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

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(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 ------------------------------------------------------------------------------------------------------------------------------------------------------------- -- 4. 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 9 -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.
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