WO2025016302A1

WO2025016302A1 - Pharmaceutical formulations for inhalation and uses thereof

Info

Publication number: WO2025016302A1
Application number: PCT/CN2024/105133
Authority: WO
Inventors: Hui Wang; Xing LIANG; Andrey KUKHARENKO
Original assignee: InSilico Medicine IP Ltd
Current assignee: InSilico Medicine IP Ltd
Priority date: 2023-07-14
Filing date: 2024-07-12
Publication date: 2025-01-23
Anticipated expiration: 2026-01-14
Also published as: TW202517265A; AR133230A1

Abstract

Provided herein are pharmaceutical formulations of Compound A or pharmaceutically acceptable salts thereof for inhalation. Also provided herein are methods of making and using a Compound A pharmaceutical formulation for inhalation for the treatment of a disease or a condition such as idiopathic pulmonary fibrosis.

Description

PHARMACEUTICAL FORMULATIONS FOR INHALATION AND USES THEREOF

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of patent application No. PCT/CN2023/107535, filed on July 14, 2023, which is incorporated herein by reference in its entirety.

BACKGROUND

Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease resulting in progressive loss of lung function. The currently available treatment options for IPF are not efficient. The current pharmacotherapeutic compounds used for IPF (e.g., Nintedanib and Pirfenidone) can slow the progression of the disease, however, they have some therapeutic limitations: such as diarrhea, side effects related to gastrointestinal tract and skin. In addition, substantial dosing is required to overcome the first-pass elimination, and the prognosis for patients with IPF remains poor. Therefore, there are unmet needs in treatment with reduced side effects for patient with IPF.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

SUMMARY

Disclosed herein is a pharmaceutical formulation for inhalation, a pharmaceutical composition for preparation of the pharmaceutical formulation for inhalation, and a method of preparing the pharmaceutical formulation for inhalation by combining the pharmaceutical composition for preparing the pharmaceutical formulation for inhalation with a liquid vehicle.

Disclosed herein is a pharmaceutical formulation for inhalation, wherein the formulation comprises (a) Compound A or a pharmaceutically acceptable salt thereof, wherein the Compound A has a structure ofand (b) a liquid vehicle; wherein the Compound A is present in an amount of from about 0.001 mg/mL to about 200 mg/mL.

Disclosed herein is a pharmaceutical formulation for inhalation, wherein the formulation comprises (a) Compound A or a pharmaceutically acceptable salt thereof, wherein the Compound A has a structure ofand (b) a liquid vehicle; wherein the liquid pharmaceutical formulation has pH of from about 1.0 to about 11.0.

Disclosed herein is a pharmaceutical formulation for inhalation, wherein the formulation comprises (a) Compound A or a pharmaceutically acceptable salt thereof, wherein the Compound A has a structure ofand (b) a liquid vehicle; wherein the pharmaceutical formulation is stable after stored at room temperature for at least 2 weeks.

Disclosed herein is a pharmaceutical formulation for inhalation, wherein the formulation comprises (a) Compound A or a pharmaceutically acceptable salt thereof, wherein the Compound A has a structure ofand (b) a liquid vehicle; wherein the pharmaceutical formulation is a clear solution.

Disclosed herein is a pharmaceutical composition for preparation of a pharmaceutical formulation described herein or a pharmaceutical composition for reconstitution, comprising: (a) Compound A or a pharmaceutically acceptable salt thereof, wherein the Compound A has a structure of (b) a buffer, a pH-adjusting agent, or both; (c) optionally, an osmolarity adjusting agent, a sweetener, a surfactant, a chelating agent, an anti-oxidant, a preservative, or a combination thereof.

Disclosed herein is an inhalation device comprising a pharmaceutical formulation for inhalation described herein.

Disclosed herein is a method of treating or preventing a disease or a condition in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation for inhalation described herein.

Disclosed herein is a method of treating pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation for inhalation described herein.

Disclosed herein is a method of treating lung injury in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation for inhalation described herein.

Disclosed herein is a method of treating respiratory inflammation in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation for inhalation described herein.

Disclosed herein is a method of improving lung function in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation for inhalation described herein.

Disclosed herein is a method of inhibiting TNIK kinase, TGF-β induced expression of fibrotic proteins, or M2 macrophage polarization in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation for inhalation described herein.

Disclosed herein is a method of pulmonary delivery of 5′- (4-fluorophenyl) -3′-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H, 3′H- [2, 4′-biimidazole] -4-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof to a subject in need thereof, the method comprising administering a pharmaceutical formulation described herein by inhalation.

Disclosed herein is a method for administering 5′- (4-fluorophenyl) -3′-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H, 3′H- [2, 4′-biimidazole] -4-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof with reduced systemic or local toxicity to a subject in need thereof, the method comprising administering a pharmaceutical formulation described herein by inhalation.

Disclosed herein is a method for administering 5′- (4-fluorophenyl) -3′-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H, 3′H- [2, 4′-biimidazole] -4-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof with reduced dose to a subject in need thereof, the method comprising administering a pharmaceutical formulation described herein by inhalation.

Disclosed herein is a method for administering 5′- (4-fluorophenyl) -3′-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H, 3′H- [2, 4′-biimidazole] -4-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof with improved lung exposure to a subject in need thereof, the method comprising administering a pharmaceutical formulation described herein by inhalation.

Disclosed herein is a kit comprising a package enclosing pharmaceutical formulation for inhalation described herein or an inhalation device described herein. In some embodiments, the kit comprises instructions for use of the pharmaceutical formulation for inhalation.

BRIEF DESCRIPTION OF THE DRAWINGS

The features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the present disclosure are utilized, and the accompanying drawings of which:

Figure 1 depicts the workflow of an efficacy study for Compound A acetate salt in inhibiting lung inflammation using mouse with Lipopolysaccharide (LPS) -induced acute lung injury as a model.

Figure 2A shows the level of Interleukin 1-alpha (IL-1α) in different treatment groups as one of the endpoints for the efficacy study using mice with LPS-induced acute lung injury as a model, which includes a sham vehicle group for mice without lung injury, a model vehicle group for mice with lung injury that did not receive an active pharmaceutical ingredient, and treatment groups for mice with lung injury that were administered Compound A acetate salt by intratracheal delivery (i.t. ) at 0.1 mg/kg (or “mpk” as used herein interchangeably, calculated based on Compound A free base unless otherwise specified) , 0.3 mg/kg, or 1 mg/kg once a day (Q.D. ) , orally administered (P.O. ) Dexamethasone (Dex) at 10 mg/kg twice a day (B.I.D. ) , or orally administered Compound A acetate salt at 10 mg/kg once a day.

Figure 2B shows the level of Interleukin 4 (IL-4) in different treatment groups as one of the endpoints for the efficacy study using mice with LPS-induced acute lung injury as a model, which includes a sham vehicle group for mice without lung injury, a model vehicle group for mice with lung injury that did not receive an active pharmaceutical ingredient, and treatment groups for mice with lung injury that were administered Compound A acetate salt by intratracheal delivery (i.t. ) at 0.1 mg/kg, 0.3 mg/kg, or 1 mg/kg once a day (Q.D. ) , orally administered (P.O. ) Dexamethasone (Dex) at 10 mg/kg twice a day (B.I.D. ) , or orally administered Compound A acetate salt at 10 mg/kg once a day.

Figure 2C shows the level of myeloperoxidase (MPO) in different treatment groups as one of the endpoints for the efficacy study using mice with LPS-induced acute lung injury as a model, which includes a sham vehicle group for mice without lung injury, a model vehicle group for mice with lung injury that did not receive an active pharmaceutical ingredient, and treatment groups for mice with lung injury that were administered Compound A acetate salt by intratracheal delivery (i.t. ) at 0.1 mg/kg, 0.3 mg/kg, or 1 mg/kg once a day (Q.D. ) , orally administered (P.O. ) Dexamethasone (Dex) at 10 mg/kg twice a day (B.I.D. ) , or orally administered Compound A acetate salt at 10 mg/kg once a day.

Figure 2D shows the level of Transforming growth factor beta (TGF-β) in different treatment groups as one of the endpoints for the efficacy study using mice with LPS-induced acute lung injury as a model, which includes a sham vehicle group for mice without lung injury, a model vehicle group for mice with lung injury that did not receive an active pharmaceutical ingredient, and treatment groups for mice with lung injury that were administered Compound A acetate salt by intratracheal delivery (i.t. ) at 0.1 mg/kg, 0.3 mg/kg, or 1 mg/kg once a day (Q.D. ) , orally administered (P.O. ) Dexamethasone (Dex) at 10 mg/kg twice a day (B.I.D. ) , or orally administered Compound A acetate salt at 10 mg/kg once a day.

Figure 3 depicts the workflow for an efficacy study for Compound A acetate salt in inhibiting lung fibrosis using rats with Bleomycin-induced lung fibrosis as a model.

Figure 4A shows the results of forced vital capacity (FVC) in different treatment groups as one of the endpoints for the efficacy study using rat with bleomycin-induced lung fibrosis as a model, which includes a normal control group for rats without lung fibrosis, a vehicle control group for rats with lung fibrosis that did not receive an active pharmaceutical ingredient, and treatment groups for rats with lung fibrosis that were administered Compound A acetate salt at 0.1 mg/mL (dose 0.05 mg/kg) , 0.3 mg/mL (dose 0.15 mg/kg) , 1.0 mg/mL (dose 0.5 mg/kg) , 6.0 mg/mL (dose 3 mg/kg) by inhalation once a day (Q.D. ) , or were orally administered pirfenidone at 350 mg/kg or once a day.

Figure 4B shows the results of pulmonary compliance in different treatment groups as one of the endpoints for the efficacy study using rat with bleomycin-induced lung fibrosis as a model, which includes a normal control group for rats without lung fibrosis, a vehicle control group for rats with lung fibrosis that did not receive an active pharmaceutical ingredient, and rats with lung fibrosis that were administered Compound A acetate salt at 0.1 mg/mL (dose 0.05 mg/kg) , 0.3 mg/mL (dose 0.15 mg/kg) , 1.0 mg/mL (dose 0.5 mg/kg) , 6.0 mg/mL (dose 3 mg/kg) by inhalation once a day (Q.D. ) , or were orally administered pirfenidone at 350 mg/kg or once a day.

Figure 4C shows the results of airway resistance in different treatment groups as one of the endpoints for the efficacy study using rat with bleomycin-induced lung fibrosis as a model, which includes a normal control group for rats without lung fibrosis, a model control group for rats with lung fibrosis that did not receive an active pharmaceutical ingredient, and rats with lung fibrosis that were administered Compound A acetate salt at 0.1 mg/mL (dose 0.05 mg/kg) , 0.3 mg/mL (dose 0.15 mg/kg) , 1.0 mg/mL (dose 0.5 mg/kg) , 6.0 mg/mL (dose 3 mg/kg) by inhalation once a day (Q.D. ) , or were orally administered pirfenidone at 350 mg/kg or once a day.

Figure 4D shows the modified Ashcroft scores in different treatment groups as one of the endpoints for the efficacy study using rat with bleomycin-induced lung fibrosis as a model, which includes a normal control group for rats without lung fibrosis, a vehicle control group for rats with lung fibrosis that did not receive an active pharmaceutical ingredient, and rats with lung fibrosis that were administered Compound A acetate salt at 0.1 mg/mL (dose 0.05 mg/kg) , 0.3 mg/mL (dose 0.15 mg/kg) , 1.0 mg/mL (dose 0.5 mg/kg) , 6.0 mg/mL (dose 3 mg/kg) by inhalation once a day (Q.D. ) , or were orally administered pirfenidone at 350 mg/kg or once a day.

Figure 4E shows the %fibrosis area of quantitative morphometry of Masson’s trichrome staining in different treatment groups as one of the endpoints for the efficacy study using rat with bleomycin-induced lung fibrosis as a model, which includes a normal control group for rats without lung fibrosis, a vehicle control group for rats with lung fibrosis that did not receive an active pharmaceutical ingredient, and rats with lung fibrosis that were administered Compound A acetate salt at 0.1 mg/mL (dose 0.05 mg/kg) , 0.3 mg/mL (dose 0.15 mg/kg) , 1.0 mg/mL (dose 0.5 mg/kg) , 6.0 mg/mL (dose 3 mg/kg) by inhalation once a day (Q.D. ) , or were orally administered pirfenidone at 350 mg/kg or once a day.

Figure 4F shows the %inflammatory area of quantitative morphometry of hematoxylin and eosin (H&E) staining in different treatment groups as one of the endpoints for the efficacy study using rat with bleomycin-induced lung fibrosis as a model, which includes a normal control group for rats without lung fibrosis, a vehicle control group for rats with lung fibrosis that did not receive an active pharmaceutical ingredient, and rats with lung fibrosis that were administered Compound A acetate salt at 0.1 mg/mL (dose 0.05 mg/kg) , 0.3 mg/mL (dose 0.15 mg/kg) , 1.0 mg/mL (dose 0.5 mg/kg) , 6.0 mg/mL (dose 3 mg/kg) by inhalation once a day (Q.D. ) , or were orally administered pirfenidone at 350 mg/kg or once a day.

Figure 5A shows the Masson’s trichrome staining in normal control group for rats without lung fibrosis in the efficacy study using rat with bleomycin-induced lung fibrosis as a model.

Figure 5B shows the Masson’s trichrome staining in a vehicle control group for rats with lung fibrosis that did not receive an active pharmaceutical ingredient in the efficacy study using rat with bleomycin-induced lung fibrosis as a model.

Figure 5C shows the Masson’s trichrome staining in rats with lung fibrosis that were administered Compound A acetate salt at 0.1 mg/mL (dose 0.05 mg/kg) by inhalation once a day in the efficacy study using rat with bleomycin-induced lung fibrosis as a model.

Figure 5D shows the Masson’s trichrome staining in rats with lung fibrosis that were administered Compound A acetate salt at 0.3 mg/mL (dose 0.15 mg/kg) by inhalation once a day in the efficacy study using rat with bleomycin-induced lung fibrosis as a model.

Figure 5E shows the Masson’s trichrome staining in rats with lung fibrosis that were administered Compound A acetate salt at 1.0 mg/mL (dose 0.5 mg/kg) by inhalation once a day in the efficacy study using rat with bleomycin-induced lung fibrosis as a model.

Figure 5F shows the Masson’s trichrome staining in rats with lung fibrosis that were administered Compound A acetate salt at 6.0 mg/mL (dose3 mg/kg) by inhalation once a day in the efficacy study using rat with bleomycin-induced lung fibrosis as a model.

Figure 5G shows the Masson’s trichrome staining in rats with lung fibrosis that were orally administered pirfenidone at 350 mg/kg once a day in the efficacy study using rat with bleomycin-induced lung fibrosis as a model.

Figure 6A shows the H&E staining in normal control group for rats without lung fibrosis in the efficacy study using rat with bleomycin-induced lung fibrosis as a model.

Figure 6B shows the H&E staining in a vehicle control group for rats with lung fibrosis that did not receive an active pharmaceutical ingredient in the efficacy study using rat with bleomycin-induced lung fibrosis as a model.

Figure 6C shows the H&E staining in rats with lung fibrosis that were administered Compound A acetate salt at 0.1 mg/mL (dose 0.05 mg/kg) by inhalation once a day in the efficacy study using rat with bleomycin-induced lung fibrosis as a model.

Figure 6D shows the H&E staining in rats with lung fibrosis that were administered Compound A acetate salt at 0.3 mg/mL (actual dose 0.15 mg/kg) by inhalation once a day in the efficacy study using rat with bleomycin-induced lung fibrosis as a model.

Figure 6E shows the H&E staining in rats with lung fibrosis that were administered Compound A acetate salt at 1.0 mg/mL (dose 0.5 mg/kg) by inhalation once a day in the efficacy study using rat with bleomycin-induced lung fibrosis as a model.

Figure 6F shows the H&E staining in rats with lung fibrosis that were administered Compound A acetate salt at 6.0 mg/mL (dose 3 mg/kg) by inhalation once a day in the efficacy study using rat with bleomycin-induced lung fibrosis as a model.

Figure 6G shows the H&E staining in rats with lung fibrosis that were orally administered pirfenidone at 350 mg/kg once a day in the efficacy study using rat with bleomycin-induced lung fibrosis as a model.

Figure 7A shows a representative Masson’s trichrome staining in rat with bleomycin-induced lung fibrosis that received oral Compound A acetate salt at the dose of 10 mg/kg B. I. D for comparison.

Figure 7B shows the Masson’s trichrome staining in rat with bleomycin-induced lung fibrosis that received Compound A acetate salt at the dose of 0.5mg/kg Q.D. by inhalation.

Figure 8A shows a representative H&E staining in rat with bleomycin-induced lung fibrosis that received oral Compound A acetate salt at the dose of 10 mg/kg B. I. D for comparison.

Figure 8B shows the H&E staining in rat with bleomycin-induced lung fibrosis that received Compound A acetate salt at the dose of 0.5mg/kg Q.D. by inhalation.

DETAILED DESCRIPTION

Compound A is 5′- (4-fluorophenyl) -3′-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H, 3′H- [2, 4′-biimidazole] -4-carboxamide. Its molecular weight is 487 and its measured pKa values are 4.48 for basic pKa, 7.64 for basic pKa, and 10.19 for acidic pKa. Compound A has the below structural formula:

Compound A

A pharmaceutically acceptable salt of Compound A can comprise, e.g., an acetate salt, a hydrochloride salt, a fumarate salt or a citrate salt. Unless specified otherwise or obvious from context, “Compound A liquid formulation (s) , ” Compound A suspension (s) , ” “Compound A solution (s) , ” “Compound A pharmaceutical composition (s) , ” “Compound A oral formulation (s) , ” “Compound A formulation (s) , ” or “Compound A liquid pharmaceutical formulation (s) ” as used herein can refer to a pharmaceutical formulation of Compound A free base or a pharmaceutically acceptable salt thereof. Without wishing to be bound by any theory, Compound A or pharmaceutically acceptable salts thereof can inhibit TNIK kinase, inhibit TGF-β induced expression of fibrotic proteins, and inhibit M2 macrophage polarization. In some aspects, the TNIK inhibitor can inhibit fibrillar collagen, and thereby can inhibit biological activity related to regulation of the extracellular matrix, and regulation of remodeling the extracellular matrix. The TNIK inhibitor can inhibit regulation of cell growth, differentiation, cell migration, proliferation, and metabolism. In certain embodiments, inhibiting the TNIK can inhibit certain TNIK related biological pathways. In certain aspects, the inhibiting of TNIK inhibits the Wnt pathway. In certain embodiments, the inhibiting of TNIK inhibits cytoskeletal rearrangements. The inhibition of TNIK can inhibit the c-Jun N-terminal kinase pathway. The inhibition of TNIK can inhibit the phosphorylation of Gelsolin. The inhibition of TNIK can inhibit the regulation of the cytoskeleton, such as cytoskeletal rearrangements. In certain embodiments, the inhibiting of TNIK inhibits carcinogenesis. In certain aspect, the administering of the TNIK inhibitor includes a therapeutically effective amount of the compound sufficient to treat cancer by: inhibiting cancer cell growth; inhibiting cancer cell migration; inhibiting cancer cell proliferation; or inhibiting cancer cell migration.

The anti-fibrosis and anti-inflammatory function of Compound A or pharmaceutically acceptable salts thereof is validated in the bleomycin-induced lung fibrosis rat model and LPS-induced acute lung injury in mice, as described herein in the Examples. Following oral administration, Compound A or pharmaceutically acceptable salts thereof extensively distributed into tissues, resulting in lung Cmax and AUC that are higher than plasma level. By comparison, inhaled Compound A or pharmaceutically acceptable salts thereof can achieve an oral-equivalent lung AUC with lower systemic AUC.

Compound A or pharmaceutically acceptable salts thereof can be delivered directly into the deep lungs of a subject, such as by inhalation, which offers a more targeted approach that will reduce the amount of drug required and thus reduce side effects to achieve fast and effective therapeutic effects locally. In some cases, delivery by inhalation comprises delivered by intratracheal (i. t) . The AUC ratio of lung exposure/plasma from inhalation is more than 20 times higher than of oral administration, which indicates inhalation could improve lung exposures quickly with reduced systemic exposures. Therefore, the inhalation delivery of Compound A pharmaceutical formulations such as nebulization solution is an extremely efficient route of drug delivery to the targeted area of lungs.

Disclosed herein is inhalable form of Compound A or pharmaceutically acceptable salts thereof for pulmonary delivery for treatment of IPF with low dose and minimal side effects, which provides novel and effective therapeutical strategy for better management of patients with IPF disease. The present embodiments provide a safe and effective administration by inhalation of Compound A or pharmaceutically acceptable salts thereof (e.g., free base, acetate salt, hydrochloride salt, citrate salt, fumarate salt) for the treatment of pulmonary disease or conditions. The embodiments provide stable liquid formulations of Compound A or pharmaceutically acceptable salts wherein Compound A is present in an amount of from about 0.001 mg/mL to about 200 mg/mL. The embodiments provide stable liquid formulations of Compound A or pharmaceutically acceptable salts wherein Compound A is present in an amount of from about 0.01 mg/mL to about 200 mg/mL. The embodiments also provide stable liquid formulations of Compound A or pharmaceutically acceptable salts that has a pH of from about 1.0 to about 9.0. The embodiments also provide stable liquid formulations of Compound A or pharmaceutically acceptable salts that is a clear solution. Furthermore, present embodiments provide liquid formulations of Compound A that are stable for storage at room temperature or ambident conditions for at least 2 weeks.

