example, the polymer with ethylene oxide and formaldehyde (also known particular drug and Surface modifier selected, the critical as tyloxapol, Superione, and triton), poloxamers (e.g., Pluron micelle concentration of the surface modifier if it forms ics F68TM, and F108TM, which are block copolymers of eth micelles, the hydrophilic-lipophilic-balance (HLB) of the ylene oxide and propylene oxide); poloxamnines (e.g., surface modifier, the melting point of the surface modifier, the Tetronic 908TM, also known as Poloxamine 908TM, which is a water solubility of the surface modifier and/or drug, the sur tetrafunctional block copolymer derived from sequential face tension of water solutions of the surface modifier, etc. addition of propylene oxide and ethylene oxide to ethylene 0588. In the present invention, the optimal ratio of drug to diamine (BASF Wyandotte Corporation, Parsippany, N.J.)); a surface modifier is -0.1% to ~99.9% pirfenidone or pyridone charged phospholipid such as dimyristoyl phophatidylglyc analog compound, more preferably about 10% to about 90%. erol, dioctylsulfosuccinate (DOSS); Tetronic 1508TH: (T-1508) (BASF Wyandotte Corporation), dialkylesters of Microspheres sodium sulfosuccinic acid (e.g., Aerosol OTTM, which is a 0589 Microspheres can be used for pulmonary delivery of dioctyl ester of sodium sulfoSuccinic acid (American Cyana pirfenidone or pyridone analog compounds by first adding an mid)); Duponol PTM, which is a sodium lauryl sulfate (Du appropriate amount of drug compound to be solubilzed in Pont); Tritons X-200TM, which is an alkyl aryl polyether water. For example, an aqueous pirfenidone or pyridone ana sulfonate (Rohm and Haas); Crodestas F-110TM, which is a log compound solution may be dispersed in methylene chlo mixture of Sucrose Stearate and Sucrose distearate (Croda ride containing a predetermined amount (0.1-1% w/v) of Inc.); p-isononylphenoxypoly-(glycidol), also known as poly(DL-lactide-co-glycolide) (PLGA) by probe sonication Olin-logTM, or Surfactant 10-GTM, (Olin Chemicals, Stam for 1-3 min on an ice bath. Separately, a pirfenidone or pyri ford, Conn.); Crodestas SL-40TM, (Croda, Inc.); and done analog compound may be solubilized in methylene SA9CHCO, which is C8H, CH (CON(CH) CH chloride containing PLGA (0.1-1% w/v). The resulting (CHOH) (CHOH), (Eastman Kodak Co.); decanoyl-N-me water-in-oil primary emulsion or the polymer/drug Solution thylglucamide; n-decyl B-D-glucopyranoside; n-decyl B-D- will be dispersed in an aqueous continuous phase consisting maltopyranoside; n-dodecyl B-D-glucopyranoside; n-dode of 1-2% polyvinyl alcohol (previously cooled to 4°C.) by cyl B-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl probe sonication for 3-5 min on an ice bath. The resulting B-D-glucopyranoside; n-heptyl B-D-thioglucoside; n-hexyl emulsion will be stirred continuously for 2-4 hours at room B-D-glucopyranoside; nonanoyl-N-methylglucamide; temperature to evaporate methylene chloride. Microparticles n-noyl B-D-glucopyranoside; octanoyl-N-methylglucar thus formed will be separated from the continuous phase by mide; n-octyl-B-D-glucopyranoside; octyl B-D-thioglucopy centrifuging at 8000-10000 rpm for 5-10 min. Sedimented ranoside; and the like. Tyloxapol is a particularly preferred particles will be washed thrice with distilled water and freeze surface modifier for the pulmonary or intranasal delivery of dried. Freeze-dried pirfenidone or pyridone analog com steroids, even more so for nebulization therapies. pound microparticles will be stored at -20°C. 0586 Examples of surfactants for use in the solutions 0590. By non-limiting example, a spray drying approach disclosed herein include, but are not limited to, ammonium will be employed to prepare pirfenidone or pyridone analog laureth Sulfate, cetamine oxide, cetrimonium chloride, cetyl compound microspheres. An appropriate amount of pirfeni alcohol, cetyl myristate, cetyl palmitate, cocamide DEA, done or pyridone analog compound will be solubilized in US 2015/O 196543 A1 Jul. 16, 2015 methylene chloride containing PLGA (0.1-1%). This solution sion process is an optimized version of the hot melt method. will be spray dried to obtain the microspheres. The advantage of the melt-extrusion approach is lack of 0591. By non-limiting example, pirfenidone or pyridone organic solvent and continuous production process. As the analog compound microparticles will be characterized for melt-extrusion is a novel pharmaceutical technique, the lit size distribution (requirement: 90%.<5 um, 95%.<10 um), erature dealing with it is limited. The technical set-up shape, drug loading efficiency and drug release using appro involves a mixture and extrusion of pirfenidone or pyridone priate techniques and methods. analog compound, hydroxypropyl-b-cyclodextrin (HP-b- 0592. By non-limiting example, this approach may also be CD), and hydroxypropylmethylcellulose (HPMC), in order used to sequester and improve the water solubility of solid, to, by non-limiting example create a AUC shape-enhancing AUC shape-enhancing formulations, such as low-solubility formulation of pirfenidone or pyridone analog compound. pirfenidone or pyridone analog compounds or salt forms for Cyclodextrin is a toroidal-shaped molecule with hydroxyl nanoparticle-based formulations. groups on the outer Surface and a cavity in the center. Cyclo 0593. A certain amount of pirfenidone or pyridone analog dextrinsequesters the drug by forming an inclusion complex. compound can be first dissolved in the minimal quantity of The complex formation between cyclodextrins and drugs has ethanol 96% necessary to maintain the fluoroquinolnoe in been investigated extensively. It is known that water-soluble solution when diluted with water from 96 to 75%. This solu polymer interacts with cyclodextrin and drug in the course of tion can then be diluted with water to obtain a 75% ethanol complex formation to form a stabilized complex of drug and Solution and then a certain amount of paracetamol can be cyclodextrin co-complexed with the polymer. This complex added to obtain the following w/w drug/polymer ratios: 1:2. is more stable than the classic cyclodextrin-drug complex. As 1:1, 2:1, 3:1, 4:1, 6:1, 9:1, and 19:1. These final solutions are one example, HPMC is water soluble; hence using this poly spray-dried under the following conditions: feed rate, 15 mer with HP-b-CD in the melt is expected to create an aque mL/min: inlet temperature, 110° C.; outlet temperature, 85° ous soluble AUC shape-enhancing formulation. By non-lim C.; pressure 4 bar and throughput of drying air, 35 m3/hr. iting example, this approach may also be used to sequester Powder is then collected and stored under vacuum in a dess and improve the water solubility of solid, AUC shape-enhanc iccator. ing formulations, such as low-solubility pirfenidone or pyri done analog compounds or salt forms for nanoparticle-based Solid Lipid Particles formulations. 0594 Preparation of pirfenidone or pyridone analog com Co-Precipitates pound Solid lipid particles may involve dissolving the drug in a lipid melt (phospholipids such as phophatidylcholine and 0596 Co-precipitate pirfenidone or pyridone analog com phosphatidyl serine) maintained at least at the melting tem pound formulations may be prepared by formation of co perature of the lipid, followed by dispersion of the drug precipitates with pharmacologically inert, polymeric materi containing meltina hot aqueous Surfactant Solution (typically als. It has been demonstrated that the formation of molecular 1-5% w/v) maintained at least at the melting temperature of Solid dispersions or co-precipitates to create an AUC shape the lipid. The coarse dispersion will be homogenized for 1-10 enhancing formulations with various water-soluble polymers minusing a Microfluidizer R to obtain a nanoemulsion. Cool can significantly slow their in vitro dissolution rates and/or in ing the nanoemulsion to a temperature between 4-25°C. will Vivo absorption. In preparing powdered products, grinding is re-solidify the lipid, leading to formation of solid lipid nano generally used for reducing particle size, since the dissolution particles. Optimization of formulation parameters (type of rate is strongly affected by particle size. Moreover, a strong lipid matrix, Surfactant concentration and production param force (Such as grinding) may increase the Surface energy and eters) will be performed so as to achieve a prolonged drug cause distortion of the crystal lattice as well as reducing delivery. By non-limiting example, this approach may also be particle size. Co-grinding drug with hydroxypropylmethyl used to sequester and improve the water solubility of solid, cellulose, b-cyclodextrin, chitin and chitosan, crystalline cel AUC shape-enhancing formulations, such as low-solubility lulose, and gelatin, may enhance the dissolution properties pirfenidone or pyridone analog compounds or salt forms for such that AUC shape-enhancement is obtained for otherwise nanoparticle-based formulations. readily bioavailable pirfenidone or pyridone analog com pounds. By non-limiting example, this approach may also be Melt-Extrusion AUC Shape-Enhancing Formulation used to sequester and improve the water solubility of solid, AUC shape-enhancing formulations, such as low-solubility 0595 Melt-Extrusion AUC shape-enhancing pirfenidone pirfenidone or pyridone analog compounds or salt forms for or pyridone analog compound formulations may be prepara nanoparticle-based formulations. tion by dissolving the drugs in micelles by adding Surfactants or preparing micro-emulsion, forming inclusion complexes Dispersion-Enhancing Peptides with other molecules Such as cyclodextrins, forming nano particles of the drugs, or embedding the amorphous drugs in 0597 Compositions may include one or more di- or trip a polymer matrix. Embedding the drug homogeneously in a eptides containing two or more leucine residues. By further polymer matrix produces a solid dispersion. Solid dispersions non-limiting example, U.S. Pat. No. 6,835,372 disclosing can be prepared in two ways: the solvent method and the hot dispersion-enhancing peptides, is hereby incorporated by ref melt method. The solvent method uses an organic Solvent erence in its entirety. This patent describes the discovery that wherein the drug and appropriate polymer are dissolved and di-leucyl-containing dipeptides (e.g., dileucine) and tripep then (spray) dried. The major drawbacks of this method are tides are superior in their ability to increase the dispersibility the use of organic solvents and the batch mode production of powdered composition. process. The hot melt method uses heat in order to disperse or 0598. In another embodiment, highly dispersible particles dissolve the drug in an appropriate polymer. The melt-extru including an amino acid are administered. Hydrophobic US 2015/O 196543 A1 Jul. 16, 2015