In one aspect, provided herein are pharmaceutical formulations of Compound A or pharmaceutically acceptable salts thereof for inhalation. In some embodiments, provided herein are liquid pharmaceutical formulations of Compound A or pharmaceutically acceptable salts thereof for inhalation. These Compound A formulations described herein are useful for the treatment of diseases, conditions, or symptoms thereof, such as idiopathic pulmonary fibrosis. The formulations can be advantageous in many aspects. The pharmaceutical formulations provided herein can be easily manufactured following the GMP standards. Compound A or pharmaceutically acceptable salts thereof can be solubilized/dispersed in pharmaceutical formulations provided herein to reach a desired concentration, such as 20 mg/mL. The pharmaceutical formulations provided herein can have good stability suitable for long-term storage, for example, stable at room temperature for 24 months. The liquid formulations provided herein can be nebulized and generate droplets having a desirable mass median aerodynamic diameter (MMAD) (e.g., about 2-3 μm or lower) and a desirable Geometric Standard Deviation (GSD) (e.g., about 1 μm to about 2 μm) that is suitable for lung drug delivery.

Furthermore, the formulations provided herein can be advantageous over oral administration of Compound A in that they increases lung exposures thus allow smaller doses, reduced toxicity or side effects, and larger safety window. Compound A shows dose-dependency trend in both plasma and lung exposures. The formulations provided herein are well tolerated with no or minimal local toxicity or systemic toxicity. The systemic safety margin can be more than 100. The local safety margin can be more than 28.

Compound A liquid formulation for inhalation

In some embodiments, the pharmaceutical composition for inhalation described herein is a liquid formulation. Liquid formulations can include solutions (both aqueous and nonaqueous) and suspensions or other routes of administration (e.g., oral) . Other liquid formulations can include emulsions, syrups, slurries, juices, elixirs, dispersions, and the like.

In one aspect, described herein are liquid pharmaceutical formulations comprising Compound A or a pharmaceutically acceptable salt thereof (e.g., free base, acetate salt, hydrochloride salt, citrate salt, or fumarate salt) . In some embodiments, the liquid pharmaceutical formulation comprises Compound A free base or a pharmaceutically acceptable salt thereof in an amount of about 0.001 mg/mL to about 200 mg/mL. In some embodiments, the liquid pharmaceutical formulation comprises Compound A free base or a pharmaceutically acceptable salt thereof in an amount of about 0.01 mg/mL to about 200 mg/mL. In some embodiments, a liquid pharmaceutical formulation described herein comprises a liquid vehicle. In some embodiments, a liquid pharmaceutical formulation described herein is a solution for inhalation. In some embodiments, a liquid pharmaceutical formulation described herein is a clear solution. In some embodiments, a liquid pharmaceutical formulation described herein has a pH of from about 1.0 to about 11.0. In some embodiments, a liquid pharmaceutical formulation described herein has a pH of from about 3.0 to about 11.0. In some embodiments, the liquid pharmaceutical formulation is stable after stored at room temperature for at least 2 weeks. In some embodiments, the liquid pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of from about 0.1 mg/mL to about 60 mg/mL. In some embodiments, the liquid pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of from about 0.1 mg/mL to about 120 mg/mL. In some embodiments, the liquid pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of from about 0.001 mg/mL to about 30 mg/mL. In some embodiments, the liquid pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of from about 0.001 mg/mL to about 30 mg/mL and the liquid pharmaceutical formulation has a pH of about 3.0-5.5. In some embodiments, the liquid pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of from about 0.001 mg/mL to about 30 mg/mL and the liquid pharmaceutical formulation has a pH of about 3.0-5.0. In some embodiments, the liquid pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of from about 0.001 mg/mL to about 15 mg/mL and the liquid pharmaceutical formulation has a pH of about 3.0-5.5. In some embodiments, the osmolality of the liquid pharmaceutical formulation is from about 50 mOsmol/kg to about 6000 mOsmol/kg. In some embodiments, the osmolality of the liquid pharmaceutical formulation is from about 250 mOsmol/kg to about 400 mOsmol/kg. In some embodiments, the osmolality of the liquid pharmaceutical formulation is from about 280 mOsmol/kg to about 360 mOsmol/kg. In some embodiments, the liquid pharmaceutical formulation has a pH of about 3.0 to about 5.5. In some embodiments, the liquid pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the liquid pharmaceutical formulation from about 3.0 to about 5.5. In some embodiments, the liquid pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the liquid pharmaceutical formulation from about 3.5 to about 7.0. In some embodiments, the liquid pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the liquid pharmaceutical formulation from about 3.5 to about 6.5. In some embodiments, the liquid pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the liquid pharmaceutical formulation from about 3.5 to about 6.0. In some embodiments, the liquid pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the liquid pharmaceutical formulation from about 3.5 to about 5.5. In some embodiments, the liquid pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the liquid pharmaceutical formulation from about 3.5 to about 5.0. In some embodiments, the liquid pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the liquid pharmaceutical formulation from about 3.5 to about 4.5. In some embodiments, the liquid pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the liquid pharmaceutical formulation from about 3.5 to about 4.0. In some embodiments, the liquid pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the liquid pharmaceutical formulation from about 4.0 to about 4.5. In some embodiments, the liquid pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the liquid pharmaceutical formulation is about 3.5. In some embodiments, the liquid pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the liquid pharmaceutical formulation is about 4.0. In some embodiments, the liquid pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the liquid pharmaceutical formulation is about 4.25. In some embodiments, the liquid pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the liquid pharmaceutical formulation is about 4.5. In some embodiments, the liquid pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the liquid pharmaceutical formulation is about 4.75. In some embodiments, the liquid pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the liquid pharmaceutical formulation is about 5.0. In some embodiments, the liquid pharmaceutical formulation comprises a phosphate buffer that that is configured to maintain a pH of the liquid pharmaceutical formulation from about 5.0 to about 9.0.

In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof (e.g., free base, acetate salt, hydrochloride salt, citrate salt, or fumarate salt) is present in liquid formulations for inhalation described herein in an amount of from about 0.001 mg/mL to about 500 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of from about 0.001 mg/mL to about 100 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of from about 0.001 mg/mL to about 50 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of from about 0.001 mg/mL to about 60 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of from about 0.001 mg/mL to about 30 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of from about 0.01 mg/mL to about 250 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of from about 0.05 mg/mL to about 100 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of from about 0.1 mg/mL to about 80 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of from about 0.1 mg/mL to about 60 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of from about 0.1 mg/mL to about 50 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of from about 0.1 mg/mL to about 40 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of from about 1 mg/mL to about 30 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of from about 1 mg/mL to about 10 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 15 mg/mL to about 25 mg/mL. In some embodiments, a daily dose of the formulation is about 0.1mg-120mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 2 mg, about 2 mg, about 5 mg, about 10 mg, about 20 mg, about 30mg, about 40mg, about 50 mg, about 60 mg, about 70 mg, about 80mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg.

In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof (e.g., free base, acetate salt, hydrochloride salt, citrate salt, or fumarate salt) is present in liquid formulations for inhalation described herein in an amount of or about 0.001 mg/mL to about 0.01 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 0.01 mg/mL to about 0.1 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 0.1 mg/mL to about 1 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 1 mg/mL to about 3 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 3 mg/mL to about 10 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 10 mg/mL to about 15 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 10 mg/mL to about 20 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof (e.g., free base, acetate salt, hydrochloride salt, citrate salt, fumarate salt) is present in liquid formulations described herein in an amount of or about 15 mg/mL to about 20 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 20 mg/mL to about 25 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 25 mg/mL to about 30 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 30 mg/mL to about 40 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 40 mg/mL to about 50 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 50 mg/mL to about 60 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 60 mg/mL to about 70 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 70 mg/mL to about 80 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 80 mg/mL to about 90 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 90 mg/mL to about 100 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 100 mg/mL to about 150 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 150 mg/mL to about 200 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations for inhalation described herein in an amount of or about 200 mg/mL to about 250 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 250 mg/mL to about 300 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 300 mg/mL to about 350 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 350 mg/mL to about 400 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in liquid formulations described herein in an amount of or about 400 mg/mL to about 500 mg/mL. In some embodiments, liquid formulations described herein comprise Compound A free base. In some embodiments, liquid formulations described herein comprise an acetate salt of Compound A. In some embodiments, liquid formulations described herein comprise a hydrochloride salt of Compound A. In some embodiments, liquid formulations described herein comprise a citrate salt of Compound A. In some embodiments, liquid formulations described herein comprise a fumarate salt of Compound A.

In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 0.01 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 0.05 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 0.1 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof (e.g., free base, acetate salt, hydrochloride salt, citrate salt, or fumarate salt) is present in the liquid pharmaceutical formulation in an amount of about 0.2 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 0.3 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 0.4 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 0.5 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 0.6 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 0.7 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 0.8 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 0.9 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 1.0 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 2.0 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 3.0 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 4.0 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 5 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 6 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 7 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 8 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 9 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 10 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 11 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 12 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 13 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 15 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 16 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 17 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 18 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 19 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 20 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 21 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 22 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 23 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 24 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 25 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 30 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 30 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 40 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 50 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 60 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 70 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 80 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 90 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 100 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 150 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 200 mg/mL. In some embodiments, Compound A free base or a pharmaceutically acceptable salt thereof is present in the liquid pharmaceutical formulation in an amount of about 250 mg/mL. In some embodiments, liquid formulations described herein comprise Compound A free base. In some embodiments, liquid formulations described herein comprise an acetate salt of Compound A. In some embodiments, liquid formulations described herein comprise a hydrochloride salt of Compound A. In some embodiments, liquid formulations described herein comprise a citrate salt of Compound A. In some embodiments, liquid formulations described herein comprise a fumarate salt of Compound A.

In some aspects, provided herein is a liquid pharmaceutical formulation comprising Compound A free base or a pharmaceutically acceptable salt thereof, a liquid carrier (e.g., water) , a citrate buffer or a phosphate buffer, and optionally a preservative. In some cases, the liquid pharmaceutical formulation comprises additional excipients such as an additional liquid carrier, osmolarity adjusting agents, sweeteners, surfactants, wetting agents, chelating agents, anti-oxidants, salts and additional buffers. In some cases, the liquid pharmaceutical formulation comprises a salt selected from the group consisting of sodium chloride, magnesium chloride, sodium bromide, magnesium bromide, calcium chloride and calcium bromide. In some cases, the salt is present in an amount of from about 0.01%to about 2%w/v, from about 0.01%w/v to about 0.01 %w/v, from about 0.1%w/v to about 0.5 %w/v, from about 0.5%w/v to about 1.5 %w/v, about 0.5%w/v, about 0.75%w/v, about 0.9%w/v, about 1 %w/v, about 1.5%w/v, or about 2 %w/v.

In some aspects, provided herein is a liquid pharmaceutical formulation, comprising Compound A or a pharmaceutically acceptable salt thereof (e.g., free base, acetate salt, hydrochloride salt, citrate salt, or fumarate salt) and water. In some embodiments, the liquid pharmaceutical formulation comprises citrate buffer. In some embodiments, the liquid pharmaceutical formulation comprises citric acid and sodium citrate. In some embodiments, the liquid pharmaceutical formulation is a solution for inhalation. In some embodiments, the liquid pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of about 0.1 to about 50 mg/mL. In some embodiments, the liquid pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of about 0.001 to about 10 mg/mL. In some embodiments, the liquid pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of about 10 to about 20 mg/mL. In some embodiments, the liquid pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of about 20 to about 30 mg/mL. In some embodiments, the liquid pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of about 0.1 to about 1 mg/mL. In some embodiments, the liquid pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of about 1 to about 5 mg/mL. In some embodiments, the liquid pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of about 5 to about 20 mg/mL. In some embodiments, the liquid pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of about 5 mg/mL. In some embodiments, the liquid pharmaceutical formulation comprises citrate buffer in an amount of from about 10 mM to about 100 mM, from about 25 to about 60 mM, or from about 30 mM to about 50 mM. In some embodiments, the liquid pharmaceutical formulation comprises citric acid in an amount of from about 0.1%w/v to about 2.0 %w/v, from about 0.2%w/v to about 1.0 %w/v, or from about 0.2%w/v to about 0.5 %w/v. In some embodiments, the liquid pharmaceutical formulation comprises citric acid in an amount of about 0.25%w/v, about 0.35%w/v, about 0.45%w/v, or about 0.6%w/v. In some embodiments, the liquid pharmaceutical formulation comprises sodium citrate is present in the liquid pharmaceutical formulation in an amount from about 0.2%w/v to about 1.0 %w/v, or from about 0.4%w/v to about 0.8 %w/v. In some embodiments, the liquid pharmaceutical formulation comprises about 0.4%w/v, about 0.6%w/v or about 0.8%w/v sodium citrate. In some embodiments, the liquid pharmaceutical formulation further comprises a suitable amount of preservatives, such as EDTA or antioxidants. In some embodiments, the liquid pharmaceutical formulation has a pH of about 3.0 to about 5.5. In some embodiments, the liquid pharmaceutical formulation has a pH of about 4.0 to about 5.5. In some embodiments, the liquid pharmaceutical formulation has a pH of about 4.5. In some embodiments, the liquid pharmaceutical formulation has a pH of about 5.0. In some embodiments, the liquid pharmaceutical formulation has an osmolality of about 280-350 mOsmol/kg.

In some embodiments, the liquid pharmaceutical formulation comprises about 0.5%w/v Compound A or a pharmaceutically acceptable salt thereof (e.g., free base, acetate salt, hydrochloride salt, citrate salt, or fumarate salt) . In some embodiments, the liquid pharmaceutical formulation comprises about 0.4%w/v citric acid. In some embodiments, the liquid pharmaceutical formulation comprises about 0.4%w/v sodium citrate. In some embodiments, the liquid pharmaceutical formulation comprises about 0.75%w/v sodium chloride. In some embodiments, the liquid pharmaceutical formulation comprises about 0.05%w/v EDTA.

In some embodiments, a liquid pharmaceutical formulation described herein comprises Compound A free base. In some embodiments, a liquid pharmaceutical formulation described herein comprises a pharmaceutically acceptable salt of Compound A. In some embodiments, the Compound A or a pharmaceutically acceptable salt thereof is an acetate salt of Compound A, a hydrochloride salt of Compound A, a fumarate salt of Compound A, or a citrate salt of Compound A. In some embodiments, a pharmaceutically acceptable salt of Compound A is acetate salt of Compound A. In some embodiments, a pharmaceutically acceptable salt of Compound A is hydrochloride salt of Compound A. In some embodiments, a pharmaceutically acceptable salt of Compound A is fumarate salt of Compound A. In some embodiments, a pharmaceutically acceptable salt of Compound A is citrate salt of Compound A. Pharmaceutically acceptable salts of Compound A can include acid addition salts with organic and inorganic acids, for example, sulfuric (i.e., sulfate and bisulfate) , phosphoric (i.e., mono-or dibasic phosphate) , carbonic (i.e., carbonate or bicarbonate) , carboxylic acids e.g., acetic acid and trifluoroacetic acid (i.e., acetate and trifluoroacetate) , tartaric acid (i.e. tartrate) , malic acid (i.e. malate) ; maleic acid (i.e. maleate) ; ascorbic acid (i.e. ascorbate) ; lactic acid (i.e. lactate) ; glutamic acid (i.e. glutamate) and succinic acid (i.e. succinate) . In some embodiments, a liquid pharmaceutical formulation described herein comprises acetate salt of Compound A.

Pharmaceutical composition for preparation of pharmaceutical formulations for inhalation

In some aspects, provided herein is a Compound A pharmaceutical composition for preparation of pharmaceutical formulations for inhalation described herein. Compound A and suitable excipients, such as those described herein, can be stored in the form of dry powder for preparation of pharmaceutical formulations described herein prior to administration by inhalation. In some cases, a Compound A pharmaceutical composition for preparation of liquid pharmaceutical formulations is a lyophilized formulation. In some cases, the liquid pharmaceutical formulation is prepared by solubilizing or dispersing the pharmaceutical composition in a liquid vehicle described herein, such as water.

In some cases, a Compound A pharmaceutical composition for preparation of liquid formulations comprises a buffering agent described herein. In some cases, a Compound A pharmaceutical composition for preparation of liquid formulations comprises a pH-adjusting agent described herein. In some cases, a Compound A pharmaceutical composition for preparation of liquid formulations comprises a buffering agent described herein and a pH-adjusting agent described herein. In some cases, a Compound A pharmaceutical composition for preparation of liquid formulations comprises an osmolarity adjusting agent described herein. In some cases, a Compound A pharmaceutical composition for preparation of liquid formulations comprises a sweetener or a flavoring agent described herein. In some cases, a Compound A pharmaceutical composition for preparation of liquid formulations comprises a preservative described herein. In some cases, a Compound A pharmaceutical composition for preparation of liquid formulations comprises a chelating agent described herein. In some cases, a Compound A pharmaceutical composition for preparation of liquid formulations comprises an antioxidant described herein. In some cases, a Compound A pharmaceutical composition for preparation of liquid formulations comprises a combination of any one of the foregoing excipients. In some cases, a Compound A pharmaceutical composition for preparation of liquid formulations comprises the foregoing excipients in an amount sufficient to prepare or reconstitute a Compound A liquid formulation described herein.

In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 0.1%to about 99.9%w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof (e.g., free base, acetate salt, hydrochloride salt, citrate salt, or fumarate salt) is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 1%to about 99%w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 0.01 %w/w to about 10 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 0.1 %w/w to about 20 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 1 %w/w to about 5 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 5 %w/w to about 10 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 10 %w/w to about 15 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 15 %w/w to about 20 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 20 %w/w to about 30 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 30 %w/w to about 40 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 40 %w/w to about 50 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 50 %w/w to about 60 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 60 %w/w to about 70 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 70 %w/w to about 80 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 80 %w/w to about 90 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 90 %w/w to about 95 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 95 %w/w to about 99 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 10 %w/w to about 40 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from or about 20 %w/w to about 30 %w/w. In some embodiments, compositions described herein comprise Compound A free base. In some embodiments, compositions described herein comprise an acetate salt of Compound A. In some embodiments, compositions described herein comprise a hydrochloride salt of Compound A. In some embodiments, compositions described herein comprise a citrate salt of Compound A. In some embodiments, compositions described herein comprise a fumarate salt of Compound A.

In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 1 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof (e.g., free base, acetate salt, hydrochloride salt, citrate salt, or fumarate salt) is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 5 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 10 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 15 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 18 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 20 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 22.5 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 25 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 30 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 35 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 40 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 50 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 60 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 70 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 80 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 90 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 95 %w/w. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 99 %w/w.

In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 0.1%to about 95%w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 1%to about 80%w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 0.01 %w/w to about 10 % w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 0.1 %w/w to about 20 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 1 %w/w to about 5 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 5 %w/w to about 10 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 10 %w/w to about 15 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 15 %w/w to about 20 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 20 %w/w to about 30 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 30 %w/w to about 40 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 40 %w/w to about 50 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 50 %w/w to about 60 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 60 %w/w to about 70 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 70 %w/w to about 80 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 10 %w/w to about 60 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from or about 20 %w/w to about 50 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from or about 30 %w/w to about 40 %w/w. In some cases, the buffering agent is a buffering agent described herein, for example, citric acid (e.g., citric acid monohydrate) and sodium citrate (e.g., sodium citrate dihydrate) .

In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 1 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 5 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 10 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 15 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 18 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 20 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 22 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 25 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 30 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 40 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 50 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 60 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 70 %w/w. In some cases, a buffering agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 80 %w/w. In some cases, the buffering agent is a buffering agent described herein, for example, citric acid (e.g., citric acid monohydrate) and sodium citrate (e.g., Sodium citrate dihydrate) .

In some cases, the buffering agent is citric acid and sodium citrate. In some cases, citric acid is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 0.1 %w/w to about 20 %w/w. In some cases, citric acid is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 1 %w/w to about 5 %w/w. In some cases, citric acid is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 5 %w/w to about 10 %w/w. In some cases, citric acid is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 10 %w/w to about 15 %w/w. In some cases, citric acid is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 15 %w/w to about 20 %w/w. In some cases, citric acid is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 20 %w/w to about 30 %w/w. In some cases, citric acid is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 30 %w/w to about 40 %w/w. In some cases, citric acid is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 10%w/w. In some cases, citric acid is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 12.5 %w/w. In some cases, citric acid is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 15 %w/w. In some cases, citric acid is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 17.5 %w/w. In some cases, citric acid is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 18 %w/w. In some cases, citric acid is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 20 %w/w. In some cases, citric acid is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 25 %w/w. In some cases, sodium citrate is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 0.1 %w/w to about 40 %w/w. In some cases, sodium citrate is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 1 %w/w to about 10 %w/w. In some cases, sodium citrate is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 5 %w/w to about 20 % w/w. In some cases, sodium citrate is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 20 %w/w to about 30 %w/w. In some cases, sodium citrate is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 15 %w/w to about 40 %w/w. In some cases, sodium citrate is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 20 %w/w to about 30 %w/w. In some cases, sodium citrate is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 30 %w/w to about 40 %w/w. In some cases, sodium citrate is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 10%w/w. In some cases, sodium citrate is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 15 %w/w. In some cases, sodium citrate is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 20 %w/w. In some cases, sodium citrate is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 25 %w/w. In some cases, sodium citrate is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 30 %w/w. In some cases, sodium citrate is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 35 %w/w. In some cases, sodium citrate is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 40 %w/w.

In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 0.1%to about 99 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 1%to about 80%w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 0.01 %w/w to about 10 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 0.1 %w/w to about 20 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 1 %w/w to about 5 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 5 %w/w to about 10 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 10 %w/w to about 15 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 15 %w/w to about 20 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 20 %w/w to about 30 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 30 %w/w to about 40 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 40 %w/w to about 50 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 50 %w/w to about 60 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 60 %w/w to about 70 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 70 %w/w to about 80 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 10 %w/w to about 80 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from or about 20 %w/w to about 65 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from or about 30 %w/w to about 50 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from or about 50 %w/w to about 70 %w/w. In some cases, the osmolarity adjusting agent is an osmolarity adjusting agent described herein, for example, sodium chloride.

In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 1 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 5 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 10 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 15 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 18 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 20 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 22 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 25 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 30 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 40 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 50 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 60 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 70 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 80 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 90 %w/w. In some cases, an osmolarity adjusting agent is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 95 %w/w. In some cases, the osmolarity adjusting agent is an osmolarity adjusting agent described herein, for example, sodium chloride.

In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 0.1 %w/w to about 90 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 1 %w/w to about 20 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 10 %w/w to about 40 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 20 %w/w to about 50 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 45 %w/w to about 70 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 50 %w/w to about 80 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 35 %w/w to about 45 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of from about 60 %w/w to about 70 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 60%w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 15 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 20 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 25 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 30 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 35 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 40 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 45 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 50 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 55 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 60 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 65 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 70 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 75 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 80 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 85 %w/w. In some cases, sodium chloride is present in the pharmaceutical composition for preparation of liquid formulations in an amount of about 90 %w/w.

In some cases, the pharmaceutical composition for preparation of liquid formulations comprises Compound A acetate salt in an amount of about 22.5 %w/w, citric acid in an amount of about 12.5 %w/w and sodium citrate in an amount of about 25 %w/w, and sodium chloride in an amount of about 40%. In some cases, the pharmaceutical composition for preparation of liquid formulations comprises Compound A acetate salt in an amount of about 35%w/w and sodium chloride in an amount of about 65%.

Also provided herein is a method of preparing liquid pharmaceutical formulations described herein, the method comprises dispersing the pharmaceutical composition for preparation of liquid formulations described herein in a liquid vehicle described herein, such as water, thereby forming the liquid pharmaceutical formulations.

Liquid vehicle

In some aspects, pharmaceutical formulations for inhalation described herein are liquid pharmaceutical formulations for inhalation, and comprise Compound A or pharmaceutically acceptable salts thereof and a liquid vehicle. In some embodiments, the Compound A liquid formulations described herein comprise a liquid vehicle, such as a liquid.

The liquid vehicle can be aqueous. The liquid vehicle can comprise water. In some embodiments, a liquid pharmaceutical formulation described herein comprises a liquid vehicle that is water. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 10%to about 99.9%w/v, about 20%to about 99.9%w/v, about 30%to about 99.9%w/v, about 40%to about 99.9%w/v, about 50%to about 99.9%w/v, about 60%to about 99.9%w/v, or about 70%to about 99.9%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 10%to about 99.9%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 20%to about 99.9%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 30%to about 99.9%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 40%to about 99.9%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 50%to about 99.9%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 60%to about 99.9%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 70%to about 99.9%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 80%to about 99.9%w/v, about 90%to about 99.9%w/v, or about 95%to about 99.9%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 95%to about 99.9%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 80%to about 99.9%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 90%to about 99.9%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 95%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 96%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 97%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 98%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 99%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 99.5 %w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 99.9%w/v. In some embodiments, water is present in the liquid pharmaceutical formulation in an amount of about 10 %w/v to about 15 %w/v, about 15 %w/v to about 20 %w/v, about 20 %w/v to about 30 %w/v, about 30 %w/v to about 40 %w/v, about 40 %w/v to about 50 %w/v, about 50 %w/v to about 60 %w/v, about 60 %w/v to about 70 %w/v, about 70 %w/v to about 80 %w/v, about 80 %w/v to about 90 %w/v, about 90 %w/v to about 95 %w/v, about 95 %w/v to about 98 %w/v, about 98 %w/v to about 99 %w/v, or about 99 %w/v to about 99.9 %w/v. In some embodiments, the liquid vehicle has a pH of about 4-5.

The liquid vehicle can be non-aqueous, for example lipids. In some cases, a lipid comprises a C₉-C₂₄ fatty acid, (e.g., C₉-C₁₂ fatty acid, C₉-C₁₅ fatty acid, C₉-C₁₈ fatty acid, or C₁₂-C₁₈ fatty acid) , a C₉-C₂₄ fatty alcohol (e.g., C₉-C₁₂ fatty alcohol, C₉-C₁₅ fatty alcohol, C₉-C₁₈ fatty alcohol, or C₁₂-C₁₈ fatty alcohol) , or a combination thereof. In some cases, a lipid comprises a C₉-C₂₄ fatty acid. In some cases, a lipid comprises a C₉-C₁₂ fatty acid. In some cases, a lipid comprises a C₉-C₁₅ fatty acid. In some cases, a lipid comprises a C₉-C₁₈ fatty acid. In some cases, a lipid comprises a C₁₂-C₁₈ fatty acid. Exemplary fatty acids can include Lauric acid, Myristic acid, Myristoleic acid, Palmitoleic acid, Oleic acid, Elaidic acid, Vaccenic acid, Linoleic acid, Linolelaidic acid, γ-Linolenic acid, α-Linolenic acid, and Stearidonic acid. In some cases, a lipid comprises a C₉-C₂₄ fatty alcohol. In some cases, a lipid comprises a C₉-C₁₂ fatty alcohol. In some cases, a lipid comprises a C₉-C₁₅ fatty alcohol. In some cases, a lipid comprises a C₉-C₁₈ fatty alcohol. In some cases, a lipid comprises a C₁₂-C₁₈ fatty alcohol. Exemplary fatty alcohols can include lauryl, stearyl, and oleyl alcohols. In some cases, a lipid comprises a mixture of lipids from a combination of the foregoing. In some embodiments, lipids can include an edible vegetable oil, such as soybean oil, partially hydrogenated soybean oil, corn oil, sunflower oil, or peanut oil. Other examples of vegetable oils include almond oil, argan oil, avocado oil, canola oil, coconut oil, cocoa butter, corn oil, cottonseed oil, grape-seed oil, lemon oil, linseed oil, orange oil, olive oil, palm oil, peanut oil, safflower oil, soybean oil, sunflower oil, walnut oil, and wheat germ oil. In some embodiments, lipids comprises safflower oil, sesame oil, soybean oil, vegetable oil, or castor oil. In some instances, lipids include commercially available synthetic edible oils that are equivalent to the vegetable oils. For example, the triglycerides of the C₈-C₁₀ fatty acids of fractionated coconut oil are available under the trade name of "Miglyol. " Specifically, Miglyol is a triglyceride of capric and caprylic acids with glycerol. The oils can also include sugar fatty acids known as "Olestras. ” In some cases, a lipid comprise Capmul MCM C8, Miglyol 812, Lauroglycol 90, Maisine 35-1, Capryol 90, Oleic acid, castor oil, vegetable oil, soybean oil, safflower oil, sesame oil, corn oil, olive oil, or any combinations thereof. In some cases, a lipid comprises Capmul MCM C8. In some cases, a lipid comprises Miglyol 812. In some cases, a lipid comprises Lauroglycol 90. In some cases, a lipid comprises Maisine 35-1. In some cases, a lipid comprises Capryol 90.In some cases, a lipid comprises oleic acid. In some cases, a lipid comprises Soybean SR oil. In some cases, a lipid comprises safflower SR oil. In some cases, a lipid comprises sesame oil. In some cases, a lipid comprises corn oil. In some cases, a lipid comprises olive oil. In some cases, a lipid also functions as a surfactant.

The liquid vehicle can include ethanol, propylene glycol, glycol, glycerin, polyethylene glycol (PEG) , lipid, ether alcohol, polyether, sugar alcohol (optionally sorbitol) or a combination thereof. In some cases, the liquid vehicle comprises propylene glycol, glycerol, diethylene glycol monoethyl ether, PEG, or any combinations thereof. In some cases, the PEG has a molecular weight of about 300 g/mol to about 400 g/mol.

In some embodiments, the liquid vehicle comprises propylene glycol. In some embodiments, the liquid vehicle comprises glycerin. In some embodiments, the liquid vehicle comprises sugar alcohols (e.g., sorbitol) . In some embodiments, the liquid vehicle comprises alcohol, such as ethyl alcohol or ethanol. In some embodiments, the liquid vehicle comprises glycol. In some embodiments, the liquid vehicle comprises polyether. In some embodiments, the liquid vehicle comprises lipids, such as Capmul MCM C8, Miglyol 812, Lauroglycol 90, Maisine 35-1, Capryol 90, Oleic acid, Soybean SR oil, Safflower SR oil, Sesame oil, Corn oil, Olive Oil, or any combinations thereof. In some embodiments, the liquid vehicle comprises sugar alcohol, such as sorbitol.

In some embodiments, the liquid vehicle comprises PEG. In some embodiments, the PEG has an average molecular weight of about 200 to about 10,000 g/mol. In some embodiments, the PEG has an average molecular weight of about 200 to about 500 g/mol, about 500 to about 1000 g/mol, about 1000 to about 5000 g/mol, about 5000 to about 10,000 g/mol. In some embodiments, the PEG has an average molecular weight of about 200 to about 500 g/mol. In some embodiments, the PEG has an average molecular weight of about 300 to about 500 g/mol. In some embodiments, the PEG has an average molecular weight of about 350 to about 450 g/mol. In some embodiments, the PEG has an average molecular weight of about 400 g/mol. In some embodiments, the PEG has a number average molecular weight of about 200 to about 10,000 g/mol. In some embodiments, the PEG has a number average molecular weight of about 200 to about 500 g/mol, about 500 to about 1000 g/mol, about 1000 to about 5000 g/mol, about 5000 to about 10,000 g/mol. In some embodiments, the liquid vehicle comprises PEG having a number average molecular weight of about 300 to about 400 g/mol.

In some embodiments, the liquid vehicle is present in a liquid pharmaceutical formulation described herein in an amount of about 10 %w/v to about 15 %w/v, about 15 %w/v to about 20 %w/v, about 20 %w/v to about 30 %w/v, about 30 %w/v to about 40 %w/v, about 40 %w/v to about 50 %w/v, about 50 %w/v to about 60 %w/v, about 60 %w/v to about 70 %w/v, about 70 %w/v to about 80 %w/v, about 80 %w/v to about 90 %w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 0.01%w/v to about 90%w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 1%w/v to about 80%w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of from about 1%w/v to about 70%w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of from about 1%w/v to about 60%w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of from about 1%w/v to about 50%w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of from about 1%w/v to about 40%w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of from about 1%w/v to about 30%w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of from about 1%w/v to about 20%w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 10 %w/v to about 20 %w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 20 %w/v to about 30 %w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 30 %w/v to about 40 %w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 40 %w/v to about 50 %w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 50 %w/v to about 60 %w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 60 %w/v to about 70 %w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 70 %w/v to about 80 %w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 80 %w/v to about 90 %w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 90 %w/v to about 99 %w/v.

In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 10 %w/v to about 15 %w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 15 %w/v to about 20 %w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 20 %w/v to about 25 %w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 25 %w/v to about 30 %w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 30 %w/v to about 35 %w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of from about 3%w/v to about 10%w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 5%w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 10%w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 15%w/v. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 20%w/v. In some embodiments, the liquid vehicle comprises propylene glycol. In some embodiments, the liquid vehicle is present in the liquid pharmaceutical formulation in an amount of about 35 %w/v to about 40 %w/v. In some embodiments, the liquid vehicle comprises propylene glycol. In some embodiments, the liquid vehicle comprises PEG 300 or PEG 400. In some embodiments, the liquid vehicle comprises glycerol. In some embodiments, the liquid vehicle comprises diethylene glycol monoethyl ether (e.g., sold under the trade name ) . In some embodiments, the liquid vehicle comprises Capmul MCM C8, Miglyol 812, Lauroglycol 90, Maisine 35-1, Capryol 90, Oleic acid, Soybean SR oil, Safflower SR oil, Sesame oil, Corn oil, Olive Oil, or any combinations thereof.

Buffer and pH-adjusting agent

In some aspects, pharmaceutical formulations and/or the pharmaceutical compositions of the present disclosure include a buffer or a pH-adjusting agent. A pH-adjusting agent can adjust the pH of the liquid formulations described herein. A buffer can provide protection from changes in pH ( "pH shift" ) during storage. Buffers of the present disclosure can provide a pH of from about 4.0 to about 6.0, about 4.5 to about 5.5, or about 5.0 in the composition. Buffers can also be selected and employed at concentrations sufficient to resist a pH change of more than 0.5 pH units over a long term, such as over a period of two years. Buffers can maintain pH of Compound A liquid pharmaceutical formulation described herein. In some cases, buffers provide stability of the Compound A liquid pharmaceutical formulation over a long term, such as over a period of two years. In some cases, the buffer is configured to provide a pH of from about 1.0 to about 11.0, from about 2.5 to about 7.5, from about 3.0 to about 7.0, from about 3.0 to about 6.5, from about 3.5 to about 6.0, or from about 4.0 to about 5.5. In some cases, the buffer is configured to provide a pH of from about 3.0 to about 11.0. In some cases, the buffer is configured to provide a pH of from about 3.0 to about 5.5.

A buffer and its concentration can be selected to provide a desired pH for the formulation as described herein. A buffer can comprise two buffering agents (e.g., a weak acid and a conjugate salt thereof) . The buffer can comprise three buffering agents or more. In some embodiments, the buffer comprises a weak acid and a conjugate salt thereof.

In some embodiments, a pharmaceutical formulation and/or pharmaceutical composition for preparation thereof described herein comprises a buffer. A buffering agent can be weak acids and their conjugate base or salts thereof. In some embodiments, a buffering agent comprises a cation selected from sodium, potassium, magnesium, calcium, and aluminum, and an anion selected from carbonate, bicarbonate, hydroxide, gluconate, glycinate, glutamate, mesylate, aspartate, oxalate, succinate, and other appropriate amino acid salts. In some embodiments, a buffering agent comprises citric acid, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, phosphoric acid, lactic acid, tartaric acid, fumaric acid, succinic acid, glutamic acid, gluconic acid, malic acid, oxalic acid, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, other calcium salts, amino acid (such as histidine, lysine, aspartic acid) a mixture thereof.

In some embodiments, a buffering agent comprises citric acid and citrate. In some embodiments, a buffering agent comprises phosphoric acid and phosphate. In some embodiments, a buffering agenting agent comprises acetic acid and acetate. In some embodiments, a buffering agent comprises benzoic acid and benzoate. In some embodiments, a buffering agent comprises sorbic acid and sorbate. In some embodiments, a buffering agent comprises carbonate. In some embodiments, a buffering agent comprises bicarbonate. In some embodiments, a buffering agent comprises glycine/glycine HCl. In some embodiments, a buffering agent comprises monobasic/dibasic phosphate. In some embodiments, a buffering agent comprises tartaric acid and tartrate. In some embodiments, a buffering agent comprises propionic acid and propionate. In some embodiments, a buffering agent comprises malic acid and malate. In some embodiments, a buffering agent comprises fumaric acid and fumarate. In some embodiments, a buffering agent comprises ascorbic acid and ascorbate. In some embodiments, a buffering agent comprises formic acid and formate. In some embodiments, a buffering agent comprises lactic acid and lactate. In some embodiments, a buffering agent comprises gluconic acid and gluconate. In some embodiments, a buffering agent comprises aspartic acid and aspartate. In some embodiments, a buffering agent comprises glutamic acid and glutamate. In some embodiments, a buffering agent comprises maleic acid and maleate. In some embodiments, a buffering agent comprises succinic acid and or succinate.

In some embodiments, a buffering agent comprises citrate, tartrate, acetate, carbonate, phosphate, metaphosphate, glycerophosphate, polyphosphate, pyrophosphate, oxide, lactate, fumarate, or a combination thereof. In some embodiments, a buffering agenting agent comprises citrate. In some embodiments, a buffering agent comprises tartrate. In some embodiments, a buffering agent comprises acetate. In some embodiments, a buffering agent comprises carbonate. In some embodiments, a buffering agent comprises phosphate. In some embodiments, a buffering agent comprises metaphosphate. In some embodiments, a buffering agent comprises glycerophosphate. In some embodiments, a buffering agent comprises polyphosphate. In some embodiments, a buffering agent comprises pyrophosphate. In some embodiments, a buffering agent comprises oxide. In some embodiments, a buffering agent comprises lactate. In some embodiments, a buffering agent comprises fumarate. In some embodiments, the buffer is citrate buffer. In some embodiments, the buffer is phosphate buffer.

In some embodiments, a buffering agenting agent is present in an amount of about 5%w/v or less. In some embodiments, a buffering agent is present in an amount of about 4%w/v or less. In some embodiments, a buffering agent is present in an amount of about 3%w/v or less. In some embodiments, a buffering agent is present in an amount of about 2%w/v or less. In some embodiments, a buffering agent is present in an amount of about 1%w/v or less. In some embodiments, a buffering agent is present in an amount of about 0.9%w/v or less. In some embodiments, a buffering agent is present in an amount of about 0.8%w/v or less. In some embodiments, a buffering agent is present in an amount of about 0.7%w/v or less. In some embodiments, a buffering agent is present in an amount of about 0.6%w/v or less. In some embodiments, a buffering agent is present in an amount of about 0.5%w/v or less. In some embodiments, a buffering agent is present in an amount of about 0.4%w/v or less. In some embodiments, a buffering agent is present in an amount of about 0.3%w/v or less. In some embodiments, a buffering agent is present in an amount of or about 0.2%w/v or less.

In some embodiments, the buffer comprises citrate buffer. In some cases, the buffering agent comprises citric acid and sodium citrate. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of from about 0.01%w/v to about 8.0%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of from about 0.05%w/v to about 5.0%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of from about 0.05%w/v to about 3.5%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of from about 0.05%w/v to about 2.5 %w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of from about 0.1%w/v to about 2.0 %w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of from about 0.1%w/v to about 1.5 %w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of from about 0.1%w/v to about 1.0 %w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of from about 0.1%w/v to about 0.8 %w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of from about 0.2%w/v to about 0.6 %w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of or about 0.2%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of about 0.25%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of about 0.3%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of about 0.35%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of about 0.4%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of about 0.45%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of about 0.5%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of about 0.55%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of or about 0.6%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of or about 0.7%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of or about 0.8%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of or about 0.9%w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of from about 0.05%w/v to about 5%w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of from about 0.1%w/v to about 3.0 %w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of from about 0.2%w/v to about 2.0 %w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of from about 0.3%w/v to about 1.0 %w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of from about 0.4%w/v to about 0.8 %w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.2%w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.3%w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.4%w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.45%w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.5%w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.55%w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.6%w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.65%w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.7%w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.75%w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.8%w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.9%w/v. In some embodiments, sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 1.0%w/v. In some embodiments, the liquid pharmaceutical formulation comprises citric acid and sodium citrate in a weight ratio of from about 1: 50 to about 50: 1, about 1: 20 to about 20: 1, about 1: 15 to about 15: 1, about 1: 10 to about 10: 1, about 1: 5 to about 5: 1, about 1: 3 to about 3: 1, or about 1: 2 to about 2:1. In some embodiments, the liquid pharmaceutical formulation comprises citric acid and sodium citrate in a weight ratio of from about 5: 1 to about 1: 15. In some embodiments, the liquid pharmaceutical formulation comprises citric acid and sodium citrate in a weight ratio of from about 4: 1 to about 1: 1. In some embodiments, the liquid pharmaceutical formulation comprises citric acid and sodium citrate in a weight ratio of from about 1: 1 to about 1: 10. In some embodiments, the liquid pharmaceutical formulation comprises citric acid and sodium citrate in a weight ratio of from about 2: 1 to about 1: 8. In some embodiments, the liquid pharmaceutical formulation comprises citric acid and sodium citrate in a weight ratio of from about 8: 5 to about 1: 5. In some embodiments, the liquid pharmaceutical formulation comprises citric acid and sodium citrate in a weight ratio of from about 8: 5 to about 1: 1. In some embodiments, the liquid pharmaceutical formulation comprises citric acid and sodium citrate in a weight ratio of from about 1: 1 to about 1: 2. In some embodiments, the liquid pharmaceutical formulation comprises citric acid and sodium citrate in a weight ratio of from about 1: 2 to about 1: 5. In some embodiments, the liquid pharmaceutical formulation comprises citric acid and sodium citrate in a weight ratio of from about 1: 1. In some embodiments, the liquid pharmaceutical formulation comprises citric acid and sodium citrate in a weight ratio of from about 1: 2. In some embodiments, the liquid pharmaceutical formulation comprises citric acid and sodium citrate in a weight ratio of from about 8: 5. In some embodiments, the liquid pharmaceutical formulation comprises citric acid and sodium citrate in a weight ratio of from about 1: 5. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of about 0.2%w/v to about 1.0%w/v and sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.2%w/v to about 1.0%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of about 0.4%w/v and sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.4%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of about 0.3%w/v and sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.3%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of about 0.35%w/v and sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.6%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of about 0.9%w/v and sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 0.5%w/v. In some embodiments, citric acid is present in the liquid pharmaceutical formulation in an amount of about 0.2%w/v and sodium citrate is present in the liquid pharmaceutical formulation in an amount of about 1.0%w/v.