amino acids are preferred. Suitable amino acids include natu teine, methionine, Valine, leucine, tyosine, isoleucine, pheny rally occurring and non-naturally occurring hydrophobic lalanine, tryptophan. Preferred hydrophobic amino acids amino acids. Some naturally occurring hydrophobic amino include leucine, isoleucine, alanine, Valine, phenylalanine acids, including but not limited to, non-naturally occurring and glycine. Combinations of hydrophobic amino acids can amino acids include, for example, beta-amino acids. Both D. also be employed. Furthermore, combinations of hydropho Land racemic configurations of hydrophobic amino acids can bic and hydrophilic (preferentially partitioning in water) be employed. Suitable hydrophobic amino acids can also amino acids, where the overall combination is hydrophobic, include amino acid analogs. As used herein, an amino acid can also be employed. analog includes the D or L configuration of an amino acid 0603 The amino acid can be present in the particles of the having the following formula: —NH CHR CO . invention in an amount of at least 10 weight%. Preferably, the wherein R is an aliphatic group, a Substituted aliphatic group, amino acid can be present in the particles in an amount rang a benzyl group, a Substituted benzyl group, an aromatic group ing from about 20 to about 80 weight%. The salt of a hydro or a Substituted aromatic group and wherein R does not cor phobic amino acid can be present in the particles of the respond to the side chain of a naturally-occurring amino acid. invention in an amount of at least 10 weight percent. Prefer As used herein, aliphatic groups include straight chained, ably, the amino acid salt is present in the particles in an branched or cyclic C1-C8 hydrocarbons which are com amount ranging from about 20 to about 80 weight %. In pletely saturated, which contain one or two heteroatoms Such preferred embodiments the particles have a tap density of less as nitrogen, oxygen or Sulfur and/or which contain one or than about 0.4 g/cm3. more units of desaturation. Aromatic groups include carbocy 0604 Methods of forming and delivering particles which clic aromatic groups such as phenyl and naphthyl and hetero include an amino acid are described in U.S. Pat. No. 6,586, cyclic aromatic groups such as imidazolyl, indolyl, thienyl, 008, entitled Use of Simple Amino Acids to Form Porous furanyl, pyridyl, pyranyl, oxazolyl, benzothienyl, benzofura Particles During Spray Drying, the teachings of which are nyl, quinolinyl, isoquinolinyl and acridinty1. incorporated herein by reference in their entirety. 0599 Suitable substituents on an aliphatic, aromatic or benzyl group include —OH, halogen (—Br. —Cl. —I and Proteins/Amino Acids —F)—O (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group), —CN, NO, 0605 Protein excipients may include albumins such as —COOH, -NH. NH (aliphatic group, substituted ali human serum albumin (HSA), recombinant human albumin phatic, benzyl, substituted benzyl, aryl or substituted aryl (rHA), gelatin, casein, hemoglobin, and the like. Suitable group), —N(aliphatic group, Substituted aliphatic, benzyl, amino acids (outside of the dileucyl-peptides of the inven substituted benzyl, aryl or substituted aryl group), —COO tion), which may also function in a buffering capacity, include (aliphatic group, Substituted aliphatic, benzyl, Substituted alanine, glycine, arginine, betaine, histidine, glutamic acid, benzyl, aryl or substituted aryl group), —CONH – CONH aspartic acid, cysteine, lysine, leucine, isoleucine, Valine, (aliphatic, Substituted aliphatic group, benzyl, Substituted methionine, phenylalanine, aspartame, tyrosine, tryptophan, benzyl, aryl or Substituted aryl group)). —SH, -S (aliphatic, and the like. Preferred are amino acids and polypeptides that substituted aliphatic, benzyl, substituted benzyl, aromatic or function as dispersing agents. Amino acids falling into this substituted aromatic group) and—NH CO.dbd.NH) NH. category include hydrophobic amino acids such as leucine, A substituted benzylic or aromatic group can also have an Valine, isoleucine, tryptophan, alanine, methionine, phenyla aliphatic or Substituted aliphatic group as a Substituent. A lanine, tyrosine, histidine, and proline. Dispersibility-en Substituted aliphatic group can also have a benzyl, Substituted hancing peptide excipients include dimers, trimers, tetram benzyl, aryl or Substituted aryl group as a Substituent. A ers, and pentamers comprising one or more hydrophobic substituted aliphatic, substituted aromatic or substituted ben amino acid components such as those described above. Zyl group can have one or more Substituents. Modifying an Carbohydrates amino acid substituent can increase, for example, the lypo philicity or hydrophobicity of natural amino acids which are 0606. By non-limiting example, carbohydrate excipients hydrophilic. may include monosaccharides Such as fructose, maltose, 0600. A number of the suitable amino acids, amino acids galactose, glucose, D-mannose, Sorbose, and the like; disac analogs and salts thereof can be obtained commercially. Oth charides, such as lactose, Sucrose, trehalose, cellobiose, and ers can be synthesized by methods known in the art. the like; polysaccharides, such as raffinose, melezitose, mal 0601 Hydrophobicity is generally defined with respect to todextrins, dextrans, starches, and the like; and alditols. Such the partition of an amino acid between a nonpolar solvent and as mannitol. Xylitol, maltitol, lactitol. Xylitol Sorbitol (gluci water. Hydrophobic amino acids are those acids which show tol), pyranosyl Sorbitol, myoinositol, isomalt, trehalose and a preference for the nonpolar solvent. Relative hydrophobic the like. ity of amino acids can be expressed on a hydrophobicity Scale on which glycine has the value 0.5. On Such a scale, amino Polymers acids which have a preference for water have values below 0.5 0607. By non-limiting example, compositions may also and those that have a preference for nonpolar solvents have a include polymeric excipients/additives, e.g., polyvinylpyr value above 0.5. As used herein, the term hydrophobic amino rolidones, derivatized celluloses such as hydroxymethylcel acid refers to an amino acid that, on the hydrophobicity scale, lulose, hydroxyethylcellulose, and hydroxypropylmethylcel has a value greater or equal to 0.5, in other words, has a lulose, Ficols (a polymeric Sugar), hydroxyethylstarch, tendency to partition in the nonpolar acid which is at least dextrates (by non-limiting example cyclodextrins may equal to that of glycine. include, 2-hydroxypropyl-beta-cyclodextrin, 2-hydroxypro 0602 Examples of amino acids which can be employed pyl-gamma-cyclodextrin, randomly methylated beta-cyclo include, but are not limited to:glycine, proline, alanine, cys dextrin, dimethyl-alpha-cyclodextrin, dimethyl-beta-cyclo US 2015/O 196543 A1 Jul. 16, 2015 dextrin, maltosyl-alpha-cyclodextrin, glucosyl-1-alpha commonly it can be present in the particles in an amount cyclodextrin, glucosyl-2-alpha-cyclodextrin, alpha ranging from about 10 to about 60 weight%. cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and 0.614. In another embodiment of the invention, the phos sulfobutylether-beta-cyclodextrin), polyethylene glycols, pholipids or combinations thereofare selected to impart con and pectin may also be used. trolled release properties to the highly dispersible particles. 