In some embodiments, the buffer is present in the Compound A liquid formulations described herein in an amount of from about 1 mM to about 1000 mM, about 1 mM to about 10mM, about 0.01 mM to about 20 mM, about 5 mM to about 25 mM, from about 10 mM to about 500 mM, from about 10 mM to about 400 mM, from about 10 mM to about 300 mM, from about 10 mM to about 300 mM, from about 10 mM to about 150 mM, from about 10 mM to about 50 mM, from about 20 mM to about 40 mM, from about 50 mM to about 100 mM, or from about 80 mM to about 120 mM. In some embodiments, the buffer is present in the Compound A liquid formulations described herein in an amount of from about 1 mM to about 1000 mM. In some embodiments, the buffer is present in an amount of from about 1 mM to about 10mM. In some embodiments, the buffer is present in an amount of about 0.01 mM to about 20 mM.In some embodiments, the buffer is present in an amount of about 5 mM to about 25 mM. In some embodiments, the buffer is present in an amount of from about 10 mM to about 500 mM. In some embodiments, the buffer is present in an amount of from about 10 mM to about 400 mM. In some embodiments, the buffer is present in an amount of from about 10 mM to about 300 mM. In some embodiments, the buffer is present in an amount of from about 10 mM to about 300 mM. In some embodiments, the buffer is present in an amount of from about 10 mM to about 150 mM. In some embodiments, the buffer is present in an amount of from about 10 mM to about 50 mM. In some embodiments, the buffer is present in an amount of from about 20 mM to about 40 mM. In some embodiments, the buffer is present in an amount of from about 40 mM to about 80 mM. In some embodiments, the buffer is present in an amount of from about 50 mM to about 100 mM. In some embodiments, the buffer is present in an amount of from about 80 mM to about 120 mM. In some embodiments, the buffer is present in an amount of about 50 mM. In some embodiments, the buffer is present in an amount of about 60 mM. In some embodiments, the buffer is present in an amount of about 70 mM. In some embodiments, the buffer is present in an amount of about 80 mM. In some embodiments, the buffer is present in an amount of about 90 mM. In some embodiments, the buffer is present in an amount of about 100 mM. In some embodiments, the buffer is present in an amount of about 110 mM. In some embodiments, the buffer is present in an amount of about 120 mM. In some cases, the buffer is citrate buffer. In some cases, the buffer is phosphate buffer.

In some embodiments, the pH of the Compound A liquid formulations can be adjusted with a pH-adjusting agent. Any pH-adjusting agent suitable use for liquid formulation can be used. In some cases, a pH-adjusting agent include a strong acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc. ) or a strong base (sodium hydroxide, potassium hydroxide, etc. ) , or any suitable acids or bases described herein (e.g., components used in buffers described herein) . In some cases, a pH-adjusting agent comprises sodium hydroxide, potassium hydroxide, magnesium hydroxide, hydrochloric acid, acetic acid, sulfuric acid, sulfate, or any combinations thereof. In some cases, a pH-adjusting agent comprises sodium hydroxide. In some cases, a pH-adjusting agent comprises hydrochloric acid. In some cases, a pH-adjusting agent is added during the preparation of the liquid pharmaceutical formulation. In some cases, a pH-adjusting agent comprises sodium chloride, sodium biphosphate, sodium phosphate, sodium hydroxide, ammonium hydroxide, potassium hydroxide, magnesium hydroxide, hydrochloric acid, acetic acid, boric acid, sodium borate decahydrate, sodium acetate, sulfuric acid, sulfate, ammonium sulfate, ammonium or arginine, aspartic acid, benzene sulfonic acid, benzoate sodium/acid , carbonate dioxide, tartrate sodium/acid, tromethamine, or any combinations thereof.

In some embodiments, the pH-adjusting agent is present in the Compound A liquid formulations described herein in an amount of from about 1 mM to about 1000 mM, about 1 mM to about 10mM, about 0.01 mM to about 20 mM, about 5 mM to about 25 mM, from about 10 mM to about 500 mM, from about 10 mM to about 400 mM, from about 10 mM to about 300 mM, from about 10 mM to about 300 mM, from about 10 mM to about 150 mM, from about 10 mM to about 50 mM, from about 20 mM to about 40 mM, from about 50 mM to about 100 mM, or from about 80 mM to about 120 mM. In some embodiments, the pH-adjusting agent is present in the Compound A liquid formulations described herein in an amount of from about 1 mM to about 1000 mM. In some embodiments, the pH-adjusting agent is present in an amount of from about 1 mM to about 10mM. In some embodiments, the pH-adjusting agent is present in an amount of from about 0.01 mM to about 20 mM. In some embodiments, the pH-adjusting agent is present in an amount of from about 5 mM to about 25 mM. In some embodiments, the pH-adjusting agent is present in an amount of form about 10 mM to about 500 mM. In some embodiments, the pH-adjusting agent is present in an amount of form about 10 mM to about 400 mM. In some embodiments, the pH-adjusting agent is present in an amount of form about 10 mM to about 300 mM. In some embodiments, the pH-adjusting agent is present in an amount of form about 10 mM to about 300 mM. In some embodiments, the pH-adjusting agent is present in an amount of form about 10 mM to about 150 mM. In some embodiments, the pH-adjusting agent is present in an amount of form about 10 mM to about 50 mM. In some embodiments, the pH-adjusting agent is present in an amount of form about 20 mM to about 40 mM. In some embodiments, the pH-adjusting agent is present in an amount of form about 50 mM to about 100 mM. In some embodiments, the pH-adjusting agent is present in an amount of from or from about 80 mM to about 120 mM.

In some embodiments, buffers described herein maintains a pH of a liquid pharmaceutical formulation described herein within a certain range. In some embodiments, liquid pharmaceutical formulation described herein has pH of from about 1.0 to about 11.0. In some embodiments, a liquid pharmaceutical formulation described herein has a pH of from about 2.0 to about 11.0. In some embodiments, a liquid pharmaceutical formulation described herein has a pH of from about 3.0 to about 11.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of from about 1.5 to about 10.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of from about 1.5 to about 9.5. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 2.0 to about 9.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 2.5 to about 8.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 3.0 to about 7.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 3.0 to about 5.5. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 3.5 to about 6.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 3.5 to about 5.5. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 3.5 to about 5.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 3.5 to about 4.5. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 4.0 to about 5.5. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 4.0 to about 5.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 2.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 2.5. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 3.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 3.25. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 3.5. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 3.75. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 4.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 4.1. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 4.2. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 4.25. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 4.3. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 4.4. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 4.5. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 4.6. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 4.7. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 4.8. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 4.9. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 5.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 5.25. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 5.5. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 5.75. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 6.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 6.5. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 7.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 7.5. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 8.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 8.5. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 9.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 9.5. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 10.0. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 10.5. In some embodiments, liquid pharmaceutical formulation described herein has pH of about 11.0. In some embodiments, buffers described herein are configured to adjust and maintain pH to a forgoing range.

In some embodiments, buffers described herein are configured to adjust and maintain pH within the range of about 3.5 to about 7.0. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 3.5 to about 6.0. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 4.0 to about 5.5. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 3.5 to about 5.0. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 3.5 to about 4.5. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 4.0 to about 4.5. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 4.5 to about 5.0. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 5.0 to about 5.5. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 4.0. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 4.25. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 4.5. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 4.75. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 5.0. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 5.25. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 5.5. In some cases, the buffer is citrate buffer.

In some embodiments, buffers described herein are configured to adjust and maintain pH within the range of about 5.0 to about 9.0. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 5.5 to about 8.0. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 6.0 to about 7.5. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 5.0 to about 6.5. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 6.5 to about 8.5. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 7.0 to about 8.0. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 6.0. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 6.25. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 6.5. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 6.75. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 7.0. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 7.25. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 7.5. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 7.75. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 8.0. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 8.5. In some embodiments, buffers described herein are configured to adjust and maintain pH at about 9.0. In some cases, the buffer is phosphate buffer.

In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH within the range of about 1.0 to about 11.0. In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH within the range of about 3.0 to about 9.0. In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH within the range of about 4.0 to about 8.0. In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH within the range of about 5.0 to about 9.0. In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH within the range of about 3.5 to about 7.0. In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH within the range of about 4.0 to about 5.5. In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH within the range of about 4.0 to about 4.5. In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH within the range of about 4.0 to about 5.0. In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH within the range of about 4.5 to about 5.5. In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH of about 4.0. In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH within a range of about 6.0 to about 8.0. In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH of about 6.0. In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH of about 6.5. In some embodiments, a pH- adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH of about 7.0. In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH of about 7.25. In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH of about 7.5. In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH of about 7.75. In some embodiments, a pH-adjusting agent described herein is configured to adjust pH of the Compound A liquid formulations described herein to a pH of about 8.0.

Preservatives

In some embodiments, liquid formulations for inhalation and/or the pharmaceutical compositions described herein further comprise a preservative. Preservatives can include anti-microbials, antioxidants, chelating agents, and other agents that enhance sterility, such that a low bioburden is maintained in the formulation of the present disclosure from preparation through storage, and during routine use by patients and clinicians. Exemplary preservatives include BHA, BHT, ascorbic acid, ascorbyl palmitate, citric acid, EDTA and its salts, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens (such as methylparaben, ethylparaben, propylparaben, butylparaben and their salts) , benzoic acid, sodium benzoate, potassium sorbate, vanillin, and the like. In some embodiments, the preservative comprises EDTA.

In some embodiments, a preservative comprises an antimicrobial agent, a chelating agent, an antioxidant, or a combination thereof. In some embodiments, the preservative comprises an antimicrobial agent. In some embodiments, the preservative comprises a chelating agent. In some embodiments, the preservative comprises an antioxidant. In some embodiments, the preservative comprises an antimicrobial agent and an antioxidant. In some embodiments, the preservative comprises an antimicrobial agent, a chelating agent, and an antioxidant.

In some embodiments, a preservative comprises sodium benzoate, sodium sorbate, EDTA and its salts, parabens (such as methylparaben, ethylparaben, propylparaben, butylparaben and their salts) , potassium sorbate, benzyl alcohol, benzoic acid, sorbic acid, antibacterial agents such as halogenated diphenyl ether (e.g., triclosan) , herbal extracts and essential oils (e.g., rosemary extract, tea extract, magnolia extract, thymol, menthol, eucalyptol, geraniol, carvacrol, citral, hinokitol, catechol, methyl salicylate, epigallocatechin gallate, epigallocatechin, gallic acid, miswak extract, sea-buckthorn extract) , bisguanide antiseptics (e.g., chlorhexidine, alexidine or octenidine) , quaternary ammonium compounds (e.g., cetylpyridinium chloride (CPC) , benzalkonium chloride, tetradecylpyridinium chloride (TPC) , N-tetradecyl-4-ethylpyridinium chloride (TDEPC) ) , phenolic antiseptics, hexetidine, octenidine, sanguinarine, povidone iodine, delmopinol, salifluor, phthalic acid, monoperthalic acid and its esters, ascorbyl stearate, oleoyl sarcosine, alkyl sulfate, dioctyl sulfosuccinate, salicylanilide, domiphen bromide, delmopinol, octapinol and other piperidino derivatives, nicin preparations, or any combination thereof. In some embodiments, the preservative is present in the liquid pharmaceutical formulation in an amount of about 0.01 %to about 10 %w/v. In some embodiments, the preservative is present in the liquid pharmaceutical formulation in an amount of about 0.01 %to about 0.1 %w/v, about 0.1 %to about 0.5 %w/v, about 0.5 %to about 1 %w/v, about 1 %to about 2 %w/v, about 2 %to about 3%w/v, about 3 %to about 4 %w/v, about 4 %to about 5 %w/v, about 5 %to about 7 %w/v, or about 7 %to about 10 %w/v. In some embodiments, the preservative is present in the liquid pharmaceutical formulation in an amount of about 0.05 %to about 1 %w/v. In some embodiments, the preservative is present in the liquid pharmaceutical formulation in an amount of about 0.1 %to about 0.5 %w/v. In some embodiments, the preservative is present in the liquid pharmaceutical formulation in an amount of about 0.2 %to about 0.25 %w/v. In some embodiments, the preservative is present in the liquid pharmaceutical formulation in an amount of about 0.1 %w/v. In some embodiments, the preservative is present in the liquid pharmaceutical formulation in an amount of about 0.01 %w/v. In some embodiments, the preservative is present in an amount of about 1%w/v or less. In some embodiments, the preservative is present in an amount of about 0.9%w/v or less. In some embodiments, the preservative is present in an amount of about 0.8%w/v or less. In some embodiments, the preservative is present in an amount of about 0.7%w/v or less. In some embodiments, the preservative is present in an amount of about 0.6%w/v or less. In some embodiments, the preservative is present in an amount of about 0.5%w/v or less. In some embodiments, the preservative is present in an amount of about 0.4%w/v or less. In some embodiments, the preservative is present in an amount of about 0.3%w/v or less. In some embodiments, the preservative is present in an amount of about 0.2%w/v or less. In some embodiments, the preservative is present in an amount of from about 0.001%w/v to about 1%w/v. In some embodiments, the preservative is present in an amount of from about 0.001%w/v to about 0.5%w/v. In some embodiments, the preservative is present in an amount of from about 0.005%w/v to about 0.2%w/v. In some embodiments, the preservative is present in an amount of from about 0.005%w/v to about 0.1%w/v. In some embodiments, the preservative is present in an amount of from about 0.005%w/v to about 0.01%w/v. In some embodiments, the preservative is present in an amount of from about 0.01%w/v to about 0.05%w/v. In some embodiments, the preservative is present in an amount of from about 0.01%w/v to about 0.1%w/v. In some embodiments, the preservative is present in an amount of from about 0.1%w/v to about 2%w/v. In some embodiments, the preservative is present in an amount of from about 0.01%w/v to about 0.2%w/v. In some embodiments, the preservative is present in an amount of from about 0.01%w/v to about 0.3%w/v. In some embodiments, the preservative is present in an amount of from about 0.01%w/v to about 0.4%w/v. In some embodiments, the preservative is present in an amount of from about 0.01%w/v to about 0.5%w/v. In some embodiments, the preservative is present in an amount of from about 0.05 %w/v to about 0.2%w/v. In some embodiments, the preservative is present in an amount of from about 0.1 %w/v to about 0.5%w/v.

In some embodiments, a preservative comprises an antimicrobial agent. In some embodiments, the antimicrobial agent comprises a paraben or a mixture of parabens, benzyl alcohol, benzoic acid or a pharmaceutically acceptable salt thereof, sorbic acid or a pharmaceutically acceptable salt thereof, phenoxyethanol, propionic acid, or a combination thereof. In some embodiments, an antimicrobial agent is present in the liquid pharmaceutical formulation in an amount of about 0.01 %to about 10 %w/v. In some embodiments, the antimicrobial agent is present in the liquid pharmaceutical formulation in an amount of about 0.01 %to about 0.1 %w/v, about 0.1 %to about 0.5 %w/v, about 0.5 %to about 1 %w/v, about 1 %to about 5 %w/v, or about 5 %to about 10 %w/v. In some embodiments, the antimicrobial agent is present in the liquid pharmaceutical formulation in an amount of about 0.05 %to about 1 %w/v. In some embodiments, the antimicrobial agent is present in the liquid pharmaceutical formulation in an amount of about 0.1 %to about 0.5 %w/v. In some embodiments, the antimicrobial agent is a mixture of parabens or salts thereof. In some embodiments, the antimicrobial agents are present in an amount sufficient to provide antimicrobial effectiveness to the Compound A liquid formulation for inhalation described herein.

In some embodiments, the preservative comprises an antioxidant, for example, vitamin A, monothioglycerol, ascorbic acid, sodium bisulfite, sodium sulfite, α-Tocopherol acetate (vitamin E) , butylated hydroxyanisole (BHA) , butylated hydroxytoluene (BHT) , or a combination thereof. In some embodiments, the antioxidant comprises vitamin A, monothioglycerol, ascorbic acid, sodium bisulfite, sodium sulfite, α-Tocopherol acetate (vitamin E) , butylated hydroxyanisole (BHA) , butylated hydroxytoluene (BHT) , propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates or a combination thereof. In some embodiments, the antioxidant is butylated hydroxyanisole (BHA) . In some embodiments, the antioxidant is butylated hydroxytoluene (BHT) . In some embodiments, the antioxidant is butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) .

In some embodiments, an antioxidant is present in the liquid pharmaceutical formulation in an amount of about 0.001 %w/v to about 0.5 %w/v. In other embodiments, the antioxidant is present in the liquid pharmaceutical formulation in an amount of about 0.001 %w/v to about 0.005 %w/v, about 0.005 %w/v to about 0.007 %w/v, about 0.007 %w/v to about 0.01 %w/v, about 0.01 %w/v to about 0.011 %w/v, about 0.011 %w/v to about 0.015 %w/v, about 0.015 %w/v to about 0.02 %w/v, about 0.02 %w/v to about 0.03 %w/v, about 0.03 %w/v to about 0.05 %w/v, about 0.05 %w/v to about 0.1 %w/v, or about 0.1 %w/v to about 0.5 %w/v. In some embodiments, the antioxidant is present in the liquid pharmaceutical formulation in an amount of about 0.005 %w/v to about 0.05 %w/v. In some embodiments, the antioxidant is present in the liquid pharmaceutical formulation in an amount of about 0.008 %w/v to about 0.02 %w/v. In some embodiments, the antioxidant is present in the liquid pharmaceutical formulation in an amount of about 0.001 %w/v to about 0.01 %w/v. In some embodiments, the antioxidant is present in the liquid pharmaceutical formulation in an amount of about 0.05 %w/v to about 0.1%w/v.

In some embodiments, the preservative comprises a chelating agent, such as disodium ethylenediaminetetraacetic acid, polyphosphates, citric acid, calcium disodium edetate, ethylenediaminetetraacetic acid (EDTA) , or a combination thereof. In some embodiments, the preservative agent is EDTA. In some embodiments, a chelating agent is present in the liquid pharmaceutical formulation in an amount of about 0.001 %w/v to about 5 %w/v. In other embodiments, the chelating agent is present in the liquid pharmaceutical formulation in an amount of about 0.001 %w/v to about 0.005 %w/v, about 0.005 %w/v to about 0.01 %w/v, about 0.01 %w/v to about 0.05 %w/v, about 0.05 %w/v to about 0.1 %w/v, about 0.1 %w/v to about 0.5 %w/v, about 0.5 %w/v to about 1 %w/v, about 1 %w/v to about 2 %w/v, or about 2 %w/v to about 5 %w/v. In some embodiments, the chelating agent is present in the liquid pharmaceutical formulation in an amount of about 0.005 %w/v to about 0.5 %w/v. In some embodiments, the chelating agent is present in the liquid pharmaceutical formulation in an amount of about 0.01 %w/v to about 0.2 %w/v. In some embodiments, the chelating agent is present in the liquid pharmaceutical formulation in an amount of about 0.05 %w/v to about 0.2 %w/v. In some embodiments, the chelating agent is present in the liquid pharmaceutical formulation in an amount of about 0.1 %w/v to about 0.5%. In some embodiments, the chelating agent is present in the liquid pharmaceutical formulation in an amount of about 0.05 %w/v to about 2 %w/v. In some embodiments, the preservative comprises EDTA.

In some embodiments, EDTA is present in the liquid pharmaceutical formulation in an amount of about 0.001 %w/v to about 5 %w/v. In some embodiments, EDTA is present in the liquid pharmaceutical formulation in an amount of about 0.001 %w/v to about 0.005 %w/v, about 0.005 %w/v to about 0.01 %w/v, about 0.01 %w/v to about 0.05 %w/v, about 0.05 %w/v to about 0.1 %w/v, about 0.1 %w/v to about 0.5 %w/v, about 0.5 %w/v to about 1 %w/v, about 1 %w/v to about 2 %w/v, or about 2 %w/v to about 5 %w/v. In some embodiments, EDTA is present in the liquid pharmaceutical formulation in an amount of about 0.001 %w/v to about 1 %w/v. In some embodiments, EDTA is present in the liquid pharmaceutical formulation in an amount of about 0.005 %w/v to about 0.5 %w/v. In some embodiments, EDTA is present in the liquid pharmaceutical formulation in an amount of about 0.1 %w/v to about 0.5%. In some embodiments, EDTA is present in the liquid pharmaceutical formulation in an amount of about 0.01 %w/v to about 0.2 %w/v. In some embodiments, EDTA is present in the liquid pharmaceutical formulation in an amount of about 0.05 %w/v to about 0.2 %w/v. In some embodiments, EDTA is present in the liquid pharmaceutical formulation in an amount of about 0.01 %w/v to about 0.1 %w/v. In some embodiments, EDTA is present in the liquid pharmaceutical formulation in an amount of about 0.02 %w/v to about 0.08 %w/v. In some embodiments, EDTA is present in the liquid pharmaceutical formulation in an amount of about 0.04 %w/v to about 0.06 %w/v. In some embodiments, EDTA is present in the liquid pharmaceutical formulation in an amount of about 0.05 %w/v.

Surfactant

In some embodiments, Compound A pharmaceutical formulations for inhalation and/or pharmaceutical compositions described herein comprise a surfactant. In some embodiments, surfactants are compounds or mixture of compounds comprising a hydrophobic group (usually a hydrocarbon chain) and a hydrophilic group.

Any surfactant suitable for use Compound A liquid formulations described herein can be used. A surfactant used in the liquid formulations described herein can comprise a non-ionic surfactant. A surfactant used in the liquid formulations described herein can comprise an ionic surfactant. A surfactant used in the liquid formulations described herein can comprise a zwitterionic surfactant. A surfactant used in the liquid formulations described herein can comprise a cationic surfactant. A surfactant used in the liquid formulations described herein can comprise an anionic surfactant. A surfactant used in the liquid formulations described herein can comprise a mixture of the foregoing.

In some embodiments, a non-ionic surfactant has no charged groups in its head. Exemplary nonionic surfactants include, without limitation, fatty alcohols, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and oleyl alcohol. Exemplary nonionic surfactants include, but are not limited to, polyethylene glycol alkyl ethers (such as octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether) , polypropylene glycol alkyl ethers, glucoside alkyl ethers (such as decyl glucoside, lauryl glucoside, octyl glucoside) , polyethylene glycol octylphenyl ethers (such as Triton X-100) , polyethylene glycol alkylphenyl ethers (such as nonoxynol-9) , glycerol alkyl esters (such as glyceryl laurate) , polyoxyethylene glycol sorbitan alkyl esters (such as polysorbate) , sorbitan alkyl esters (such as Spans) , cocamide MEA, cocamide DEA, block copolymers of polyethylene glycol and polypropylene glycol (such as poloxamers) , polyethoxylated tallow amine (POEA) , and Tocopheryl polyethylene glycol 1000 succinate (simply TPGS or Vitamin E TPGS) . In some embodiments, a non-ionic surfactant comprises one or more of fatty alcohols, e.g., cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and oleyl alcohol. In some embodiments, the non-ionic surfactant comprises a C₉-C₃₀ fatty alcohol or fatty acid. In some embodiments, the non-ionic surfactant comprises a C₁₂-C₂₄ fatty alcohol or fatty acid. In some embodiments, the non-ionic surfactant comprises a C₁₂-C₁₈ fatty alcohol or fatty acid. Exemplary nonionic surfactants include, but are not limited to, polyethylene glycol alkyl ethers (such as octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether) , polypropylene glycol alkyl ethers, glucoside alkyl ethers (such as decyl glucoside, lauryl glucoside, octyl glucoside) , polyethylene glycol octylphenyl ethers (such as Triton X-100) , polyethylene glycol alkylphenyl ethers (such as nonoxynol-9) , glycerol alkyl esters (such as glyceryl laurate) , polyoxyethylene glycol sorbitan alkyl esters (such as polysorbate) , sorbitan alkyl esters (such as Spans) , cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (such as poloxamers) , polyethoxylated tallow amine (POEA) , and Tocopheryl polyethylene glycol 1000 succinate (simply TPGS or Vitamin E-TPGS) . Anionic surfactants can include Sodium lauryl sulphate (SLS) . Cationic surfactants can include Benzalkonium chloride and Cetylpyridinium chloride.

Exemplary surfactants suitable for use in Compound A liquid formulations described herein can include polysorbate, polyethoxylated glyceride, polyoxylglycerides, polyethylene-polypropylene glycol, tocopherols, oleoyl polyoxylglycerides, linoleoyl macrogoglycerides, or lauroyl macrogolglycerides, or any combinations thereof. In some cases, the surfactant comprises polysorbate (sold under trade names such as20, 80, etc. ) . In some cases, the surfactant comprises polyethoxylated glyceride. In some cases, the surfactant comprises polyoxylglycerides. In some cases, the surfactant comprises polyethylene-polypropylene glycol. In some cases, the surfactant comprises tocopherols. In some cases, the surfactant comprises oleoyl polyoxylglycerides. In some cases, the surfactant comprises linoleoyl macrogoglycerides. In some cases, the surfactant comprises or lauroyl macrogolglycerides.

In some cases, a surfactant used in the Compound A liquid formulations described herein comprises Poloxamer (e.g., Poloxamer 188, Poloxamer 407) , caprylocaproyl polyoxyl-8 glycerides (e.g., sold under the trade name Labrasol) , Polyoxyl 40 hydrogenated castor oil (e.g., sold under the trade name Kolliphor RH40) , Polyoxyl 35 Castor Oil (e.g., sold under the trade name Kolliphor EL) , Polyoxyl 15 Hydrostearate (e.g., sold under the trade name Kolliphor HS 15) , oleoyl polyoxyl-6 glycerides (e.g., sold under the trade name Labrafil M1944 CS) , Linoleoyl Polyoxyl-6 glycerides (e.g., sold under the trade name Labrafil M2125 CS) , D-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS) , Lauroyl Polyoxyl-32 glycerides (e.g., sold under the trade name Gelucire 44/14) , Stearoyl polyoxyl-32 glycerides (e.g., sold under the trade name Gelucire 50/13) , or polysorbate 20, or any combinations thereof. In some cases, a surfactant comprises Poloxamer (e.g., Poloxamer 188, Poloxamer 407) . In some cases, the surfactant comprises caprylocaproyl polyoxyl-8 glycerides (e.g., In some cases, the surfactant comprises sold under the trade name Labrasol) . In some cases, the surfactant comprises Polyoxyl 40 hydrogenated castor oil (e.g., In some cases, the surfactant comprises sold under the trade name Kolliphor RH40) . In some cases, the surfactant comprises Polyoxyl 35 Castor Oil (e.g., In some cases, the surfactant comprises sold under the trade name Kolliphor EL) . In some cases, the surfactant comprises Polyoxyl 15 Hydrostearate (e.g., In some cases, the surfactant comprises sold under the trade name Kolliphor HS 15) . In some cases, the surfactant comprises oleoyl polyoxyl-6 glycerides (e.g., In some cases, the surfactant comprises sold under the trade name Labrafil M1944 CS) . In some cases, the surfactant comprises Linoleoyl Polyoxyl-6 glycerides (e.g., In some cases, the surfactant comprises sold under the trade name Labrafil M2125 CS) . In some cases, the surfactant comprises D-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS) . In some cases, the surfactant comprises Lauroyl Polyoxyl-32 glycerides (e.g., In some cases, the surfactant comprises sold under the trade name Gelucire 44/14) . In some cases, the surfactant comprises Stearoyl polyoxyl-32 glycerides (e.g., In some cases, the surfactant comprises sold under the trade name Gelucire 50/13) . In some cases, the surfactant comprises polysorbate 20.

In some cases, a surfactant is present in the liquid pharmaceutical composition in an amount of from about 0.01%w/v to about 30%w/v. In some cases, a surfactant is present in the liquid pharmaceutical composition in an amount of from 0.1%w/v to about 5%w/v. In some cases, a surfactant is present in the liquid pharmaceutical composition in an amount of from 0.5%w/v to about 5%w/v. In some cases, a surfactant is present in the liquid pharmaceutical composition in an amount of from 1%w/v to about 10%w/v. In some cases, a surfactant is present in the liquid pharmaceutical composition in an amount of from 10%w/v to about 20%w/v. In some cases, a surfactant is present in the liquid pharmaceutical composition in an amount of from 20%w/v to about 30%w/v. In some cases, a surfactant is present in the liquid pharmaceutical composition in an amount of from 10%w/v to about 15%w/v. In some cases, a surfactant is present in the liquid pharmaceutical composition in an amount of from 15%w/v to about 20%w/v. In some cases, a surfactant is present in the liquid pharmaceutical composition in an amount of from about 20%w/v to about 25%w/v. In some cases, a surfactant is present in the liquid pharmaceutical composition in an amount of from 1%w/v to about 4%w/v. In some cases, a surfactant is present in the liquid pharmaceutical composition in an amount of from about 0.5%w/v to about 25%w/v. In some cases, a surfactant is present in the liquid pharmaceutical composition in an amount of from about 1%w/v to about 20%w/v.

In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 0.1%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 0.2%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 0.3%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 0.4%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 0.5%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 0.6%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 0.7%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 0.8%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 0.9%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 1%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 2%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 3%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 4%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 5%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 6%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 7%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 8%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 9%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 10%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 11%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 12%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 13%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 14%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 15%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 16%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 17%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 18%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 19%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 20%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 21%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 22%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 23%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 24%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 25%w/v. In some cases, a surfactant is present in the Compound A liquid pharmaceutical formulation described herein in an amount of from about 30%w/v.

Osmolarity adjusting agent

In some embodiments, Compound A liquid formulations for inhalation and/or pharmaceutical compositions described herein comprise an osmolarity adjusting agent. The osmolarity adjusting agent (or “tonicity agent” as used herein interchangeably) can be used to adjust the osmolarity of the liquid formulations and to improve the absorption of the formulation in the lungs of a subject when administered to a subject by inhalation. In some cases, the liquid pharmaceutical formulations described herein comprises osmolarity adjusting agents so that the liquid pharmaceutical formulations are substantially isotonic with physiologic fluids. In some cases, isotonic Compound A liquid pharmaceutical formulations when delivered by an inhalation device described herein, such as a nebulizer, can moisturize upper respiratory tract, ease congestion and help deliver the inhaled Compound A. In other cases, the liquid pharmaceutical formulations described herein comprises osmolarity adjusting agents so that the liquid pharmaceutical formulations are hypertonic with physiologic fluids. In yet another case, the liquid pharmaceutical formulations described herein comprises osmolarity adjusting agents so that the liquid pharmaceutical formulations are hypotonic with physiologic fluids.

Osmolarity adjusting agents illustratively include dextrose, glycerin, mannitol, potassium chloride, sodium chloride, magnesium chloride, calcium chloride and bromide salts, such as sodium bromide, magnesium bromide, or calcium chloride. In some cases, the liquid pharmaceutical formulations described herein comprises sodium chloride. In some cases, the osmolarity adjusting agent comprises potassium chloride, magnesium chloride, sodium chloride, sodium bromide, magnesium bromide, calcium chloride or calcium bromide. In some cases, the osmolarity adjusting agent is sodium chloride.

In some embodiments, a suitable amount of osmolarity adjusting agent is present in liquid pharmaceutical formulation described herein. In some embodiments, an osmolarity adjusting agent is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.01 %w/v to about 20 %w/v. In some embodiments, an osmolarity adjusting agent is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.01%w/v to about 10%w/v. In some embodiments, an osmolarity adjusting agent is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.05%w/v to about 5%w/v. In some embodiments, an osmolarity adjusting agent is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.1%w/v to about 2.5 %w/v. In some embodiments, an osmolarity adjusting agent is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.2%w/v to about 2 %w/v. In some embodiments, an osmolarity adjusting agent is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.2%w/v to about 1.5 %w/v. In some embodiments, an osmolarity adjusting agent is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.5%w/v to about 1.5 %w/v. In some embodiments, an osmolarity adjusting agent is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.25%w/v to about 0.75%w/v. In some embodiments, an osmolarity adjusting agent is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.5%w/v to about 0.75%w/v. In some embodiments, an osmolarity adjusting agent is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.8%w/v to about 1 %w/v. In some embodiments, an osmolarity adjusting agent is present in a liquid pharmaceutical formulation described herein in an amount of from about 1.0%w/v to about 1.2 %w/v. In other embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 0.01 %w/v to about 0.05 %w/v, about 0.05 %w/v to about 0.1 %w/v, about 0.1 %w/v to about 0.5 %w/v, about 0.5 %w/v to about 1 %w/v, about 0.5 %w/v to about 2 %w/v, about 0.5 %w/v to about 1.5 %w/v, about 0.7 %w/v to about 1.5 %w/v, or about 0.8 %w/v to about 1.2 %w/v. In some embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 0.2 %w/v. In some embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 0.3 %w/v. In some embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 0.4 %w/v. In some embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 0.5 %w/v. In some embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 0.6 %w/v. In some embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 0.7 %w/v. In some embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 0.8 %w/v. In some embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 0.9 %w/v. In some embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 1.0 %w/v. In some embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 1.1 %w/v. In some embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 1.2 %w/v. In some embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 1.5 %w/v. In some embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 2.0 %w/v. In some embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 2.5 %w/v. In some embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 5 %w/v. In some embodiments, the osmolarity adjusting agent is present in the liquid pharmaceutical formulation in an amount of about 10 %w/v. In some embodiments, the osmolarity adjusting agent is sodium chloride.

In some embodiments, Compound A liquid formulations described herein comprise sodium chloride. In some embodiments, sodium chloride is present in a liquid pharmaceutical formulation described herein in an amount of about 0.01 %w/v to about 20 %w/v. In some embodiments, sodium chloride is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.01%w/v to about 10%w/v. In some embodiments, sodium chloride is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.01%w/v to about 5%w/v. In some embodiments, sodium chloride is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.01%w/v to about 2.5 %w/v. In some embodiments, sodium chloride is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.1%w/v to about 2 %w/v. In some embodiments, sodium chloride is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.1%w/v to about 1.5 %w/v. In some embodiments, sodium chloride is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.1%w/v to about 1.5 %w/v. In some embodiments, sodium chloride is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.25%w/v to about 0.75%w/v. In some embodiments, sodium chloride is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.5%w/v to about 0.8%w/v. In some embodiments, sodium chloride is present in a liquid pharmaceutical formulation described herein in an amount of from about 0.8%w/v to about 1 %w/v. In some embodiments, sodium chloride is present in a liquid pharmaceutical formulation described herein in an amount of from about 1.0%w/v to about 1.2 %w/v. In other embodiments, sodium chloride is present in the liquid pharmaceutical formulation in an amount of about 0.01 %w/v to about 0.05 %w/v, about 0.05 %w/v to about 0.1 %w/v, about 0.1 %w/v to about 0.5 %w/v, about 0.5 %w/v to about 1 %w/v, about 0.5 %w/v to about 2 %w/v, about 0.5 %w/v to about 1.5 %w/v, about 0.7 %w/v to about 1.5 %w/v, or about 0.8 %w/v to about 1.2 %w/v. In some embodiments, sodium chloride is present in the liquid pharmaceutical formulation in an amount of about 0.2 %w/v. In some embodiments, sodium chloride is present in the liquid pharmaceutical formulation in an amount of about 0.3 %w/v. In some embodiments, sodium chloride is present in the liquid pharmaceutical formulation in an amount of about 0.4 %w/v. In some embodiments, sodium chloride is present in the liquid pharmaceutical formulation in an amount of about 0.5 %w/v. In some embodiments, sodium chloride is present in the liquid pharmaceutical formulation in an amount of about 0.6 %w/v. In some embodiments, sodium chloride is present in the liquid pharmaceutical formulation in an amount of about 0.7 %w/v. In some embodiments, sodium chloride is present in the liquid pharmaceutical formulation in an amount of about 0.75 %w/v. In some embodiments, sodium chloride is present in the liquid pharmaceutical formulation in an amount of about 0.8 %w/v. In some embodiments, sodium chloride is present in the liquid pharmaceutical formulation in an amount of about 0.9 %w/v. In some embodiments, sodium chloride is present in the liquid pharmaceutical formulation in an amount of about 1.0 %w/v.

In some embodiments, Compound A liquid formulations described herein comprise bromide salt, such as sodium bromide, magnesium bromide, or calcium chloride. In some cases, a bromide salt is present in liquid formulations described herein in an amount of from about 0.01%w/v to about 2%w/v, from about 0.01%w/v to about 0.1%w/v, from about 0.1 %w/v to about 0.5%w/v, from about 0.5%w/v to about 1%w/v, from about 1%w/v to about 1.5 %w/v, from about 1.5 %w/v to about 2.0 %w/v.

In some cases, osmolarity adjusting agents is configured to adjust osmolarity of the Compound A liquid formulations described herein. In some cases, the osmolarity of the pharmaceutical formulation is from about 10 mOsmol/L to about 6000 mOsmol/L, from about 10 mOsmol/L to about 5000 mOsmol/L, from about 20 mOsmol/L to about 4000 mOsmol/L, from about 40 mOsmol/L to about 3000 mOsmol/L, or from about 50 mOsmol/L to about 2000 mOsmol/L.

In some cases, Compound A liquid formulations described herein has an osmolality from about 1 mOsmol/kg to about 6000 mOsmol/kg. In some cases, Compound A liquid formulations described herein has an osmolality from about 10 mOsmol/kg to about 5000 mOsmol/kg. In some cases, Compound A liquid formulations described herein has an osmolality from about 20 mOsmol/kg to about 4000 mOsmol/kg. In some cases, Compound A liquid formulations described herein has an osmolality from about 40 mOsmol/kg to about 3000 mOsmol/kg. In some cases, Compound A liquid formulations described herein has an osmolality from about 50 mOsmol/kg to about 2000 mOsmol/kg. In some cases, Compound A liquid formulations described herein has an osmolality from about 1 mOsmol/kg to about 50 mOsmol/kg. In some cases, Compound A liquid formulations described herein has an osmolality from about 50 mOsmol/kg to about 200 mOsmol/kg. In some cases, Compound A liquid formulations described herein has an osmolality from about 200 mOsmol/kg to about 500 mOsmol/kg. In some cases, Compound A liquid formulations described herein has an osmolality from about 500 mOsmol/kg to about 1000 mOsmol/kg. In some cases, Compound A liquid formulations described herein has an osmolality from about 1000 mOsmol/kg to about 1500 mOsmol/kg. In some cases, Compound A liquid formulations described herein has an osmolality from about 1500 mOsmol/kg to about 2000 mOsmol/kg. In some cases, Compound A liquid formulations described herein has an osmolality from about 2000 mOsmol/kg to about 3000 mOsmol/kg. In some cases, Compound A liquid formulations described herein has an osmolality from about 3000 mOsmol/kg to about 4000 mOsmol/kg. In some cases, Compound A liquid formulations described herein has an osmolality from about 4000 mOsmol/kg to about 5000 mOsmol/kg. In some cases, Compound A liquid formulations described herein has an osmolality from about 5000 mOsmol/kg to about 6000 mOsmol/kg.

In some embodiments, the osmolality is at least about 10 mOsmol/kg. In some embodiments, the osmolality is at least about 50 mOsmol/kg. In some embodiments, the osmolality is at least about 100 mOsmol/kg. In some embodiments, the osmolality is at least about 200 mOsmol/kg. In some embodiments, the osmolality is at least about 300 mOsmol/kg. In some embodiments, the osmolality is at least about 400 mOsmol/kg. In some embodiments, the osmolality is at least about 500 mOsmol/kg. In some embodiments, the osmolality is at least about 600 mOsmol/kg. In some embodiments, the osmolality is at least about 700 mOsmol/kg. In some embodiments, the osmolality is at least about 800 mOsmol/kg. In some embodiments, the osmolality is at least about 900 mOsmol/kg. In some embodiments, the osmolality is at least about 1000 mOsmol/kg. In some embodiments, the osmolality is at least about 1300 mOsmol/kg. In some embodiments, the osmolality is at least about 1500 mOsmol/kg. In some embodiments, the osmolality is at least about 1700 mOsmol/kg. In some embodiments, the osmolality is at least about 2000 mOsmol/kg. In some embodiments, the osmolality is at least about 2300 mOsmol/kg. In some embodiments, the osmolality is at least about 2500 mOsmol/kg. In some embodiments, the osmolality is at least about 2800 mOsmol/kg. In some embodiments, the osmolality is at least about 3000 mOsmol/kg. In some embodiments, the osmolality is at least about 3500 mOsmol/kg. In some embodiments, the osmolality is at least about 4000 mOsmol/kg. In some embodiments, the osmolality is at least about 4500 mOsmol/kg. In some embodiments, the osmolality is at least about 5000 mOsmol/kg.

In some embodiments, the osmolality is at most about 50 mOsmol/kg. In some embodiments, the osmolality is at most about 100 mOsmol/kg. In some embodiments, the osmolality is at most about 200 mOsmol/kg. In some embodiments, the osmolality is at most about 300 mOsmol/kg. In some embodiments, the osmolality is at most about 400 mOsmol/kg. In some embodiments, the osmolality is at most about 500 mOsmol/kg. In some embodiments, the osmolality is at most about 600 mOsmol/kg. In some embodiments, the osmolality is at most about 700 mOsmol/kg. In some embodiments, the osmolality is at most about 800 mOsmol/kg. In some embodiments, the osmolality is at most about 900 mOsmol/kg. In some embodiments, the osmolality is at most about 1000 mOsmol/kg. In some embodiments, the osmolality is at most about 1300 mOsmol/kg. In some embodiments, the osmolality is at most about 1500 mOsmol/kg. In some embodiments, the osmolality is at most about 1700 mOsmol/kg. In some embodiments, the osmolality is at most about 2000 mOsmol/kg. In some embodiments, the osmolality is at most about 2300 mOsmol/kg. In some embodiments, the osmolality is at most about 2500 mOsmol/kg. In some embodiments, the osmolality is at most about 2800 mOsmol/kg. In some embodiments, the osmolality is at most about 3000 mOsmol/kg. In some embodiments, the osmolality is at most about 3500 mOsmol/kg. In some embodiments, the osmolality is at most about 4000 mOsmol/kg. In some embodiments, the osmolality is at most about 4500 mOsmol/kg. In some embodiments, the osmolality is at most about 5000 mOsmol/kg. In some embodiments, the osmolality is at most about 5500 mOsmol/kg. In some embodiments, the osmolality is at most about 6000 mOsmol/kg.