0608 Highly dispersible particles administered comprise The phase transition temperature of a specific phospholipid a bioactive agent and a biocompatible, and preferably biode can be below, about or above the physiological body tempera gradable polymer, copolymer, or blend. The polymers may be ture of a patient. Preferred phase transition temperatures tailored to optimize different characteristics of the particle range from 30 degrees C. to 50 degrees C. (e.g., within +/-10 including: i) interactions between the agent to be delivered degrees of the normal body temperature of patient). By select and the polymer to provide stabilization of the agent and ing phospholipids or combinations of phospholipids accord retention of activity upon delivery; ii) rate of polymer degra ing to their phase transition temperature, the particles can be dation and, thereby, rate of drug release profiles; iii) Surface tailored to have controlled release properties. For example, by characteristics and targeting capabilities via chemical modi administering particles which include a phospholipid or com fication; and iv) particle porosity. bination of phospholipids which have a phase transition tem 0609 Surface eroding polymers such as polyanhydrides perature higher than the patient’s body temperature, the may be used to form the particles. For example, polyanhy release of dopamine precursor, agonist or any combination of drides such as poly(p-carboxyphenoxy)hexane anhydride precursors and/or agonists can be slowed down. On the other (PCPH) may be used. Biodegradable polyanhydrides are hand, rapid release can be obtained by including in the par described in U.S. Pat. No. 4,857.311. Bulk eroding polymers ticles phospholipids having lower transition temperatures. Such as those based on polyesters including poly(hydroxy acids) also can be used. For example, polyglycolic acid Taste Masking, Flavor. Other (PGA), polylactic acid (PLA), or copolymers thereof may be 0615. As also described above, pirfenidone or pyridone used to form the particles. The polyester may also have a analog compound formulations disclosed herein and related charged or functionalizable group, such as an amino acid. In compositions, may further include one or more taste-masking a preferred embodiment, particles with controlled release agents such as flavoring agents, inorganic salts (e.g., sodium properties can beformed of poly(D.L-lactic acid) and/or poly chloride), Sweeteners, antioxidants, antistatic agents, Surfac (DL-lactic-co-glycolic acid) (PLGA) which incorporate a tants (e.g., polysorbates such as "TWEEN 20” and "TWEEN surfactant such as dipalmitoyl phosphatidylcholine (DPPC). 80), sorbitan esters, saccharin (e.g., sodium saccharin or 0610. Other polymers include polyamides, polycarbon other saccharin forms, which as noted elsewhere herein may ates, polyalkylenes such as polyethylene, polypropylene, be present in certain embodiments at specific concentrations poly(ethylene glycol), poly(ethylene oxide), poly(ethylene or at specific molar ratios relative to a pyridone analog com terephthalate), polyvinyl compounds such as polyvinyl alco pound Such aspirfenidone), bicarbonate, cyclodextrins, lipids hols, polyvinyl ethers, and polyvinyl esters, polymers of (e.g., phospholipids such as lecithin and other phosphatidyl acrylic and methacrylic acids, celluloses and other polysac cholines, phosphatidylethanolamines), fatty acids and fatty charides, and peptides or proteins, or copolymers or blends esters, Steroids (e.g., cholesterol), and chelating agents (e.g., thereof. Polymers may be selected with or modified to have EDTA, zinc and other such suitable cations). Other pharma the appropriate stability and degradation rates in Vivo for ceutical excipients and/or additives suitable for use in the different controlled drug delivery applications. compositions according to the invention are listed in "Rem 0611 Highly dispersible particles can be formed from ington: The Science & Practice of Pharmacy”, 19" ed., Wil functionalized polyester graft copolymers, as described in liams & Williams, (1995), and in the “Physician’s Desk Ref Hrkach et al., Macromolecules, 28: 4736-4739 (1995); and erence', 52" ed., Medical Economics, Montvale, N.J. Hrkach et al., “Poly(L-Lactic acid-co-amino acid) Graft (1998). Copolymers: A Class of Functional Biodegradable Biomate 0616 By way of non-limiting example, taste-masking rials” in Hydrogels and Biodegradable Polymers for Bioap agents in pirfenidone or pyridone analog compound formu plications, ACS Symposium Series No. 627, Raphael M, lations, may include the use of flavorings, Sweeteners, and Ottenbrite et al., Eds. American Chemical Society, Chapter other various coating strategies, for instance, Sugars such as 8, pp. 93-101, 1996. Sucrose, dextrose, and lactose, carboxylic acids, menthol, 0612. In a preferred embodiment of the invention, highly amino acids or amino acid derivatives such as arginine, dispersible particles including a bioactive agent and a phos lysine, and monosodium glutamate, and/or synthetic flavor pholipid are administered. Examples of Suitable phospholip oils and flavoring aromatics and/or natural oils, extracts from ids include, among others, phosphatidylcholines, phosphati plants, leaves, flowers, fruits, etc. and combinations thereof. dylethanolamines, phosphatidylglycerols, These may include cinnamon oils, oil of wintergreen, pep phosphatidylserines, phosphatidylinositols and combina permint oils, clover oil, bay oil, anise oil, eucalyptus, Vanilla, tions thereof. Specific examples of phospholipids include but citrus oil such as lemon oil, orange oil, grape and grapefruit are not limited to phosphatidylcholines dipalmitoyl phos oil, fruit essences including apple, peach, pear, Strawberry, phatidylcholine (DPPC), dipalmitoyl phosphatidylethanola raspberry, cherry, plum, pineapple, apricot, etc. Additional mine (DPPE), distearoyl phosphatidyicholine (DSPC), Sweeteners include Sucrose, dextrose, aspartame (Nu dipalmitoyl phosphatidylglycerol (DPPG) or any combina traSweet(R), acesulfame-K. Sucralose and Saccharin (e.g., tion thereof. Other phospholipids are known to those skilled Sodium saccharin or other saccharin forms, which as noted in the art. In a preferred embodiment, the phospholipids are elsewhere herein may be present in certain embodiments at endogenous to the lung. specific concentrations or at specific molar ratios relative to a 0613. The phospholipid, can be present in the particles in pyridone analog compound such as pirfenidone), organic an amount ranging from about 0 to about 90 weight%. More acids (by non-limiting example citric acid and aspartic acid). US 2015/O 196543 A1 Jul. 16, 2015