Suspending agent

In some embodiments, Compound A liquid formulations for inhalation and/or pharmaceutical compositions described herein is a suspension. A thickening agent, or suspending agent, may be added to prepare a suspension from a solution. Suspending agents are agents which facilitate the suspension and, in some cases, the dissolution of an active agent in a solvent or solution component. In some cases, suspending agents ensure more uniform mixing of active and solution components.

A subcategory of suspending agents is solubilizers. Solubilizers are agents which facilitate the dissolution of a solid or, in some cases, a semi-solid agent in a solution component. In some embodiments of the invention, a solid-form active agent may be dissolved in a suspending agent, prior to mixing it with the solution component. Conversely, the suspending agent and the solution component may be prepackaged together, particularly if the concern is ensuring the uniform blending of active agent within the solution component rather than the loss of solid (i.e., powdery) active agent. In still other variations, the suspending agent may be premixed with solution component.

Non-limiting examples of suspending agents useful in the compositions of the present disclosure include, but are not limited to, glycerin, hexylene glycol, propylene glycol, sorbitol, acacia, cholesterol, diethanolamine (adjunct) , glyceryl monostearate, lanolin alcohols, lecithin, mono-and di-glycerides, monoethanolamine (adjunct) , oleic acid (adjunct) , oleyl alcohol (stabilizer) , poloxamer, polyoxyethylene 50 Stearate, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, propylene glycol diacetate, propylene glycol monostearate, sodium lauryl sulfate, sodium stearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monstearate, stearic acid, trolamine, emulsifying wax, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, docusate sodium, nonoxynol 9, nonoxynol 10, Octoxynol 9, polyoxyl 50 Stearate, tyloxapol, and a combination thereof.

Still other suspending agents include humectants and wetting agents. Humectants are agents which retain moisture. Examples of humectants include, but are not limited to, glycerin, hexylene glycol, propylene glycol, and sorbitol. See, for example, US Publication No. US 2004/0191276, which is incorporated herein by reference.

In some embodiments, a suspending agent described herein is present in the liquid vehicle or in the suspension is from about 0.2%to about 10%w/v, about 0.5%to about 2%w/v, about 0.5%to about 5%w/v, about 0.5%to about 10%w/v, or about 0.2%to about 20%w/v.

In some embodiments of the present disclosure, the concentration of a suspending agent described herein is about 0.1%w/v, about 0.2%w/v, about 0.3%w/v, about 0.4%w/v, about 0.5%w/v, about 0.6%w/v, about 0.7%w/v, about 0.8%w/v, about 0.9%w/v, about 1.0%w/v, about 1.1%w/v, about 1.2%w/v, about 1.3%w/v, about 1.4%w/v, about 1.5%w/v, about 1.6%w/v, about 1.7%w/v, about 1.8%w/v, about 1.9%w/v, about 2.0%w/v, about 2.1%w/v, about 2.2%w/v, about 2.3%w/v, about 2.4%w/v, about 2.5%w/v, about 2.6%w/v, about 2.7%w/v, about 2.8%w/v, about 2.9%w/v, about 3.0%w/v, about 3.1%w/v, about 3.2%w/v, about 3.3%w/v, about 3.4%w/v, about 3.5%w/v, about 3.6%w/v, about 3.7%w/v, about 3.8%w/v, about 3.9%w/v, about 4.0%w/v, about 4.1%w/v, about 4.2%w/v, about 4.3%w/v, about 4.4%w/v, about 4.5%w/v, about 4.6%w/v, about 4.7%w/v, about 4.8%w/v, about 4.9%w/v, or about 5.0%w/v in the diluent or in the suspension.

In some embodiments of the present disclosure, the concentration of the suspending agent in a liquid diluent or in a suspension described herein is from about 0.5%w/v to about 2.0%w/v. In some embodiments of the present disclosure, the concentration of the suspending agent is from about 1.0%w/v to about 1.5%w/v in the diluent or in the suspension. In some embodiments of the present disclosure, the concentration of the suspending agent is about 1%w/v to about 2.0%w/v. In some embodiments of the present disclosure, the concentration of the suspending agent is about 0.5%w/v to about 5%w/v. In some embodiments of the present disclosure, the concentration of the suspending agent is about 0.5%w/v to about 3%w/v. In some embodiments of the present disclosure, the concentration of the suspending agent is about 1%w/v to about 4%w/v. In some embodiments of the present disclosure, the concentration of the suspending agent is about 1%w/v to about 10%w/v. In some embodiments of the present disclosure, the concentration of the suspending agent is about 5%w/v to about 20%w/v. In some embodiments of the present disclosure, the concentration of the suspending agent is about 5%w/v to about 15%w/v. In some embodiments of the present disclosure, the concentration of the suspending agent is about 10%w/v to about 30%w/v.

Additional excipients

In further embodiments, a Compound A liquid formulation for inhalation described herein and/or pharmaceutical compositions comprises additional excipients including, but not limited to flavoring agents and anti-bulking agents.

In some embodiments, Compound A liquid formulations and/or pharmaceutical compositions described herein comprise a flavoring agent. The flavoring agent or flavorant can be used to enhance the flavor or aroma of the dose, and to improve general palatability of the dose, thus helping to mask any flavor of the active pharmaceutical ingredient, which patients may find unpleasant. In some embodiments, the amount of Compound A in the liquid pharmaceutical formulation are so low that most patients do not taste any flavor. The flavoring agent (e.g., a sweetener) can provide an improved experience for patients, such as in pediatric population, and better compliance with the drug regimen desired by clinicians. Suitable natural or artificial flavors can be selected from pharmaceutically acceptable options as described in standard pharmacy references which are known to those skilled in the art. Suitable natural or synthetic flavoring agents can be selected from standard reference books, such as Remington: The Science and Practice of Pharmacy (2000) and Fenaroli's Handbook of Flavor Ingredients (1994) . Exemplary flavoring agents or flavorants include synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof. These may also include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Other useful flavors include vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. Flavors which have been found to be particularly useful include commercially available strawberry, orange, grape, cherry, vanilla, mint and citrus flavors and mixtures thereof. The amount of flavoring may depend on a number of factors, including the organoleptic effect desired. Flavors can present in any amount as desired by those of ordinary skill in the art.

Thickeners impart viscosity or weight to the resultant liquid forms from liquid pharmaceutical formulations of Compound A or pharmaceutically acceptable salts thereof described herein. Exemplary thickeners include dextrin, cellulose derivatives (carboxymethylcellulose and its salts, ethylcellulose, hydroxyethyl cellulose, methylcellulose, hypromellose, and the like) starches, pectin, polyethylene glycol, polyethylene oxide, trehalose and certain gums (xanthan gum, locust bean gum, etc. ) . In certain embodiments, the Compound A liquid formulation comprises a thickener.

Additional excipients are contemplated in the Compound A pharmaceutical formulation embodiments. These additional excipients are selected based on function and compatibility with the Compound A liquid formulations described herein and may be found, for example in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, PA: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, (Easton, PA: Mack Publishing Co 1975) ; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms (New York, NY: Marcel Decker 1980) ; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed (Lippincott Williams &Wilkins 1999) , herein incorporated by reference in their entirety.

Inhalation Device

Provided herein, in one aspect, is an inhalation device comprising liquid pharmaceutical formulations described herein. Also provided herein, in one aspect, is an inhalation device that is within a kit comprising a pharmaceutical formulation for inhalation described herein or the pharmaceutical composition for preparation of a pharmaceutical formulation for inhalation described herein.

As used herein, the term “inhalation device” refers to a device or container that is used to administer, adapted to administer, or configured to administer its contents to a subject by inhalation. In some cases, an inhalation device is configured to convert the pharmaceutical formulation into emitted droplets when administering to a subject. In some embodiments, the inhalation device is a device customarily used for by inhalation dispensing a pharmaceutical formulation as droplets or aerosols to a subject. In some embodiments, the inhalation device is a nebulizer. In some embodiments, the inhalation device is inhaler. In some embodiments, the inhalation device is an atomizer, aerosolizer, vaporizer (e.g., thermal vaporization, ) or the like, which forms droplets for inhalation by a subject from a solution or liquid containing Compound A or pharmaceutically acceptable salts thereof. The droplets can have a certain particle size. The inhalation device can be used to administer Compound A liquid pharmaceutical formulations described herein to a subject in need thereof to treat a disease or a condition described herein (e.g., IPF) . In some embodiments, an inhalation device described herein contains a desired amount of a pharmaceutical formulation described herein for direct administration to a subject via administration by inhalation. In some embodiments, the inhalation device is a nebulizer or inhaler suitable for pulmonary delivery of liquid formulations. In some embodiments, the inhalation device is configured to deliver a single dose. In some embodiments, the inhalation device is configured to deliver a single dose in multiple breaths. In some embodiments, the inhalation device is configured to deliver multi-doses. In some embodiments, the inhalation device is configured to deliver a liquid formulation that is propellant-free. In some embodiments, the inhalation device does not need power supply. In some embodiments, the inhalation device needs power supply. In some embodiments, the inhalation device can be adapted to include an electronic indicator that shows when a subject using it is breathing. In some embodiments, the inhalation device can be adapted to include a software that adjusts the aerosol emission based on the breathing pattern of a subject, which offers the benefits of reducing drug loss and increases the inhaled mass. In some cases, the inhalation device can comprise breath-actuated or coordination inhalation device. In some embodiments, the inhalation device can be used with an inhalation aid, for example, a spacer or a valved holding chamber.

Liquid Nebulizer

In some cases, the inhalation device is a nebulizer. Any known nebulizer suitable for pulmonary delivery of liquid formulations can be used for administration of the Compound A liquid formulation described herein. Such nebulizers can include, jet nebulizers, ultrasonic nebulizers, pulsating membrane nebulizers, nebulizers with a vibrating mesh or plate with multiple apertures, and nebulizers comprising a vibration generator and an aqueous chamber (e.g., Pari ) .

Nebulizers can offer certain advantages, such as they do not require patient coordination between inhalation and actuation, which make them suitable for pediatric, elderly, ventilated, non-conscious patients, or those who are unable to use an inhaler. Nebulizers can also have the capability of delivering larger doses compared to the other aerosol devices, although this may require longer administration times.

In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in less than about 30 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in less than about 25 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in less than about 20 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in less than about 15 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in less than about 10 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in less than about 6 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in less than about 5 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in less than about 4 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in less than about 3 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in or less than about 2 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in less than about 1 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in about 1 min to about 30 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in about 2 min to about 20 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in about 5 min to about 15 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in about 1 min to about 5 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in about 5 min to about 10 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in about 15 min to about 20 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein more than about 20 mins, such as about 30 min, about 40 min, about 50 min or about 60 min. In some embodiments, Compound A liquid formulations can be nebulized and administered in the dose described herein in about 30 min to about 60 min. In some embodiments, the methods described herein comprise nebulizing Compound A liquid formulations prior to administration by inhalation over the foregoing time period.

Output rate can be measured based on the output of emitted droplet or aerosol in mL per minute. In some embodiments, the nebulizer is configured to provide an output rate of at least about 0.1 mL/min. In some embodiments, the nebulizer is configured to provide an output rate of at least 0.2 mL/min. In some embodiments, the nebulizer is configured to provide an output rate of at least 0.3 mL/min. In some embodiments, the nebulizer is configured to provide an output rate of at least 0.4 mL/min. In some embodiments, the nebulizer is configured to provide an output rate of at least 0.5 mL/min. In some embodiments, the nebulizer is configured to provide an output rate of at least 0.6 mL/min. In some embodiments, the nebulizer is configured to provide an output rate of at least 0.7 mL/min. In some embodiments, the nebulizer is configured to provide an output rate of at least 0.8 mL/min. In some embodiments, the nebulizer is configured to provide an output rate of at least 0.9 mL/min. In some embodiments, the nebulizer is configured to provide an output rate of at least 1.0 mL/min. In some embodiments, the nebulizer is configured to provide an output rate of less than about 1.0 mL/min.

A nebulizer can comprise a compressed air (or jet) , ultrasonic, or newer nebulizer models including breath-enhanced, breath actuated, and vibrating mesh nebulizers. In some cases, jet nebulizers are based on Venturi’s principle, stating that fluid pressure decreases as its passes through a narrow sectional area. In jet nebulizers, air stream can move through a small capillary tube at high velocity creating a low pressure that drives the liquid to be aerosolized up the capillary tube. For ultrasonic nebulizers, sound waves can be created due to the vibration of piezoelectric crystals at high frequency, creating crests that break the liquid into small droplets. Vibrating mesh nebulizers, such as Parirapid and Omron U22, can have a mesh plate that, when it vibrates through the action of the piezoelectric element, it can break the liquid into very fine droplets, which can increase the volume of aerosol deposited in the alveoli.

In some cases, a nebulizer is a high efficiency liquid nebulizer with perforated membranes, for example, those described in U.S. Pat. Nos. 6,962,151, 5,152,456, 5,261,601, and 5,518,179, 6,983,747, each of which is hereby incorporated by reference in its entirety. In some cases, a suitable nebulizer include the ones listed in Table 1. In some cases, the nebulizer comprises PARI (Germany) under the trade nameNektar Therapeutics (San Carlos, CA) under the trade namesGo and Pro, andSolo, CompAIR^TM NE-C801, aM-601 MEDICATOR AEROSOL DELIVERY SYSTEM^TM, Respironics (Murrysville, CA) under the trade namesOmron (Bannockburn, IL) under the trade name (e.g., MicroNE-U22) and Activaero (Germany) under the trade nameAdditional commercial high efficiency nebulizers are also available from Aerogen (Galaway, Ireland) utilizing thenebulizer technology.

Table 1. Exemplary Nebulizers

Commercially available nebulizers suitable for use can include the

Pro, andGo, Solo, Solo/Idehaler combination, Solo or Gocombination, PARI LC-Start, PARIeFlow and eFlow PariN and Pari (PARI, GmbH) , (Omron Healthcare, Inc. ) , (Profile Therapeutics Inc. ) , (Aerogen, Inc, Mountain View, Calif. ) , Omron(Omron Healthcare, Inc. ) , Omron (Omron Healthcare, Inc. ) , Mabismist (Mabis Healthcare, Inc. ) , 6610, (The Lumiscope Company, Inc. ) , airsep (AirSep Corporation) , acorn-1 and Acorn-II (Vital Signs, Inc. ) , (Medical Industries America) , ava-(Hudson Respiratory Care Incorporated) , (Intersurgical Incorporated) , (Professional Medical Products) , Pulmo Aide (DeVilbiss Corp. ) , (Marquest) , Fan (Marquest) , MB-5 (Mefar) , Misty (Baxter) , Salter 8900 (Salter Labs) , (Medic-Aid) , (Hudson Respiratory Care) , Whisper (Marquest Medical Products) , (Aiolos Medicnnsk Teknik) , (Intertech Resources, Inc. ) , (Unomedical Inc. ) , (Respiratory Care Center) , and AERx Essence^TM (Aradigm) , LDI Nebulizer (Evit Labs) , Swirler W Radioaerosol System (AMICI, Inc. ) , Maquet SUN 145 ultrasonic, Schill untrasonic, compare and compare Elite from Omron, Monoghan AeroEclipse BAN, II BAN, Transneb, DeVilbiss 800, aerovectRx, Freeway Freedom^TM, Sidestream, Ventstream and I-neb produced by Philips, Inc. Additional non-limiting example are described in U.S. Pat. No. 10,092,552 and 6,196,219, each of which is hereby incorporated by reference in its entirety.

For aqueous and other non-pressurized liquid systems, a variety of nebulizers (including small volume nebulizers) are available to aerosolize the formulations. Compressor-driven nebulizers incorporate jet technology and use compressed air to generate the liquid aerosol. Such devices are commercially available from, for example, Healthdyne Technologies, Inc.; Invacare, Inc.; Mountain Medical Equipment, Inc.; Pari Respiratory, Inc.; Mada Medical, Inc.; Puritan-Bennet; Schuco, Inc., DeVilbiss Health Care, Inc.; and Hospitak, Inc. Ultrasonic nebulizers rely on mechanical energy in the form of vibration of a piezoelectric crystal to generate respirable liquid droplets and are commercially available from, for example, Omron Heathcare, Inc., Boehringer Ingelheim, and DeVilbiss Health Care, Inc. Vibrating mesh nebulizers rely upon either piezoelectric or mechanical pulses to respirable liquid droplets generate. Other examples of nebulizers for use with pirfenidone or pyridone analogs described herein are described in U.S. Pat. Nos. 4,268,460, 4,253,468, 4,046,146, 3,826,255, 4,649,911, 4,510,929, 4,624,251, 5,164,740, 5,586,550, 5,758,637, 6,644,304, 6,338,443, 5,906,202, 5,934,272, 5,960,792, 5,971,951, 6,070,575, 6,192,876, 6,230,706, 6,349,719, 6,367,470, 6,543,442, 6,584,971, 6,601,581, 4,263,907, 5,709,202, 5,823,179, 6,192,876, 6,644,304, 5,549,102, 6,083,922, 6,161,536, 6,264,922, 6,557,549, and 6,612,303, each of which is hereby incorporated by reference in their entirety.

Liquid Inhaler

In some cases, the inhalation device is an inhaler. Any inhaler suitable for pulmonary delivery of a liquid formulation can be used. For example, an inhaler comprises a metered-dose inhaler (MDI) or soft mist inhalers (SMIs) . In some cases, the inhaler comprises a hand-held inhaler that aerosolize propellant free-liquid formulations as a soft mist, for example Soft Mist^TM Inhaler, (Boehringer Ingelheim) , e.g., and

A metered-dose inhaler can include a propellant driven inhaler (pMDI) , which can release a metered dose of medicine upon each actuation. The medicine is formulated as a suspension or solution of a drug substance in a suitable propellant such as a halogenated hydrocarbon. pMDIs are described in, for example, Newman, S. P., aerosols and the Lung, Clarke et al, eds., pp. 197-224 (Butterworths, London, England, 1984) . The propellants for use with the MDIs may be any propellants known in the art. Examples of propellants include chlorofluoro carbons (CFCs) such as dichlorodifluoromethane, trichlorofluorometbane, and dichlorotetrafluoro ethane, hydrofluoroalkanes (HFAs) , and carbon dioxide. Examples of medicinal aerosol preparations containing HFAs are presented in U.S. Patent Nos. 6,585,958, 2,868,691, and 3,014,844, each of which is hereby incorporated by reference in their entirety. In some embodiments, a surfactant or liquid vehicle is mixed with the propellant to facilitate dissolution or suspension of the drug substance. In some embodiments, the propellant and active ingredient are contained in separate containers, such as described in U.S. Patent No. 4,534,345, which is hereby incorporated by reference in its entirety. In some embodiments, the MDI used herein is activated by a patient pushing a lever, button, or other actuator. In other embodiments, the release of the aerosol is breath activated such that, after initially arming the unit, the active compound aerosol is released once the patient begins to inhale, such as described in U.S. Patent Nos. 6,672,304, 5,404,871, 5,347,998, 5,284,133, 5,217,004, 5,119,806, 5,060,643, 4,664,107, 4,648,393, 3,789,843, 3,732,864, 3,636,949, 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 entirety. The forgoing inhalation devices can enable more of the Compound A or pharmaceutically acceptable salts thereof to get into the lungs of a subject. Another mechanism to help a subject get adequate dosage with Compound A or pharmaceutically acceptable salts thereof can include a valve mechanism that allows a patient to use more than one breath to inhale the drug, such as described in U.S. Patent Nos. 4,470,412 and 5,385,140, each of which is hereby incorporated by reference in their entirety. Additional examples of MDIs known in the art and suitable for delivery of Compound A liquid formulations described herein include U.S. Patent Nos. 6,435,177, 6,585,958, 5,642,730, 6,223,746, 4,955,371, 5,404,871, 5,364,838, and 6,523,536, each of which are hereby incorporated by reference in their entirety.

In some cases, spacers and valved holding chambers can be used with MDI, such as a pMDI. Valved holding chambers allow inhalation and prevent exhalation into the chamber, such as AeroChamberor

Droplet Size and Distribution

An inhalation device can be configured to convert a Compound A liquid formulation described herein into emitted droplets for inhalation by a subject. The distribution of aerosol particle or emitted droplet size can be expressed in terms of mass median aerodynamic diameter (MMAD) -the droplet size at which half of the mass of the aerosol is contained in smaller droplets and half in larger droplets, volumetric mean diameter (VMD) ; mass median diameter (MMD) ; fine particle fraction (FPF) -the percentage of particles that are <5 μm in diameter. These measures can be used for comparisons of the in vitro performance of different inhaler device and drug combinations. In some cases, the higher the fine particle fraction, the higher the proportion of the emitted dose that is likely to deposit the lung.

In some cases, inhaled droplets or particles are subject to deposition by one of two mechanisms: impaction, which usually predominates for larger particles, and sedimentation, which is prevalent for smaller particles. Impaction occurs when the momentum of an inhaled particle is large enough that the particle does not follow the air stream and encounters a physiological surface. In contrast, sedimentation occurs primarily in the deep lung when very small particles which have traveled with the inhaled air stream encounter physiological surfaces as a result of random diffusion within the air stream.