Such flavors may be present at from about 0.05 to about 4 or be administered in Succession with aerosol pirfenidone or percent by weight, and may be present at lower or higher pyridone analog compound therapy. amounts as a factor of one or more of potency of the effect on 0621. The most commonly prescribed agent is N-acetyl flavor, solubility of the flavorant, effects of the flavorant on cysteine (NAC), which depolymerizes mucus in vitro by solubility or other physicochemical orpharmacokinetic prop breaking disulphide bridges between macromolecules. It is erties of other formulation components, or other factors. assumed that Such reduction of sputum tenacity facilitates its 0617. Another approach to improve or mask the unpleas removal from the respiratory tract. In addition, NAC may act ant taste of an inhaled drug may be to decrease the drugs as an oxygen radical scavenger. NAC can be taken either solubility, e.g., drugs must dissolve to interact with taste orally or by inhalation. Differences between these two meth receptors. Hence, to deliver solid forms of the drug may avoid ods of administration have not been formally studied. After the taste response and result in the desired improved taste oral administration, NAC is reduced to cysteine, a precursor affect. Non-limiting methods to decrease solubility of a pir of the antioxidant glutathione, in the liver and intestine. The fenidone or pyridone analog compound solubility are antioxidant properties could be useful in preventing decline described herein, for example, through the use informulation of lung function in cystic fibrosis (CF), chronic obstructive of particular salt forms of pyridone analog compound, Such as pulmonary disease (COPD) or pulmonary fibrotic diseases complexation with Xinafoic acid, oleic acid, Stearic acid and/ (e.g., idiopathic pulmonmary fibrosis). Nebulized NAC is or pamoic acid. Additional co-precipitating agents include commonly prescribed to patients with CF, in particular in dihydropyridines and a polymer Such as polyvinyl pyrroli continental Europe, in order to improve expectoration of spu done. tum by reducing its tenacity. The ultimate goal of this is to 0618. Moreover, taste-masking may be accomplished by slow down the decline of lung function in CF. creation of lipopilic vesicles. Additional coating or capping 0622 L-lysine-N-acetylcysteinate (ACC) or Nacystelyn agents include dextrates (by non-limiting example cyclodex (NAL) is a novel mucoactive agent possessing mucolytic, trins may include, 2-hydroxypropyl-beta-cyclodextrin, 2-hy antioxidant, and anti-inflammatory properties. Chemically, it droxypropyl-gamma-cyclodextrin, randomly methylated is a salt of ACC. This drug appears to present an activity beta-cyclodextrin, dimethyl-alpha-cyclodextrin, dimethyl Superior to its parent molecule ACC because of a synergistic beta-cyclodextrin, maltosyl-alpha-cyclodextrin, glucosyl-1- mucolytic activity of L-lysine and ACC. Furthermore, its alpha-cyclodextrin, glucosyl-2-alpha-cyclodextrin, alpha almost neutral pH (6.2) allows its administration in the lungs cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and with a very low incidence of bronchospasm, which is not the sulfobutylether-beta-cyclodextrin), modified celluloses such case for the acidic ACC(pH 2.2). NAL is difficult to formulate as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, in an inhaled form because the required lung dose is very high hydroxyl propyl methyl cellulose, polyalkylene glycols, (approximately 2 mg) and the micronized drug is sticky and polyalkylene oxides, Sugars and Sugar alcohols, waxes, shel cohesive and it is thus problematic to produce a redispersable lacs, acrylics and mixtures thereof. By non-limiting example, formulation. NAL was first developed as a chlorofluorocar other methods to deliver non-dissolved forms of a pirfenidone bon (CFC) containing metered-dose inhaler (MDI) because or pyridone analog compound according to certain embodi this form was the easiest and the fastest to develop to begin the ments or, in other embodiments, non-dissolved forms of a preclinical and the first clinical studies. NAL MDI delivered pirfenidone or pyridone analog compound, are to administer 2 mg per puff, from which approximately 10% was able to the drug alone or in a simple, non-solubility affecting formu reach the lungs in healthy Volunteers. One major inconve lation, such as a crystalline micronized, dry powder, spray nience of this formulation was patient compliance because as dried, and/or nanosuspension formulation. many as 12 puffs were necessary to obtain the required dose. 0619. An alternative according to certain other preferred Furthermore, the progressive removal of CFC gases from embodiments is to include taste-modifying agents in the pir medicinal products combined with the problems of coordi fenidone or pyridone analog compound formulation. These nation met in a large proportion of the patient population (12) embodiments contemplate including in the formulation a have led to the development of a new galenical form of NAL. taste-masking Substance that is mixed with, coated onto or A dry powder inhaler (DPI) formulation was chosen to otherwise combined with the active medicament pirfenidone resolve the problems of compliance with MDIs and to com orpyridone analog compound or salt thereof. Inclusion of one bine it with an optimal, reproducible, and comfortable way to or more such agents in these formulations may also serve to administer the drug to the widest possible patient population, improve the taste of additional pharmacologically active including young children. compounds that are included in the formulations in addition 0623 The DPI formulation of NAL involved the use of a to the pirfenidone or pyridone analog compound, e.g., a nonconventional lactose (usually reserved for direct com mucolytic agent. Non-limiting examples of Such taste-modi pression of tablets), namely, a roller-dried (RD) anhydrous fying Substances include acid phospholipids, lysophospho B-lactose. When tested in vitro with a monodose DPI device, lipid, tocopherol polyethyleneglycol Succinate, and embonic this powder formulation produces a fine particle fraction acid (pamoate). Many of these agents can be used alone or in (FPF) of at least 30% of the nominal dose, namely three times combination with pirfenidone or pyridone analog compound higher than that with MDIs. This approach may be used in (or a salt thereof) or, in separate embodiments, pirfenidone or combination with a pirfenidone or pyridone analog com pyridone analog compound for aerosol administration. pound for either co-administration or fixed combination Mucolytic Agents therapy. 0624. In addition to mucolytic activity, excessive neutro 0620 Methods to produce formulations that combine phil elastase activity within airways of cystic fibrosis (CF) agents to reduce sputum Viscosity during aerosol treatment patients results in progressive lung damage. Disruption of with a pirfenidone or pyridone analog compound include the disulfide bonds on elastase by reducing agents may modify its following. These agents can be prepared in fixed combination enzymatic activity. Three naturally occurring dithiol reducing US 2015/O 196543 A1 Jul. 16, 2015 systems were examined for their effects on elastase activity: sputum Viscosity, and improved clinical outcome through 1) Escherichia colithioredoxin (Trx) system, 2) recombinant improved pulmonary function (from improved sputum human thioredoxin (rhTrx) system, and 3) dihydrolipoic acid mobility and mucociliary clearance) and decreased lung tis (DHLA). The Trx systems consisted of Trx, Trx reductase, Sue damage from the immune inflammatory response. and NADPH. As shown by spectrophotometric assay of elastase activity, the two Trx systems and DHLA inhibited Characterization of Inhalation Devices purified human neutrophil elastase as well as the elastolytic activity present in the soluble phase (sol) of CF sputum. 0627 The efficiency of a particular inhalation device can Removal of any of the three Trx system constituents pre be measured by many different ways, including an analysis of vented inhibition. Compared with the monothiols N-acetyl pharmacokinetic properties, measurement of lung deposition cysteine and reduced glutathione, the dithiols displayed percentage, measurement of respirable delivery dose (RDD), greater elastase inhibition. To streamline Trx as an investiga a determination of output rates, geometric standard deviation tional tool, a stable reduced form of rhTrx was synthesized values (GSD), and mass median aerodynamic diameter val and used as a single component. Reduced rhTrx inhibited ues (MMAD) among others. purified elastase and CF sputum solelastase without NADPH 0628 Methods and systems for examining a particular or Trx reductase. Because Trx and DHLA have mucolytic inhalation device are known. One such system consists of a effects, we investigated changes in elastase activity after computer means and a hollow cylinder in a pump means with mucolytic treatment. Unprocessed CF sputum was directly a connecting piece to which an inhalation device is to be treated with reduced rhTrx, the Trx system, DHLA, or DNase. connected. In the pump means there is a piston rod, which The Trx system and DHLA did not increase elastase activity, extends out of the hollow cylinder. A linear drive unit can be whereas reduced rhTrx treatment increased solelastase activ activated in Such a manner that one or more breathing pattern ity by 60%. By contrast, the elastase activity after DNase will be simulated on the connecting piece of the pump means. treatment increased by 190%. The ability of Trx and DHLA to In order to be able to carry out the evaluation of the inhalation limit elastase activity combined with their mucolytic effects device, the computer is connected in an advantageous con makes these compounds potential therapies for CF. figuration with a data transmission means. With the aid of the 0625. In addition, bundles of F-actin and DNA present in data transmission means, the computer can be connected with the sputum of cystic fibrosis (CF) patients but absent from another computer with specific data banks, in order to normal airway fluid contribute to the altered viscoelastic exchange the data of breathing patterns. In this manner, a properties of sputum that inhibit clearance of infected airway breathing pattern library which is as representative as pos fluid and exacerbate the pathology of CF. One approach to sible can be very rapidly formed. U.S. Pat. No. 6,106.479 alter these adverse properties is to remove these filamentous discloses this method for examining an inhalation device in aggregates using DNase to enzymatically depolymerize DNA more detail, and is hereby incorporated by reference in its to constituent monomers and gelsolinto sever F-actinto Small entirety. fragments. The high densities of negative surface charge on DNA and F-actin suggest that the bundles of these filaments, Pharmacokinetic Profile which alone exhibit a strong electrostatic repulsion, may be 0629. Pharmacokinetics is concerned with the uptake, dis stabilized by multivalent cations such as histones, antimicro tribution, metabolism and excretion of a drug Substance. A bial peptides, and other positively charged molecules preva pharmacokinetic profile comprises one or more biological lent in airway fluid. Furthermore, as a matter-a-fact, it has measurements designed to measure the absorption, distribu been observed that bundles of DNA or F-actin formed after tion, metabolism and excretion of a drug Substance. One way addition of histone H1 or lysozyme are efficiently dissolved of visualizing a pharmacokinetic profile is by means of a by soluble multivalent anions such as polymeric aspartate or blood plasma concentration curve, which is a graph depicting glutamate. Addition of poly-aspartate or poly-glutamate also mean active ingredient blood plasma concentration on the disperses DNA and actin-containing bundles in CF sputum Y-axis and time (usually in hours) on the X-axis. Some phar and lowers the elastic moduli of these samples to levels com macokinetic parameters that may be visualized by means of a parable to those obtained after treatment with DNase I or blood plasma concentration curve include: gelsolin. Addition of poly-aspartic acid also increased DNase 0630 Cmax: The maximum plasma concentration in a activity when added to samples containing DNA bundles patient. formed with histone H1. When added to CF sputum, poly aspartic acid significantly reduced the growth of bacteria, 0631 AUC: area under the curve Suggesting activation of endogenous antibacterial factors. 0632. TOE: time of exposure These findings Suggest that soluble multivalent anions have 0633 T 1/2: period of time it takes for the amount in a potential alone or in combination with other mucolytic agents patient of drug to decrease by half to selectively dissociate the large bundles of charged biopoly 0634 T.: The time to reach maximum plasma concen mers that form in CF sputum. tration in a patient 0626 Hence, NAC, unfractionated heparin, reduced glu 0635 Pharmacokinetics (PK) is concerned with the time tathione, dithiols, Trx, DHLA, other monothiols, DNAse, course of a therapeutic agent, such as pirfenidone, or a pyri dornase alfa, hypertonic formulations (e.g., osmolalities done analog compound concentration in the body. Pharma greater than about 350 mOsmol/kg), multivalent anions such codynamics (PD) is concerned with the relationship between as polymeric aspartate or glutamate, glycosidases and other pharmacokinetics and efficacy in vivo. PK/PD parameters examples listed above can be combined with pirfenidone or correlate the therapeutic agent, such as exposure with effica pyridone analog compounds and other mucolytic agents for cious activity. Accordingly, to predict the therapeutic efficacy aerosol administration to improve antifibrotic and/or antiin of a therapeutic agent, such as with diverse mechanisms of flammatory activity through better distribution from reduced action different PK/PD parameters may be used. US 2015/O 196543 A1 Jul. 16, 2015