Without wishing to be bound by any theory, for pulmonary administration, the upper airways can be avoided in favor of the middle and lower airways. Pulmonary drug delivery can be accomplished by inhalation of an aerosol through the mouth and throat. In some cases, particles having a mass median aerodynamic diameter (MMAD) of greater than about 5 microns generally do not reach the lung; instead, they tend to impact the back of the throat and are swallowed and possibly orally absorbed. In some cases, particles having diameters of about 1 to about 5 microns are small enough to reach the upper-to mid-pulmonary region (conducting airways) , but are too large to reach the alveoli. Smaller particles, i.e., about 0.5 to about 2 microns, are capable of reaching the alveolar region. Particles having diameters smaller than about 0.5 microns can also be deposited in the alveolar region by sedimentation, although very small particles may be exhaled.

Measures of particle size can be referred to as volumetric mean diameter (VMD) , mass median diameter (MMD) , or MMAD. These measurements may be made by impaction (MMD and MMAD) or by laser (VMD) . For liquid particles, VMD, MMD and MMAD may be the same if environmental conditions are maintained, e.g., standard humidity. However, if humidity is not maintained, MMD and MMAD determinations will be smaller than VMD due to dehydration during impactor measurements. For the purposes of this description, VMD, MMD and MMAD measurements are considered to be under standard conditions such that descriptions of VMD, MMD and MMAD will be comparable.

In some embodiments, the particle size of the aerosol is optimized to maximize the Compound A or pharmaceutically acceptable salts thereof deposition at the site of pulmonary pathology, extra-pulmonary, systemic distribution, and to maximize tolerability or systemic absorption.

Aerosol particle size or droplet size can be expressed in terms of the mass median aerodynamic diameter (MMAD) . Without wishing to be bound by any theory, large droplets (e.g., MMAD >5 μm) can deposit in the upper airway because they are too large to navigate the curvature of the upper airway. Without wishing to be bound by any theory, Small particles (e.g., MMAD <2 μm) may be poorly deposited in the lower airways and thus become exhaled, providing additional opportunity for upper airway deposition. Hence, intolerability (e.g., cough and bronchospasm) may occur from upper airway deposition from both inhalation impaction of large particles and settling of small particles during repeated inhalation and expiration. In some embodiment, droplet size can have an MMAD of droplet size that is from about 1 μm to about 7 μm. In some embodiment, droplet size can be e.g., MMAD=2-5 μm to maximize deposition at in lungs and to minimize intolerability associated with upper airway deposition.

Moreover, generation of a defined particle size with limited geometric standard deviation (GSD) can optimize deposition and tolerability. Narrow GSD limits the number of particles outside the desired MMAD size range. In one embodiment, an aerosol containing one or more compounds disclosed herein is provided having a MMAD from about 2 microns to about 5 microns with a GSD of less than or equal to about 2.5 microns. In another embodiment, an aerosol having an MMAD from about 2.0 microns to about 2.0 microns with a GSD from about 1.0 micron to about 2.0 microns is provided. In another embodiment, an aerosol having an MMAD from about 1.5 microns to about 3.5 microns with a GSD less than or equal to 2.0 microns is provided.

In some embodiments, described herein are emitted droplets generated by the inhalation devices described herein and wherein the emitted droplets comprises Compound A or pharmaceutically acceptable salts thereof. In some embodiments, the droplet has an MMAD of droplet size less than about 7.0 μm. In some embodiments, the droplet has an MMAD of droplet size less than about 6.0 μm. In some embodiments, the droplet has an MMAD of droplet size less than about 5.0 μm. In some embodiments, the droplet has an MMAD of droplet size less than about 4.5 μm. In some embodiments, the droplet has an MMAD of droplet size less than about 4.0 μm. In some embodiments, the droplet has an MMAD of droplet size less than about 3.5 μm. In some embodiments, the droplet has an MMAD of droplet size less than about 3.0 μm. In some embodiments, the droplet has an MMAD of droplet size less than about 2.5 μm.In some embodiments, the droplet has an MMAD of droplet size less than about 2.0 μm. In some embodiments, the droplet has an MMAD of droplet size less than about 1.5 μm. In some embodiments, the droplet has an MMAD of droplet size less than about 1.0 μm. In some embodiments, the droplet has an MMAD of droplet size more than about 2.5 μm. In some embodiments, the droplet has an MMAD of droplet size more than about 2.0 μm. In some embodiments, the droplet has an MMAD of droplet size more than about 1.5 μm. In some embodiments, the droplet has an MMAD of droplet size more than about 1.0 μm.

In some embodiments, the emitted droplet has an MMAD of droplet size of from about 0.1 μm to about 10 μm. In some embodiments, the emitted droplet has an MMAD of droplet size of from about 1 μm to about 7 μm. In some embodiments, the emitted droplet has an MMAD of droplet size of from about 0.5 μm to about 5 μm. In some embodiments, the emitted droplet has an MMAD of droplet size of from about 0.5 μm to about 1 μm. In some embodiments, the emitted droplet has an MMAD of droplet size of from about 0.5 μm to about 2 μm. In some embodiments, the droplet has an MMAD of droplet size of from about 0.5 μm to about 2.5 μm. In some embodiments, the emitted droplet has an MMAD of droplet size of from about 0.5 μm to about 3 μm. In some embodiments, the emitted droplet has an MMAD of droplet size of from about 0.5 μm to about 3.5 μm. In some embodiments, the emitted droplet has an MMAD of droplet size of from about 0.5 μm to about 4 μm. In some embodiments, the emitted droplet has an MMAD of droplet size of from about 1 μm to about 4 μm. In some embodiments, the emitted droplet has an MMAD of droplet size of from about 1 μm to about 2 μm. In some embodiments, the emitted droplet has an MMAD of droplet size of from about 1.5 μm to about 3.5 μm. In some embodiments, the emitted droplet has an MMAD of droplet size of from about 1.5 μm to about 2.5 μm. In some embodiments, the emitted droplet has an MMAD of droplet size of from about 1.5 μm to about 2.0 μm. In some embodiments, the emitted droplet has an MMAD of droplet size of from about 2.0 μm to about 2.5 μm. In some embodiments, the emitted droplet has an MMAD of droplet size of from about 2.5 μm to about 3.0 μm. In some embodiments, the emitted droplet has an MMAD of droplet size of from about 2 μm to about 3 μm.

In some embodiments, the emitted droplets have a GSD of the droplet size distribution of from about 0.5 μm to about 5 μm. In some embodiments, the emitted droplets have a GSD of the droplet size distribution of from about 1 μm to about 5 μm. In some embodiments, the emitted droplets have a GSD of the droplet size distribution of from about 0.7 μm to about 3 μm. In some embodiments, the emitted droplets have a GSD of the droplet size distribution of from about 1.0 μm to about 3.0 μm. In some embodiments, the emitted droplets have a GSD of the droplet size distribution of from about 0.8 μm to about 2.5 μm. In some embodiments, the emitted droplets have a GSD of the droplet size distribution of from about 1 μm to about 2 μm.

In some embodiments, the emitted droplets have a VMD of the droplet from about 0.5 μm to about 5 μm. In some embodiments, the emitted droplets have a VMD of the droplet from about 1 μm to about 5 μm. In some embodiments, the emitted droplets have a VMD of the droplet from about 0.7 μm to about 3 μm. In some embodiments, the emitted droplets have a VMD of the droplet from about 1.0 μm to about 3.0 μm. In some embodiments, the emitted droplets have a VMD of the droplet from about 0.8 μm to about 2.5 μm. In some embodiments, the emitted droplets have a VMD of the droplet from about 1 μm to about 2 μm.

In some embodiments, the emitted droplets have a MMD of the droplet from about 0.5 μm to about 5 μm. In some embodiments, the emitted droplets have a MMD of the droplet from about 1 μm to about 5 μm. In some embodiments, the emitted droplets have a MMD of the droplet from about 0.7 μm to about 3 μm. In some embodiments, the emitted droplets have a MMD of the droplet from about 1.0 μm to about 3.0 μm. In some embodiments, the emitted droplets have a MMD of the droplet from about 0.8 μm to about 2.5 μm. In some embodiments, the emitted droplets have a MMD of the droplet from about 1 μm to about 2 μm.

In some embodiments, the emitted droplet comprises a liquid vehicle, surfactant, a preservative, a buffer, a pH-adjusting agent, an osmolarity adjusting agent, or a combination thereof. In some embodiments, the buffer is a citrate buffer or a phosphate buffer. In some embodiments, the droplets are produced from a liquid nebulizer and a liquid formulation of Compound A or pharmaceutically acceptable salts thereof as described herein. In some embodiments, the pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of from about 0.1 mg/mL to about 60 mg/mL. In some embodiments, the osmolality of the pharmaceutical formulation is from about 50 mOsmol/kg to about 6000 mOsmol/kg. In some embodiments, the pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the pharmaceutical formulation from about 3.5 to about 7.0. In some embodiments, the pharmaceutical formulation comprises a phosphate buffer that that is configured to maintain a pH of the pharmaceutical formulation from about 5.0 to about 9.0. In some embodiments, the pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of from about 0.001 mg/mL to about 30 mg/mL. In some embodiments, the osmolality of the pharmaceutical formulation is from about 250 mOsmol/kg to about 400 mOsmol/kg. In some embodiments, the pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the pharmaceutical formulation from about 3.0 to about 5.5.

In some embodiments, the Compound A or pharmaceutically acceptable salts thereof that is intended for respiratory delivery (for either systemic or local distribution) can be administered as aqueous formulations, as suspensions or solutions in halogenated hydrocarbon propellants. Aqueous formulations may be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization. Propellant-based systems may use suitable pressurized metered-dose inhalers (pMDIs) . A desired particle size and distribution may be obtained by choosing an appropriate device.

Also described are aerosols comprising a plurality of droplets of Compound A or pharmaceutically acceptable salts thereof as described herein. In some embodiments, the at least about 30%of the emitted droplets in the aerosol have a diameter of less than about 2-3 μm. In some embodiments, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%of the emitted droplets in the aerosol have a diameter less than about 2-3 μm. In some embodiments, the aqueous aerosols are produced with a liquid nebulizer. In some embodiments, the aqueous aerosols are produced with a high efficiency liquid nebulizer. In some embodiments, the aqueous aerosols are produced with a liquid inhaler, such as a Soft Mist^TM inhaler.

Lung Deposition

Lung Deposition as used herein, refers to the fraction of the nominal dose of an active pharmaceutical ingredient (API) that is bioavailable at a specific site of pharmacologic activity upon administration of the agent to a patient via a specific delivery route. For example, a lung deposition of 30%means 30%of the active ingredient in the inhalation device just prior to administration is deposited in the lung. Likewise, a lung deposition of 60%means 60%of the Compound A or pharmaceutically acceptable salts thereof in the inhalation device just prior to administration is deposited in the lung, and so forth. Lung deposition can be determined using methods of scintigraphy or deconvolution. In some embodiments, the present disclosure provides for methods and inhalation systems for the treatment or prophylaxis of a respiratory condition in a patient, comprising administering to the patient a dose of Compound A or pharmaceutically acceptable salts thereof described herein with a liquid nebulizer. In some embodiments, the liquid nebulizer is a high efficiency liquid nebulizer. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof of at least about 5%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, or at least about 85%, based on the nominal dose of Compound A or pharmaceutically acceptable salts thereof is achieved. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 5%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 7%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 10%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 15%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 20%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 25%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 30%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 35%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 40%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 45%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 50%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 55%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 60%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 65%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 70%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 75%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 80%. In some embodiments a lung deposition of Compound A or pharmaceutically acceptable salts thereof achieved after administration of the liquid formulations described herein is at least about 85%.

Two main methods can be used to measure aerosol deposition in the lungs. First, γ-scintigraphy is performed by radiolabeling the drug with a substance like 99m-technetium, and scanning the subject after inhalation of the drug. This technique has the advantage of being able to quantify the proportion of aerosol inhaled by the patient, as well as regional distribution in the upper airway and lungs. Second, since most of the drug deposited in the lower airways will be absorbed into the bloodstream, pharmacokinetic techniques are used to measure lung deposition. This technique can assess the total amount of ICSs that interacts with the airway epithelium and is absorbed systemically, but will miss the small portion that may be expectorated or swallowed after mucociliary clearance, and cannot tell us about regional distribution.

Fine Particle Fraction (FPF)

Fine Particle Fraction (FPF) describes the efficiency of an inhalation device, such as a liquid nebulizer. FPF represents the percentage of the delivered aerosol dose, or inhaled mass, with droplets of diameter less than 5.0 μm. In some cases, droplets of less than 5.0 μm in diameter are considered to penetrate to the lung. In some embodiments, administration of a Compound A liquid formulation described herein with a liquid nebulizer provides a FPF of at least about 10%, about 20%, about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%. In some embodiments, administration of a Compound A liquid formulation described herein with a liquid nebulizer provides a FPF of at least about 10%. In some embodiments, administration of a Compound A liquid formulation described herein with a liquid nebulizer provides a FPF of at least about 20%. In some embodiments, administration of a Compound A liquid formulation described herein with a liquid nebulizer provides a FPF of at least about 30%. In some embodiments, administration of a Compound A liquid formulation described herein with a liquid nebulizer provides a FPF of at least at least about 35%. In some embodiments, administration of a Compound A liquid formulation described herein with a liquid nebulizer provides a FPF of at least at least about 40%. In some embodiments, administration of a Compound A liquid formulation described herein with a liquid nebulizer provides a FPF of at least at least about 45%. In some embodiments, administration of a Compound A liquid formulation described herein with a liquid nebulizer provides a FPF of at least at least about 50%. In some embodiments, administration of a Compound A liquid formulation described herein with a liquid nebulizer provides a FPF of at least at least about 55%. In some embodiments, administration of a Compound A liquid formulation described herein with a liquid nebulizer provides a FPF of at least at least about 60%. In some embodiments, administration of a Compound A liquid formulation described herein with a liquid nebulizer provides a FPF of at least at least about 65%. In some embodiments, administration of a Compound A liquid formulation described herein with a liquid nebulizer provides a FPF of at least at least about 70%. In some embodiments, administration of a Compound A liquid formulation described herein with a liquid nebulizer provides a FPF of at least at least about 75%. In some embodiments, administration of a Compound A liquid formulation described herein with a liquid nebulizer provides a FPF of at least about 80%.

The Delivered Dose (DD) of drug to a patient is the certain portion of volume of liquid filled into the nebulizer, i.e. the fill volume, which is emitted from the mouthpiece of the device. The difference between the nominal dose and the DD is the amount of volume lost primarily to residues, i.e. the amount of fill volume remaining in the nebulizer after administration, or is lost in aerosol form during expiration of air from the patient and therefore not deposited in the patient's body. In some embodiments, the DD of the nebulized or aerosolized formulations described herein is at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 80%, or at least about 90%.

The Respirable Delivered Dose (RDD) is an expression of the delivered mass of drug contained within emitted droplets from a nebulizer that are small enough to reach and deposit on the surface epithelium of the patient’s lung. The RDD is determined by multiplying the DD by the FPF. In some embodiments, administration of a Compound A liquid formulation described herein with a liquid nebulizer provides a RDD of at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%.

Stability

In some embodiments, Compound A formulations for inhalation described herein (e.g., liquid formulations and pharmaceutical composition for preparation of liquid formulations) are stable or shelf-stable in various storage conditions including refrigerated conditions, ambient conditions, room temperature, and accelerated conditions. Stable or shelf stable as used herein refer to liquid formulations of Compound A or pharmaceutically acceptable salts thereof having about 90%or greater of the initial Compound A or pharmaceutically acceptable salts amount and about 10 %wt or less total impurities or related substances at the end of a given storage period. Alternatively, stable or shelf stable as used herein refer to liquid formulations of Compound A or pharmaceutically acceptable salts thereof having about 95 %wt or greater of initial Compound A or pharmaceutically acceptable salts amount and about 5 %wt or less total impurities or related substances at the end of a given storage period. In some embodiments, a stable Compound A formulation is a clear solution at the end of a given storage period. In some embodiments, the liquid formulations of Compound A or pharmaceutically acceptable salts thereof are stored in an unopened container, such as an unopened bottle or unopened vial packed inside an aluminum foil bag. In some embodiments, a stable Compound A formulation is a clear solution.

The percentage of Compound A free base or a pharmaceutically acceptable salt thereof (e.g., Compound A or a pharmaceutically acceptable salt thereof) retained can be calculated from the amount of Compound A or a pharmaceutically acceptable salt thereof in the formulation at a certain time point relative to the initial amount of Compound A or a pharmaceutically acceptable salt thereof. Assay or Compound A or a pharmaceutically acceptable salt thereof content can be assessed by any suitable HPLC methods or any other known testing method. In some embodiments, a stable Compound A formulation retains at least about 90 %wt, about 91 %wt, about 92 %wt, about 93 %wt, about 94 %wt, about 95 %wt, about 96 %wt, about 97 %wt, about 98 %wt, about 99 %wt, about 99.5 %wt, or about 99.9 %wt of the initial Compound A amount (e.g., Compound A or a pharmaceutically acceptable salt thereof) . In yet other embodiments, a stable Compound A formulation retains at least about 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount. In yet other embodiments, a stable Compound A formulation retains at least about 91%wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount. In yet other embodiments, a stable Compound A formulation retains at least about 92 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount. In yet other embodiments, a stable Compound A formulation retains at least about 93 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount. In yet other embodiments, a stable Compound A formulation retains at least about 94%wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount. In yet other embodiments, a stable Compound A formulation retains at least about 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount. In yet other embodiments, a stable Compound A formulation retains at least about 96 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount. In yet other embodiments, a stable Compound A formulation retains at least about 97 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount. In yet other embodiments, a stable Compound A formulation retains at least about 98 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount. In yet other embodiments, a stable Compound A formulation retains at least about 99 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount. In yet other embodiments, a stable Compound A formulation retains at least about 99.5 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount. In yet other embodiments, a stable Compound A formulation retains at least about 99.8 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount.

The percentage of impurities can be calculated from the amount of impurities relative to the amount of Compound A or a pharmaceutically acceptable salt thereof. The percentage of impurities can be assessed by any suitable HPLC methods or any other known testing method. In some embodiments, a stable Compound A formulation contains no more than about 10 %wt, about 5 %wt, about 4 %wt, about 3 %wt, about 2.5 %wt, about 2 %wt, about 1.5 %wt, about 1 %wt, or about 0.5 %wt total impurities or related substances. In other embodiments, a stable Compound A formulation contains no more than about 10 %wt total impurities or related substances. In other embodiments, a stable Compound A formulation contains no more than about 5 %wt total impurities or related substances. In yet other embodiments, a stable Compound A formulation contains no more than about 4 %wt total impurities or related substances. In yet other embodiments, a stable Compound A formulation contains no more than about 3 %wt total impurities or related substances. In yet other embodiments, a stable Compound A formulation contains no more than about 2 %wt total impurities or related substances. In yet other embodiments, a stable Compound A formulation contains no more than about 1 %wt total impurities or related substances. In some embodiments, a formulation described herein contains no more than about 0.5%wt of total impurities after stored at accelerated conditions (e.g., about 40℃ ± 2℃ or about 60℃ ± 2℃) for at least 5 days, 10 days, or 30 days. In some embodiments, a formulation described herein contains no more than about 0.4%wt of total impurities after stored at accelerated conditions (e.g., about 40℃ ± 2℃ or about 60℃ ± 2℃) for at least 5 days, 10 days, or 30 days. In some embodiments, a Compound A formulation described herein contains no more than about 2%wt of total impurities after stored at accelerated conditions (e.g., about 40℃ ± 2℃ or about 60℃ ± 2℃) for at least 5 days, 10 days, or 30 days. In some embodiments, a formulation described herein contains no more than about 0.8%wt of total impurities after exposed to light (e.g., under condition described in Example A) for at least 5 days or 10 days. In some embodiments, a formulation described herein contains no more than about 2 %wt of total impurities after exposed to light for at least 5 days or 10 days. In some embodiments, a formulation described herein contains no more than about 0.4%wt of total impurities after exposed to light for at least 5 days or 10 days. In some embodiments, the formulation is packaged in an LDPE vial and further packed in an aluminum foil bag. In some embodiments, the formulation is packaged in an LDPE vial and further packed in an aluminum foil bag with nitrogen purging. In some embodiments, the formulation is packaged in sodium-calcium glass bottle. In some embodiments, the formulation is packaged in sodium-calcium glass bottle with nitrogen-purging.