0636 Any standard pharmacokinetic protocol can be used this hypothesis in that this metabolite serves as a marker for to determine blood plasma concentration profile in humans re-circulation of pirfenidone to the lung and other tissues following administration of a formulation comprising pir following direct aerosol administration to the lung. In some fenidone or a pyridone analog compound described herein, embodiments, re-circulated pirfenidone is likely important to and thereby establish whether that formulation meets the Support long-term, elevated pirfenidone levels in the lung and pharmacokinetic criteria set out herein. For example, but in other tissues of potential efficacy. no way limiting, a type of a randomized single-dose crossover study can be utilized using a group of healthy adult human 0642. In some embodiments, the amount of pirfenidone or subjects. The number of subjects can be sufficient to provide pyridone analog compound that is administered to a human adequate control of variation in a statistical analysis, and is by inhalation may be calculated by measuring the amount of typically about 8 or greater, although in certain embodiments pirfenidone or pyridone analog compound and associated a smaller group can be used. In one embodiment, a subject metabolites that are found in the urine. In some embodiments, receives administration, at time Zero, a single dose of a test about 80% of administered pirfenidone is excreted in the inhalation mixture comprising pirfenidone or a pyridone ana urine (with 95% being the primary metabolite, 5-carboxy log compound. Blood samples are collected from each Sub pirfenidone). In some embodiments, the calculation based on ject prior to administration and at several intervals after compound and metabolites in urine may be done through a 48 administration. Plasma can be separated from the blood urine collection (following a single administration), whereby samples by centrifugation and the separated plasma is ana the total amount of pirfenidone or pyridone analog compound lyzed, for example, by a validated high performance liquid delivered to the human is the sum of measured pirfenidone chromatography/tandem weight spectrometry (LC/APCI and its metabolites. By non-limiting example, knowing that MS/MS) procedure such as, for example, those described in 80% of pirfenidone is excreted, a 50 mg sum urinary mea Ramu et al., Journal of Chromatography B, 751:49-59 surement ofpirfenidone and its metabolites would translate to (2001). In other embodiments, data from a single subject may a delivered dose of about 63 mg (50 mg divided by 80%). If by be collected and may be used to construct a pK profile and non-limiting example the inhaled aerosol fine-particle frac may be indicative of an enhanced pharmacokinetic profile. In tion (FPF) is 75%, one may assume that about 75% of the drug still other embodiments, appropriate in vitro models may be deposited in the lung (and about 25% was swallowed, and used to construct a pK profile and may be demonstrate or subsequently absorbed from the gut with 80% excreted in the indicate an enhanced pharmacokinetic profile. urine). Integrating these two calculations, of a 63 mg deliv 0637. In some embodiments, a human pK profile can be ered dose (as measured by urinary excretion), about 47 mg may be obtained by the use of allometric scaling. In one would be the amount of inhaled aerosol pirfenidone delivered embodiment, rat aerosol lung data and plasma delivery is to the lung (the actual RDD; calculated as the product of 63 scaled to provide an indication of possible humans data. In mg and a 75% FPF). This RDD can then be used in a variety one embodiment, allometric scaling uses parameters estab of calculations, including lung tissue concentration. lished in the US FDA Guidance for Industry-Estimating the 0643. In some embodiments, method or systems described Maximum Safe Starting Dose in Initial Clinical Trials for herein provide pharmacokinetic profiles of pirfenidone or Therapeutics in Adult Healthy Volunteers. pyridone analog compounds as described herein. In some 0638 Any aqueous inhalable mixture giving the desired embodiments, method or systems described herein provide pharmacokinetic profile may be suitable for administration pharmacokinetic profiles of pirfenidone or pyridone analog according to the present methods. compounds as in Examples 6 and 7. 0639. As used herein, the “peak period of a pharmaceu ticals in vivo concentration is defined as that time of the 0644. In some embodiments, efficacy of pirfenidone or pharmaceutical dosing interval when the pharmaceutical con pyridone analog compounds in the treatment of pulmonary centration is not less than 50% of its maximum plasma or fibrosis is achieved through repeated administration to a site-of-disease concentration. In some embodiments, “peak human by inhalation. As shown in Examples 6 and 7, admin period’ is used to describe an interval of pirfenidone or a istration of pirfenidone or pyridone analog compounds to a pyridone analog compound dosing. human by inhalation provides higher Cmax levels as com 0640. In some embodiments, when considering treatment pared to oral delivery. In some embodiments, Solutions of of lung diseases, a method or system described herein pro pirfenidone or pyridone analog compounds that are adminis vides at least a two-fold enhancement in pharmacokinetic tered by inhalation provide higher Cmax levels as compared profile for treatment of the lung disease. In some embodi to oral delivery. In some embodiments, the peak period is used ments, the methods and systems described herein provide at to define the optimal dosing schedule of the pirfenidone or least a two-fold enhancement in the lung tissue pharmacoki pyridone analog compound. In some embodiments, Solutions netic profile of pirfenidone or pyridone analog compound as of pirfenidone or pyridone analog compounds are adminis compared to oral administration. tered more than once a week. 0641. In some embodiments, a delayed appearance of 0645 Small intratracheal aerosol doses deliver a rapidly 5-carboxy-pirfenidone (the primary pirfenidone liver eliminated high lung Cmax and low AUC. Human, animal metabolite) has been observed from the methods and systems and in vitro studies all indicate that pirfenidone efficacy is described herein. In some embodiments, rapid elimination of dose responsive (i.e. larger doses correlate with improved pirfenidone from the lung tissue has been observed. Compar efficacy) and Suggest Cmax is a key driver in pirfenidone ing the initial rapid elimination of pirfenidone from the lung efficacy. While lung Cmax appears important for efficacy, tissue and parallel appearance of pirfenidone in the plasma more regular pirfenidone exposure also appears important to Suggest that direct pulmonary administration may be a good enhance this effect. In some embodiments, in the context of route for systemic administration of pirfenidone. The delayed treating lung diseases in a human, more frequent direct-lung appearance of 5-carboxy-pirfenidone metabolite Supports administration of pirfenidone or pyridone analog compound US 2015/O 196543 A1 Jul. 16, 2015 may provide benefit through both repeat high Cmax dosing pound from a dose that is directly administered to the lungs of and providing more regular exposure of the active therapeutic the mammal is at least equivalent to or greater than a lung agent. tissue Cmax of up to 801 mg of an orally administered dosage 0646. In some embodiments, described herein is a method of pirfenidone or pyridone analog compound; and/or b) the for the treatment of lung disease in a mammal comprising blood AUCo. of pirfenidone or pyridone analog compound administering directly to the lungs of the mammal in need from a dose that is directly administered to the lungs of the thereof pirfenidone or a pyridone analog compound on a mammal is less than or equivalent to the blood AUCo. of up continuous dosing schedule, wherein the observedlung tissue to 801 mg of an orally administered dosage of pirfenidone or Cmax of a dose of pirfenidone or a pyridone analog com pyridone analog compound. In some embodiments, a) the pound is greater than 0.1 mcg/gram lung tissue. In some lung tissue Cmax of pirfenidone or pyridone analog com embodiments, the observed lung tissue Cmax from a dose of pound from a dose that is directly administered to the lungs of pirfenidone or a pyridone analog compound is greater than the mammal is at least equivalent to or greater than a lung 0.5 mcg/gram lung tissue. In some embodiments, the tissue Cmax of up to 801 mg of an orally administered dosage observed lung tissue Cmax from a dose of pirfenidone or a of pirfenidone or pyridone analog compound; and b) the pyridone analog compound is greater than 1.0mcg/gram lung blood AUCo. of pirfenidone or pyridone analog compound tissue. In some embodiments, the observed lung tissue Cmax from a dose that is directly administered to the lungs of the from a dose of pirfenidone or a pyridone analog compound is mammal is less than or equivalent to the blood AUCo. of up greater than 5 mcg/gram lung tissue. In some embodiments, to 801 mg of an orally administered dosage of pirfenidone or the observed lung tissue Cmax from a dose of pirfenidone or pyridone analog compound. In some embodiments, a) the a pyridone analog compound is greater than 10 mcg/gram lung tissue Cmax of pirfenidone or pyridone analog com lung tissue. In some embodiments, the observed lung tissue pound from a dose that is directly administered to the lungs of Cmax from a dose of pirfenidone or a pyridone analog com the mammal is at least equivalent to or greater than a lung pound is greater than 15 mcg/gram lung tissue. In some tissue Cmax of up to 801 mg of an orally administered dosage embodiments, the observed lung tissue Cmax from a dose of of pirfenidone or pyridone analog compound; or b) the blood pirfenidone or a pyridone analog compound is greater than 20 AUC of pirfenidone or pyridone analog compound from a mcg/gram lung tissue. In some embodiments, the observed dose that is directly administered to the lungs of the mammal lung tissue Cmax from a dose of pirfenidone or a pyridone is less than or equivalent to the bloodAUCo. of up to 801 mg analog compound is greater than 25 mcg/gram lung tissue. In of an orally administered dosage of pirfenidone or pyridone some embodiments, the observed lung tissue Cmax from a analog compound. In some embodiments, the dose comprises dose of pirfenidone or a pyridone analog compound is greater an aqueous solution of pirfenidone or a pyridone analog.com than 30 mcg/gram lung tissue. In some embodiments, the pound. In some embodiments, the dose is administered with a observed lung tissue Cmax from a dose of pirfenidone or a liquid nebulizer. In some embodiments, the pirfenidone or a pyridone analog compound is greater than 35 mcg/gram lung pyridone analog compound is administered more than once a tissue. In some embodiments, the observed lung tissue Cmax week. In some embodiments, the single doses of pirfenidone from a dose of pirfenidone or a pyridone analog compound is or a pyridone analog compound is administered more than greater than 40 mcg/gram lung tissue. In some embodiments, once a week, more than twice a week, more than three times the observed lung tissue Cmax from a dose of pirfenidone or a week, more than four times a week, more than five times a a pyridone analog compound is greater than 45 mcg/gram week more than six times a week or daily. In some embodi lung tissue. In some embodiments, the observed lung tissue ments, the pirfenidone or a pyridone analog compound is Cmax from a dose of pirfenidone or a pyridone analog com administered on a continuous daily dosing schedule. In some pound is greater than 50 mcg/gram lung tissue. In some embodiments, the pirfenidone or a pyridone analog com embodiments, the dose comprises an aqueous Solution of pound is administered once a day, twice a day, or three times pirfenidone or a pyridone analog compound. In some a day. embodiments, the dose is administered with a liquid nebu lizer. In some embodiments, the pirfenidone or a pyridone Methods of Dosing and Treatment Regimens analog compound is administered more than once a week. In 0648. In one aspect, pirfenidone or a pyridone analog Some embodiments, the pirfenidone or a pyridone analog compound is administered daily to humans in need of therapy compound is administered on a continuous daily dosing with pirfenidone or a pyridone analog compound. In some schedule. In some embodiments, the single doses of pirfeni embodiments, pirfenidone or a pyridone analog compound is done or a pyridone analog compound is administered more administered by inhalation to the human. In some embodi than once a week, more than twice a week, more than three ments, pirfenidone or a pyridone analog compound is admin times a week, more than four times a week, more than five istered once-a-day. In some embodiments, pirfenidone or a times a week more than six times a week or daily. In some pyridone analog compound is administered twice-a-day. In embodiments, the pirfenidone or a pyridone analog com Some embodiments, pirfenidone or a pyridone analog com pound is administered on a continuous daily dosing schedule. pound is administered three times-a-day. In some embodi In some embodiments, the pirfenidone or a pyridone analog ments, pirfenidone or a pyridone analog compound is admin compound is administered once a day, twice a day, or three istered every other day. In some embodiments, pirfenidone or times a day. a pyridone analog compound is administered twice a week. 0647. In some embodiments, described herein is a method 0649. In general, doses of pirfenidone or a pyridone ana for the treatment of lung disease in a mammal comprising log compound employed for treatment of the diseases or administering directly to the lungs of the mammal in need conditions described herein in humans are typically in the thereof pirfenidone or a pyridone analog compound on a range of from about 0.001 mg to about 10 mg pirfenidone/kg continuous dosing schedule. In some embodiments, a) the of body weigh per dose. In one embodiment, the desired dose lung tissue Cmax of pirfenidone or pyridone analog com is conveniently presented in a single dose or in divided doses US 2015/O 196543 A1 Jul. 16, 2015

administered simultaneously (or over a short period of time) embodiments, daily administration is three times a day. In or at appropriate intervals, for example as two, three, four or Some embodiments, daily administration is more than three more Sub-doses per day. In some embodiments, pirfenidone times a day. or a pyridone analog compound is conveniently presented in 0652 The term “continuous daily dosing schedule” refers divided doses that are administered simultaneously (or over a to the administration of a particular therapeutic agent every short period of time) once a day. In some embodiments, day at roughly the same time each day. In some embodiments, pirfenidone or a pyridone analog compound is conveniently daily administration is once a day. In some embodiments, presented in divided doses that are administered in equal daily administration is twice a day. In some embodiments, portions twice-a-day. daily administration is three times a day. In some embodi 0650. In some embodiments, pirfenidone or a pyridone ments, daily administration is more than three times a day. analog compound is administered by inhalation daily to the 0653. In some embodiments, the amount of pirfenidone or human. In some embodiments, pirfenidone or a pyridone a pyridone analog compound is administered once-a-day. In analog compound is administered orally to the human at a Some other embodiments, the amount of pirfenidone or a dose from about 0.001 mg to about 10 mg pirfenidone/kg of pyridone analog compound is administered twice-a-day. In body weigh per dose. In some embodiments, pirfenidone or a Some other embodiments, the amount of pirfenidone or a pyridone analog compound is administered by inhalation to pyridone analog compound is administered three times a day. the human on a continuous daily dosing schedule. 0654. In certain embodiments wherein improvement in the status of the disease or condition in the human is not 0651. The term “continuous dosing schedule” refers to the observed, the daily dose of pirfenidone or a pyridone analog administration of a particular therapeutic agent at regular compound is increased. In some embodiments, a once-a-day intervals. In some embodiments, continuous dosing schedule dosing schedule is changed to a twice-a-day dosing schedule. refers to the administration of a particular therapeutic agent at In some embodiments, a three times a day dosing schedule is regular intervals without any drug holidays from the particu employed to increase the amount of pirfenidone or a pyridone lar therapeutic agent. In some other embodiments, continuous analog compound that is administered. In some embodi dosing schedule refers to the administration of a particular ments, the frequency of administration by inhalation is therapeutic agent in cycles. In some other embodiments, con increased in order to provide repeat high Cmax levels on a tinuous dosing schedule refers to the administration of a more regular basis. In some embodiments, the frequency of particular therapeutic agent in cycles of drug administration administration by inhalation is increased in order to provide followed by a drug holiday (for example, a wash out period or maintained or more regular exposure to pirfenidone. In some other such period of time when the drug is not administered) embodiments, the frequency of administration by inhalation from the particular therapeutic agent. For example, in some is increased in order to provide repeat high Cmax levels on a embodiments the therapeutic agent is administered once a more regular basis and provide maintained or more regular day, twice a day, three times a day, once a week, twice a week, exposure to pirfenidone. three times a week, four times a week, five times a week, six 0655. In some embodiments, the amount of repeat high times a week, seven times a week, every other day, every third Cmax dosing providing more regular exposure of the active day, every fourth day, daily for a week followed by a week of therapeutic agent that is given to the human varies depends no administration of the therapeutic agent, daily for a two upon factors such as, but not limited to, condition and severity weeks followed by one or two weeks of no administration of of the disease or condition, and the identity (e.g., weight) of the therapeutic agent, daily for three weeks followed by one, the human, and the particular additional therapeutic agents two or three weeks of no administration of the therapeutic that are administered (if applicable). agent, daily for four weeks followed by one, two, three or four weeks of no administration of the therapeutic agent, weekly EXAMPLES administration of the therapeutic agent followed by a week of no administration of the therapeutic agent, or biweekly Example 1 administration of the therapeutic agent followed by two weeks of no administration of the therapeutic agent. In some Pirfenidone Formulations embodiments, daily administration is once a day. In some 0656. Non-limiting examples of compositions of pirfeni embodiments, daily administration is twice a day. In some done include those described in Table 1-1 through Table 1-11. TABLE 1-1 Ingredient and Amount Phosphate Buffer Phosphate Buffer Citrate Buffer Sodium Magnesium Composition (sodium salt), (sodium salt), (acidsodium salt), Chloride Chloride lO. Pirfenidone pH 6.2 (mM) pH 7.3 (mM) pH 5.8 (mM) (Imols) (Imols) Water 1 1 mg to 500 mg O.O1 mM to 500 nM q.S. to (5 Imols 5 mL. to 3 mmols) 2 1 mg to 500 mg O.O1 mM to 500 mM q.S. to (5 Imols 5 mL. to 3 mmols) 3 1 mg to 500 mg O.O1 mM to SOO mM q.S. to (5 Imols 5 mL. to 3 mmols) 4 54 Imols O.O1 to 500 150 q.S. to 5 mL.

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TABLE 1-3 Ingredient and Amount Phosphate Buffer Phosphate Buffer Citrate Buffer (monobasic dibasic (monobasic dibasic Saccharin Composition (acidsodium salt), sodium salts), pH 6.2 sodium salts), pH 7.3 (sodium salt) lO. Pirfenidone pH 5.8 (mM) (mM) (mM) (mM) Water 32 1 mg to 500 mg O.O1 to SOO 0.01 to 10.0 q.S. to 5 mL (5 Imols to 3 mmols) 33 1 mg to 500 mg O.O1 to 500 0.01 to 10.0 q.S. to 5 mL (5 Imols to 3 mmols) 34 1 mg to 500 mg O.O1 to SOO 0.01 to 10.0 q.S. to 5 mL (5 Imols to 3 mmols)

0657. In some embodiments, pirfenidone exhibited aque vations included: 1) Formulations of both buffer systems ous solubility to ~17 mg/mL across a pH range of about 4.0 to exhibited a metallic, bitter flavor and throat irritation; 2) From about 8.0. However, at this (and lower) concentration it was 0.1 to 0.7 mM sodium saccharin was required to taste mask determined that salt addition was required to improve acute these formulations; 3) 0.6 mM sodium saccharin was the best tolerability upon inhalation of a nebulized solution (other concentration and improved the flavor of 2:1 mol ratio pir wise a hypotonic solution). To address tonicity, NaCl or fenidone to magnesium in phosphate buffer more so than the MgCl, were added. In some embodiments, addition of NaCl 1:1 mol ratio; 4) The taste of 2:1 mol ratio pirfenidone to improved acute tolerability, but destabilized the formulation magnesium in citrate buffer without sodium saccharin was and resulted in precipitation upon ambient storage. In some equivalent to the 1:1 mol ratio pirfenidone to magnesium in embodiments, it was determined that addition of MgCl, phosphate buffer with 0.6 mM sodium saccharin; 5) The taste maintained a stable, Soluble solution at this concentration of 2:1 mol ratio pirfenidone to magnesium in citrate buffer with an osmolality in a tolerable range. By non-limiting with 0.2 mM sodium saccharin was equivalent to the 2:1 mol example, 81 mM MgCl, provides a 1:1 mole ratio of magne ratio pirfenidone to magnesium in phosphate buffer with 0.6 sium to pirfenidone where pirfenidone is at 15 mg/mL (or 81 mM sodium saccharin; 6) The taste of 1:1 mol ratio pirfeni mM). This effect was also observed at various pirfenidone done to magnesium in citrate buffer with 0.6 mM sodium concentrations with 1:1 and 1:2 mole ratios of magnesium to saccharin was equivalent to 2:1 mol ratio pirfenidone to mag pirfenidone, but not at ratios less than or equal to 0.25:1 or nesium in phosphate buffer 0.6 mM sodium saccharin; and 7) greater than or equal to 1:0.33 magnesium to pirfenidone, 1:1 mol ratio pirfenidone to magnesium dissolved in up to respectively. This effect was observed in 5 mM to 50 mM 40% the time required to dissolve 2:1 mol ratio pirfenidone to citrate buffer at pH 4.0 and pH 5.8, and 5 mM to 50 mM magnesium in either buffer system at ~pH 6. This effect was phosphate buffer at pH 6.2, pH 7.3 and pH 7.8. Other obser not observed at ~pH 8. TABLE 1-4 Ingredient and Amount Phosphate Buffer Cetylpyridinium (monobasic dibasic Bromide Composition Pirfenidone sodium salts), pH 5.5 Ethanol Propylene Glycerol Polysorbate 80 (or chloride) Osmolality O. (mg) to 8.5 (mM) (% viv) Glycol (% viv) (% viv) (% viv) (%) (mCosmo?kg) Water

35 O O.O1 to SOO 0.001 — SO to C.S. O. 500 to 25 SOOO 5 mL. 36: O O.O1 to SOO O.OO1 SO to C.S. O. 500 to 25 SOOO 5 mL. 37 O O.O1 to SOO O.OO1 SO to C.S. O. 500 to 25 SOOO 5 mL. 38 O O.O1 to SOO O.OOO1 SO to C.S. O. 500 to 1.0 SOOO 5 mL. 39* O O.O1 to SOO O.OOO1 SO to C.S. O. 500 to S.O SOOO 5 mL. 40 O O.O1 to SOO O.OO1 O.OO1 SO to C.S. O. 500 to 25 to 25 SOOO 5 mL. 41 O O.O1 to SOO 0.001 — O.OO1 SO to C.S. O. 500 to 25 to 25 SOOO 5 mL. 42 O O.O1 to SOO 0.001 — O.OOO1 SO to C.S. O. 500 to 25 to 1.0 SOOO 5 mL. 43 O O.O1 to SOO 0.001 — O.OOO1 SO to C.S. O. 500 to 25 to S.O SOOO 5 mL. 44 O O.O1 to SOO O.OO1 O.OO1 O.OO1 SO to C.S. O. 500 to 25 to 25 to 25 SOOO 5 mL. 45 O O.O1 to SOO O.OO1 O.OO1 O.OOO1 SO to C.S. O. 500 to 25 to 25 to 1.0 SOOO 5 mL. 46 O O.O1 to SOO O.OO1 O.OO1 O.OOO1 SO to C.S. O. 500 to 25 to 25 to S.O SOOO 5 mL.

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TABLE 1-7-continued Ingredient and Amount Citrate Buffer Chloride (citric acid ion (sodium, sodium citrate), Propylene Cetylpyridinium magnesium Composition Pirfenidone pH 3.5 to Ethanol Glycol Glycerol Polysorbate Bromide (or or calcium Osmolality lO. (mg) pH 6.5 (mM) (% viv) (% viv) (% viv) 80 (%) chloride) (%) salts) (%) (mCSmokg) Water 94 1 to O.O1 to O.OO1 O.OO1 O.OOO1 O.O1 to 5 SO to C.S. 500 500 to 25 to 25 to S.O SOOO to 5 mL. 95 1 to O.O1 to O.OO1 O.OO1 O.OO1 O.OOO1 O.O1 to 5 SO to C.S. 500 500 to 25 to 25 to 25 to 1.0 SOOO to 5 mL. 96 1 to O.O1 to O.OO1 O.OO1 O.OOO1 O.O1 to 5 SO to C.S. 500 500 to 25 to 25 to 1.0 SOOO to 5 mL. 97 1 to O.O1 to O.OO1 O.OO1 O.OO1 O.OOO1 O.O1 to 5 SO to C.S. 500 500 to 25 to 25 to 25 to S.O SOOO to 5 mL. 98 1 to O.O1 to O.OO1 O.OO1 O.OOO1 O.O1 to 5 SO to C.S. 500 500 to 25 to 25 to S.O SOOO to 5 mL.

TABLE 1-8 Ingredient and Amount Citrate Buffer (citric acid sodium Pirfenidone citrate), pH 4.0 Ethanol Propylenepy Osmolality Composition no. (mg) to pH 5.0 (mM) (% w/v) Glycol (% w/v) (mCSmo/kg) Water 99 O.S9/o 1.0% 2OO to 400 o 5 mL. OO 1.0% 2.0% 400 to 600 o 5 mL. O1 Omg (54 Imols) 1.0% 2.0% 400 to 600 o 5 mL. O2 5 (81 Imols) 1.0% 2.0% 400 to 600 o 5 mL. O3 1.0% 2.0% 400 to 600 o 5 mL. O4 1.0% 2.0% 400 to 600 o 5 mL. (202 Imols) 05 75 mg (405 Imols) 1.0% 2.0% 400 to 600 C S. o 5 mL. O6 00 mg 2.0% 4.0% 900 to 1100 .S. to 5 mL. (541 Imols) 15 mg 4.0% 8.0% 1800 to 2100 .S. to 5 mL. (621 Imols) 50 mg 6.0% 12.0% 1800 to 2100 .S. to 5 mL. (810 Imols) 09 90 mg 8.0% 16.0% 3500 to 3900 .S. to 5 mL. (1027 Imols) 10 220 mg 8.0% 16.0% 36OO to 4000 .S. to 5 mL. (1189 Imols)

TABLE 1-9 Ingredient and Amount Phosphate Buffer (monobasic dibasic Sodium Pirfenidone salts), pH 6.0 to Ethanol Propylene Osmolality Composition no. (mg) pH 7.0 (mM) (% w/v) Glycol (% w/v) (mCosmo?kg) Water

111 5 mg (27 Imols) O.S9/o 1.0% 2OO to 400 C.S. to 5 mL. 112 5 mg (27 Imols) 1.0% 2.0% 2OO to 6OO C.S. to 5 mL. 113 10 mg (54 Imols) 1.0% 2.0% 400 to 600 C.S. to 5 mL. 114 15 (81 Imols) 1.0% 2.0% 400 to 600 C.S. to 5 mL. 115 25 mg (135 Imols) 1.0% 2.0% 400 to 600 C.S. to 5 mL. 116 37.5 mg 1.0% 2.0% 400 to 600 C.S. to 5 mL. (202 Imols) 117 75 mg (405 Imols) 1.0% 2.0% 400 to 600 C.S. to 5 mL. 118 100 mg (541 Imols) 2.0% 4.0% 900 to 1100 C.S. to 5 mL. 119 115 mg (621 Imols) 4.0% 8.0% 1800 to 2100 C.S. to 5 mL. 120 150 mg (810 Imols) 6.0% 12.0% 1800 to 2100 C.S. to 5 mL. 121 190 mg 8.0% 16.0% 3500 to 3900 C.S. to 5 mL. (1027 Imols) US 2015/O 196543 A1 Jul. 16, 2015 94

TABLE 1-9-continued Ingredient and Amount Phosphate Buffer (monobasic dibasic Sodium Pirfenidone salts), pH 6.0 to Ethanol Propylene Osmolality Composition no. (mg) pH 7.0 (mM) (% w/v) Glycol (% w/v) (mCosmo?kg) Water 122 220 mg 5 8.0% 16.0% 3600 to 4000 q.S. to 5 mL (1189 Imols)

TABLE 1-10 Ingredient and Amount Citrate Buffer (citric Chloride ion acid sodium (sodium, citrate), pH 4.0 to Ethanol Propylene Glycol magnesium or Osmolality Composition no. Pirfenidone (mg) pH 5.0 (mM) (% viv) (% viv) calcium salts) (mCSmokg) Water 123 5 mg (27 Imols) 5 O.S9/o 1.0% 0.1% to 0.9% 200 to 500 q.s. to 5 mL. 124 5 mg (27 Imols) 5 1.0% 2.0% 0.1% to 0.9% 400 to 700 q.s. to 5 mL. 125 10 mg (54 Imols) 5 1.0% 2.0% 0.1% to 0.9% 400 to 700 q.s. to 5 mL. 126 15 (81 Imols) 5 1.0% 2.0% 0.1% to 0.9% 400 to 700 q.s. to 5 mL. 127 25 mg (135 Imols) 5 1.0% 2.0% 0.1% to 0.9% 400 to 700 q.s. to 5 mL. 128 37.5 mg 5 1.0% 2.0% 0.1% to 0.9% 400 to 700 q.s. to 5 mL. (202 Imols) 129 75 mg (405 Imols) 5 1.0% 2.0% 0.1% to 0.9% 400 to 700 q.s. to 5 mL. 130 100 mg (541 Imols) 5 2.0% 4.0% 0.1% to 0.9% 900 to 1200 q.s. to 5 mL. 131 115 mg (621 Imols) 5 4.0% 8.0% 0.1% to 0.9% 1800 to 2200 qis. to 5 mL 132 150 mg (810 Imols) 5 6.0% 12.0% 0.1% to 0.9% 1800 to 2200 q.s. to 5 mL. 133 190 mg 5 8.0% 16.0% 0.1% to 0.9% 3500 to 4000 q.s. to 5 mL. (1027 Imols) 134 220 mg 5 8.0% 16.0% 0.1% to 0.9% 3600 to 4100 q.s. to 5 mL. (1189 Imols)

TABLE 1-11 Ingredient and Amount Phosphate Buffer Chloride ion (monobasic dibasic (sodium, Sodium salts), pH magnesium or OSmolality Composition no. Pirfenidone (mg) 6.0 to pH 7.0 (mM.) Ethanol Propylene Glycol calcium salts) (mCSmokg) Water 135 5 mg (27 Imols) O.S9/o 1.0% 0.1% to 0.9% 200 to 500 q.s. to 5 mL. 136 5 mg (27 Imols) 1.0% 2.0% 0.1% to 0.9% 200 to 700 q.s. to 5 mL. 137 10 mg (54 Imols) 1.0% 2.0% 0.1% to 0.9% 400 to 700 q.s. to 5 mL. 138 15 (81 Imols) 1.0% 2.0% 0.1% to 0.9% 400 to 700 q.s. to 5 mL. 139 25 mg (135 Imols) 1.0% 2.0% 0.1% to 0.9% 400 to 700 q.s. to 5 mL. 140 37.5 mg 1.0% 2.0% 0.1% to 0.9% 400 to 700 q.s. to 5 mL. (202 Imols) 141 75 mg (405 Imols) 1.0% 2.0% 400 to 700 q.S. to 5 mL 142 100 mg (541 Imols) 2.0% 4.0% 0.1% to 0.9% 900 to 1200 q.s. to 5 mL. 143 115 mg (621 Imols) 4.0% 8.0% 0.1% to 0.9% 1800 to 2200 q.s. to 5 mL. 144 150 mg (810 Imols) 6.0% 12.0% 0.1% to 0.9% 1800 to 2200 q.s. to 5 mL. 145 190 mg 8.0% 16.0% 0.1% to 0.9% 3500 to 4000 q.s. to 5 mL. (1027 Imols) 146 220 mg 8.0% 16.0% 0.1% to 0.9% 3600 to 4100 q.s. to 5 mL. (1189 Imols)

Example 2 mixed thoroughly with Sonication and Vortexing. The sample was agitated at ambient temperature overnight. The sample Buffer and pH Effects Development Study was visually inspected, appearance recorded, centrifuged to sediment any un-dissolved material, and the Supernatant 0658 Pirfenidone solubility in citrate and phosphate buff withdrawn via syringe through a 0.22 Lum PVDF filter. The ers were investigated (Table 2). Pirfenidone (250mg) was filtered sample was tested with respect to: appearance, pH reconstituted with 5 mL of buffer in water or water alone and (USP<791 d), osmolality (USP<785>), and Pirfenidone con