In some embodiments, a formulation described herein contains no more than about 1 %wt, 0.5 %wt, about 0.4 %wt, about 0.3 %wt, about 0.2 %wt, or about 0.1 %wt of a single impurity. In some embodiments, a formulation described herein contains no more than about 0.5 %wt of a single impurity. In some embodiments, a formulation described herein contains no more than about 0.4 %wt of a single impurity. In some embodiments, a formulation described herein no more than about 0.3 %wt of a single impurity. In some embodiments, a formulation described herein contains no more than about 0.2 %wt of a single impurity. In some embodiments, a formulation described herein contains no more than about 0.15 %wt of a single impurity. In some embodiments, a formulation described herein contains no more than about 0.1 %wt of a single impurity. In some embodiments, the single impurity is an unknown impurity. In some embodiments, the single impurity is a known impurity. In some embodiments, the single impurity is characterized as having a relative retention time (RRT) of 0.93 (open ring) , as shown in Table A-5. In some embodiments, a formulation described herein contains no more than about 0.3%wt or about 0.15 %wt of the open ring impurity after stored at accelerated conditions (e.g., about 40℃ ± 2℃ or about 60℃ ± 2℃) for at least 5 days, 10 days, or 30 days. In some embodiments, a formulation described herein contains no more than about 0.2%wt or about 0.1 %wt of the open ring impurity after exposed to light for at least 5 days or 10 days. In some embodiments, the single impurity is characterized as having a relative retention time (RRT) of 1.35 (FPIP1) , as shown in Table A-5. In some embodiments, a formulation described herein contains no more than about 0.1%wt or about 0.05 %wt of the FPIP1 impurity after stored at accelerated conditions (e.g., about 40℃ ± 2℃ or about 60℃ ± 2℃) for at least 5 days, 10 days, or 30 days. In some embodiments, a formulation described herein contains no more than about 0.1%wt or about 0.05 %wt of the FPIP1 impurity after exposed to light for at least 5 days or 10 days. In some embodiments, the formulation is packaged in an LDPE vial and further packed in an aluminum foil bag. In some embodiments, the formulation is packaged in an LDPE vial and further packed in an aluminum foil bag with nitrogen purging. In some embodiments, the formulation is packaged in sodium-calcium glass bottle. In some embodiments, the formulation is packaged in sodium-calcium glass bottle with nitrogen-purging.

In some embodiments, a formulation described herein, when packaged in an LDPE vial and further packed in an aluminum foil bag with nitrogen purging, contains no more than about 0.2%wt of total impurities after stored at about 40℃ for at least 5 days, 10 days, or 30 days. In some embodiments, the formulation contains no more than about 0.4%wt of total impurities after stored at about 60℃ for at least 5 days, 10 days, or 30 days. In some embodiments, the formulation described herein contains no more than about 0.35%wt of total impurities after exposed to light for at least 5 days or 10 days. In some embodiments, the formulation contains no more than about 0.05%wt of the open ring impurity after stored at about 40℃ for at least 5 days, 10 days, or 30 days. In some embodiments, the formulation contains no more than about 0.15%wt of the open ring impurity after stored at about 60℃ for at least 5 days, 10 days, or 30 days. In some embodiments, the formulation contains no more than about 0.05%wt of the open ring impurity after exposed to light for at least 5 days or 10 days. In some embodiments, the formulation contains no more than about 0.05%wt of the FPIP1 impurity after stored at about 40℃ for at least 5 days, 10 days, or 30 days. In some embodiments, the formulation contains no more than about 0.05%wt of the FPIP1 impurity after stored at about 60℃ for at least 5 days, 10 days, or 30 days. In some embodiments, the formulation contains no more than about 0.05%wt of the FPIP1 impurity after exposed to light for at least 5 days or 10 days.

In some embodiments, a stable Compound A liquid solution is a clear solution without precipitation, sediment, or haziness upon visual examination. In some embodiments, a Compound A liquid solution described herein remains to be a clear solution without precipitation, sediment, or haziness upon visual examination after stored at about 2℃ to about 8℃ for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, a Compound A liquid solution described herein remains to be a clear solution without precipitation, sediment, or haziness upon visual examination after stored at ambient or room temperature conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, and at least 24 months. In some embodiments, a Compound A liquid solution described herein remains to be a clear solution without precipitation, sediment, or haziness upon visual examination after stored at accelerated conditions (e.g., about 40℃ ± 2℃ or about 60℃ ± 2℃) , for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 month or at least 12 months. In some embodiments, a Compound A liquid solution described herein remains to be a clear solution without precipitation, sediment, or haziness upon visual examination after exposed to light for at least 5 days, 10 days, 30 days, or longer.

In some embodiments, a stable Compound A liquid solution that comprises a citrate buffer maintains a pH of from about 3.5 to about 5.0 or from about 3.5 to about 4.5 at the end of a given storage period. In some embodiments, the Compound A liquid solution that comprises a citrate buffer maintains a pH value that does not shift more than 0.5 or 0.25 from an initial pH value after stored at about 2℃ to about 8℃ for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the Compound A liquid solution that comprises a citrate buffer maintains a pH value that does not shift more than 0.5 or 0.25 from an initial pH value after stored at ambient or room temperature conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, and at least 24 months. In some embodiments, the Compound A liquid solution that comprises a citrate buffer maintains a pH value that does not shift more than 0.5 or 0.25 from an initial pH value after stored at accelerated conditions (e.g., about 40℃ ± 2℃ or about 60℃ ± 2℃) , for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 month or at least 12 months. In some embodiments, the Compound A liquid solution that comprises a citrate buffer maintains a pH value that does not shift more than 0.5 or 0.25 from an initial pH value after exposed to light for at least 5 days, 10 days, 30 days, or longer.

In some embodiments, Compound A formulations for inhalation described herein are stable when stored at refrigerated conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the Compound A formulations described herein are stable when stored at about 2℃ to about 8℃ for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months.

In some embodiments, a Compound A formulation for inhalation described herein contains no more than 5 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 1, 2, or 3 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 6 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 9 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 12 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 15 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 18 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 24 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 30 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 36 months.

In some embodiments, a Compound A formulation for inhalation contains no more than 3 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 1, 2, or 3 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 6 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 9 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 12 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 15 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 18 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 24 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 30 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 2℃ to about 8℃ for 36 months.

In some embodiments, a Compound A formulation for inhalation described herein retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 1, 2, or 3 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 6 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 9 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 12 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 15 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 18 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 24 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 30 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 36 months.

In some embodiments, a Compound A formulation for inhalation described herein at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 1, 2, or 3 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 6 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 9 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 12 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 15 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 18 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 24 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 30 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 2℃ to about 8℃ for 36 months.

In some embodiments, a Compound A formulation for inhalation described herein contains no more than 5 %wt of total impurities or related substances after stored at refrigerated conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at refrigerated conditions for 1, 2, or 3 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at refrigerated conditions for 6 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at refrigerated conditions for 9 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at refrigerated conditions for 12 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at refrigerated conditions for 15 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at refrigerated conditions for 18 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at refrigerated conditions for 24 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at refrigerated conditions for 30 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at refrigerated conditions for 36 months.

In some embodiments, a Compound A formulation for inhalation contains no more than 3 %wt of total impurities or related substances after stored at refrigerated conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at refrigerated conditions for 1, 2, or 3 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at refrigerated conditions for 6 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at refrigerated conditions for 9 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at refrigerated conditions for 12 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at refrigerated conditions for 15 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at refrigerated conditions for 18 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at refrigerated conditions for 24 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at refrigerated conditions for 30 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at refrigerated conditions for 36 months.

In some embodiments, a Compound A formulation for inhalation described herein retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for at least at least 1 month, at least 2 months, 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 1, 2, or 3 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 6 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 9 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 12 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 15 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 18 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 24 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 30 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 36 months.

In some embodiments, a Compound A formulation for inhalation described herein at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 1, 2, or 3 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 6 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 9 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 12 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 15 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 18 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 24 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 30 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at refrigerated conditions for 36 months.

In some embodiments, Compound A or a pharmaceutically acceptable salt thereof liquid compositions described herein are stable after stored at ambient or room temperature conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, and at least 24 months. In some embodiments, temperature excursions are permitted when the Compound A or a pharmaceutically acceptable salt thereof liquid compositions are stored at room temperature conditions. In some embodiments, temperature excursions for room temperature conditions are permitted up to 30℃. In some embodiments, the Compound A formulations described herein are stable after stored at ambient or room temperature conditions with temperature excursions permitted up to 30℃ for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, and at least 24 months.

In some embodiments, the Compound A formulation for inhalation described herein contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 25℃ for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 25℃ for 3 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 25℃ for 6 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 25℃ for 9 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 25℃ for 12 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 25℃ for 15 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 25℃ for 18 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 25℃ for 24 months.

In some embodiments, a Compound A formulation for inhalation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 25℃ for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 25℃ for 3 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 25℃ for 6 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 25℃ for 9 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 25℃ for 12 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 25℃ for 15 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 25℃ for 18 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 25℃ for 24 months.

In some embodiments, a Compound A formulation for inhalation described herein retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃ for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃ for 3 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃ for 6 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃ for 9 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃ for 12 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃ for 15 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃ for 18 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃ for 24 months.

In some embodiments, a Compound A formulation for inhalation described herein retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃ for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃ for 3 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃ for 6 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃ for 9 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃ for 12 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃ for 15 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃ for 18 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃ for 24 months.

In some embodiments, a Compound A formulation for inhalation described herein contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 3 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 6 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 9 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 12 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 15 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 18 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 24 months.

In some embodiments, a Compound A formulation for inhalation described herein contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 3 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 6 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 9 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 12 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 15 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 18 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 24 months.

In some embodiments, a Compound A formulation for inhalation described herein retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 3 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 6 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 9 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 12 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 15 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 18 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 24 months.

In some embodiments, a Compound A formulation for inhalation described herein retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 3 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 6 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 9 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 12 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 15 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 18 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 25℃, with temperature excursions permitted up to 30℃, for 24 months.

In some embodiments, the Compound A formulation for inhalation described herein contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 30℃ for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 30℃ for 3 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 30℃ for 6 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 30℃ for 9 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 30℃ for 12 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 30℃ for 15 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 30℃ for 18 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 15℃ to about 30℃ for 24 months.

In some embodiments, a Compound A formulation for inhalation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 30℃ for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 30℃ for 3 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 30℃ for 6 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 30℃ for 9 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 30℃ for 12 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 30℃ for 15 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 30℃ for 18 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 15℃ to about 30℃ for 24 months.

In some embodiments, a Compound A formulation for inhalation described herein retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 30℃ for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 30℃ for 3 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 30℃ for 6 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 30℃ for 9 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 30℃ for 12 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 30℃ for 15 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 30℃ for 18 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 30℃ for 24 months.

In some embodiments, a Compound A formulation for inhalation described herein retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 30℃ for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 30℃ for 3 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 30℃ for 6 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 30℃ for 9 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 30℃ for 12 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 30℃ for 15 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 30℃ for 18 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 15℃ to about 30℃ for 24 months.

In some embodiments, a Compound A formulation for inhalation described herein contains no more than 5 %wt of total impurities or related substances after stored at room temperature for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at room temperature for 3 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at room temperature for 6 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at room temperature for 9 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at room temperature for 12 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at room temperature for 15 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at room temperature for 18 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at room temperature for 24 months.

In some embodiments, a Compound A formulation for inhalation described herein contains no more than 3 %wt of total impurities or related substances after stored at room temperature for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at room temperature for 3 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at room temperature for 6 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at room temperature for 9 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at room temperature for 12 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at room temperature for 15 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at room temperature for 18 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at room temperature for 24 months.

In some embodiments, a Compound A formulation for inhalation described herein retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at room temperature for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at room temperature for 3 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at room temperature for 6 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at room temperature for 9 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at room temperature for 12 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at room temperature for 15 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at room temperature for 18 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at room temperature for 24 months.

In some embodiments, a Compound A formulation for inhalation described herein retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at room temperature for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at room temperature for 3 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at room temperature for 6 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at room temperature for 9 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at room temperature for 12 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at room temperature for 15 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at room temperature for 18 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at room temperature for 24 months.

In some embodiments, a Compound A formulation for inhalation described herein contains no more than 5 %wt of total impurities or related substances after stored at ambient conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at ambient conditions for 1, 2, or 3 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at ambient conditions for 6 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at ambient conditions for 9 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at ambient conditions for 12 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at ambient conditions for 15 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at ambient conditions for 18 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at ambient conditions for 24 months.

In some embodiments, a Compound A formulation for inhalation described herein contains no more than 3 %wt of total impurities or related substances after stored at ambient conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at ambient conditions for 1, 2, or 3 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at ambient conditions for 6 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at ambient conditions for 9 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at ambient conditions for 12 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at ambient conditions for 15 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at ambient conditions for 18 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at ambient conditions for 24 months.

In some embodiments, a Compound A formulation for inhalation described herein retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at ambient conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at ambient conditions for 1, 2, or 3 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at ambient conditions for 6 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at ambient conditions for 9 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at ambient conditions for 12 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at ambient conditions for 15 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at ambient conditions for 18 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at ambient conditions for 24 months.

In some embodiments, a Compound A formulation for inhalation described herein retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at ambient conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, or at least 24 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at ambient conditions for 1, 2, or 3 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at ambient conditions for 6 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at ambient conditions for 9 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at ambient conditions for 12 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at ambient conditions for 15 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at ambient conditions for 18 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at ambient conditions for 24 months.

In some embodiments, Compound A formulations for inhalation described herein are stable after stored at accelerated conditions, for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 month or at least 12 months. In some embodiments, the Compound A formulations described herein are stable after stored at about 40℃ ± 2℃, for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 month or at least 12 months.

In some embodiments, a Compound A formulation for inhalation described herein contains no more than 5 %wt of total impurities or related substances after stored at about 40℃ ± 2℃ for at least 3 months, at least 6 months, at least 9 months, or at least 12 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 40℃ ± 2℃ for 3 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 40℃ ± 2℃ for 6 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 40℃ ± 2℃ for 9 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at about 40℃ ± 2℃ for 12 months.

In some embodiments, a Compound A formulation for inhalation described herein contains no more than 3 %wt of total impurities or related substances after stored at about 40℃ ± 2℃ for at least 3 months, at least 6 months, at least 9 months, at or least 12 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 40℃ ± 2℃ for 3 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 40℃ ± 2℃ for 6 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 40℃ ± 2℃ for 9 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at about 40℃ ± 2℃ for 12 months.

In some embodiments, a Compound A formulation for inhalation described herein retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 40℃ ± 2℃ for at least 3 months, at least 6 months, at least 9 months, or at least 12 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 40℃ ± 2℃ for 3 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 40℃ ± 2℃ for 6 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 40℃ ± 2℃ for 9 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 40℃ ± 2℃ for 12 months.

In some embodiments, a Compound A formulation for inhalation described herein retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 40℃ ± 2℃ for at least 3 months, at least 6 months, at least 9 months, or at least 12 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 40℃ ± 2℃ for 3 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 40℃ ± 2℃ for 6 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 40℃ ± 2℃ for 9 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at about 40℃ ± 2℃ for 12 months.

In some embodiments, a Compound A formulation for inhalation described herein contains no more than 5 %wt of total impurities or related substances after stored at accelerated conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, or at least 12 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at accelerated conditions for 1, 2, or 3 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at accelerated conditions for 6 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at accelerated conditions for 9 months. In some embodiments, the Compound A formulation contains no more than 5 %wt of total impurities or related substances after stored at accelerated conditions for 12 months.

In some embodiments, a Compound A formulation for inhalation described herein contains no more than 3 %wt of total impurities or related substances after stored at accelerated conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at or least 12 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at accelerated conditions for 1, 2, or 3 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at accelerated conditions for 6 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at accelerated conditions for 9 months. In some embodiments, the Compound A formulation contains no more than 3 %wt of total impurities or related substances after stored at accelerated conditions for 12 months.

In some embodiments, a Compound A formulation for inhalation described herein retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at accelerated conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, or at least 12 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at accelerated conditions for 1, 2, or 3 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at accelerated conditions for 6 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at accelerated conditions for 9 months. In some embodiments, the Compound A formulation retains at least 90 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at accelerated conditions for 12 months.

In some embodiments, a Compound A formulation for inhalation described herein retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at accelerated conditions for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, or at least 12 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at accelerated conditions for 1, 2, or 3 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at accelerated conditions for 6 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at accelerated conditions for 9 months. In some embodiments, the Compound A formulation retains at least 95 %wt of the initial Compound A or a pharmaceutically acceptable salt thereof amount after stored at accelerated conditions for 12 months.

In some embodiments, Compound A formulations for inhalation described herein are stable or shelf-stable when in use after stored in various conditions including refrigerated conditions, room temperature, ambient conditions, and accelerated conditions. Stable or shelf stable as used herein refer to liquid formulations of Compound A or pharmaceutically acceptable salts thereof having about 95 %or greater of the initial Compound A or a pharmaceutically acceptable salt thereof amount, no more than 3%wt of total impurities or related substances at the end of a given storage period. Alternatively, stable or shelf stable as used herein refer to liquid formulations of Compound A or pharmaceutically acceptable salts thereof having about 90 %wt or greater of initial Compound A or a pharmaceutically acceptable salt thereof amount, no more than 5 %wt total impurities or related substances at the end of a given storage period. In some embodiments, the liquid formulations of Compound A or pharmaceutically acceptable salts thereof are in use when stored in an opened container.

Refrigerated Condition, Room Temperature, accelerated Conditions, Temperature Excursions

Refrigerated temperature, also as defined by the USP, is between 2 and 8 degrees Celsius, and is sometimes designated by the nominal value of 5 degrees Celsius. In some embodiments, refrigerated temperatures can be defined as 5 ± 3℃. In each case, the formulations described in the present disclosure that were shown to be stable showed acceptable recovery of the expected Compound A from the dose, where acceptable is >95 %or alternately >90 %of the nominal or starting dose of Compound A or a pharmaceutically acceptable salt thereof (e.g., free base, acetate salt, hydrochloride salt, citrate salt, or fumarate salt) , as well as maintaining acceptably constant therapeutic potential. Refrigerated conditions include temperature and/or relative humidity (RH) in typical refrigeration units (e.g., 5±3℃. ) . In some instances, a refrigerated condition is about 2℃, about 3℃, about 4℃, about 5℃, about 6℃, about 7℃, or about 8℃. In some instances, a refrigerated condition is about 2℃ to about 8℃.

As used herein, the term “room temperature, ” “ambient conditions, ” or “ambient temperature” refers to room temperature or “controlled room temperature. ” In some embodiments, the room temperatures are about 15℃ to about 25℃. In some embodiments, the room temperatures are about 15℃to about 30 ℃. In some embodiments, the room temperatures are 25 ± 5℃. In some embodiments, the controlled room temperatures are about 20℃ to about 25 ℃. In some embodiments, ambient conditions are about 15℃ to about 30℃. In some embodiments, ambient conditions are about 25 ± 5℃ and 60 ± 5 %RH. In some embodiments, ambient conditions are about 25 ± 2℃ and 60 ± 5 %RH. In some embodiments, the room temperature is about 25℃ and about 60 %RH. In some instances, a room temperature or ambient temperature is at about 20℃, about 21℃, about 22℃, about 23℃, about 24℃, about 25℃, about 26℃, about 27℃, about 28℃, about 29℃, and about 30℃. In other instances, an ambient condition is about 55 %RH, about 60 %RH, or about 65 %RH. In some embodiments, ambient conditions are about 25 ± 2℃ and 40 ± 5 %RH.

As used herein, the term “temperature excursions” or “temperature excursion” refers to a deviation from a pre-determined condition, such as a deviation from a “controlled room temperature. ” In some instances, the deviation is about ± 5℃, ± 6℃, ± 7℃, ± 8℃, ± 9℃, ± 10℃ from the controlled room temperature. In some instances, the deviation is about ± 5℃ from the controlled room temperature. In some instances, temperature excursion for controlled room temperature is about 15℃ to about 30℃. In some instances, the temperature excursion takes place less than 1 %, 2 %, 3 %, 4 %, 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, or 50 %of the time during the entire period when the pharmaceutical formulation is measured for stability.

Accelerated conditions for the Compound A liquid formulations for inhalation described herein include temperature and/or relative humidity (RH) that are at or above ambient levels or room temperature (e.g., 25±5℃; 55±10 %RH) . In some instances, an accelerated condition is at about 25℃, about 30 ℃, about 35 ℃, about 40 ℃, about 45 ℃, about 50 ℃, about 55 ℃ or about 60 ℃. In other instances, an accelerated condition is above 55 %RH, about 65 %RH, about 70 %RH, about 75 %RH or about 80 %RH or below 40%RH. In further instances, an accelerated condition is about 40 ℃ ± 2℃ and 60 ± 5 %RH. In other instances, an accelerated condition is about 40 ℃ ± 2℃ and 20 ± 5 %RH. In yet further instances, an accelerated condition is about 40 ℃ ± 2℃ and 75±5 %RH humidity. In some embodiments, an accelerated condition is about 60 ℃ ± 2℃.

Functional Improvements

Reducing Pulmonary Fibrosis

In one aspect, pharmaceutical formulations provided herein, when administered to a subject by inhalation, exhibits a higher efficacy in reducing pulmonary fibrosis than an efficacy of a reference oral formulation of Pirfenidone. In some cases, the reference oral formulation of Pirfenidone is administered at a dose that is at least about 5-fold of a dose of the pharmaceutical formulation administered by inhalation.

In some cases, the pharmaceutical formulations provided herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 0.5-fold, about 0.6-fold, about 0.7-fold, about 0.8-fold, about 0.9-fold, about 1.0-fold, about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 5-fold, or about 10-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation administered by inhalation.

In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 0.5-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 0.6-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 0.7-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 0.8-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 0.9-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 1.0-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits at least the same efficacy in reducing pulmonary fibrosis compared to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is from about 20-fold to about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits at least the same efficacy in reducing pulmonary fibrosis compared to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is about 150-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits at least the same efficacy in reducing pulmonary fibrosis compared to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is about 700-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 1.1-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 1.2-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 1.3-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 1.4-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 1.5-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 2-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 2.5-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 3-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 5-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that is at least about 10-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation.

In some cases, the pharmaceutical formulations provided herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that substantially similar to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 60-fold of a dose of the pharmaceutical formulation administered by inhalation. In some cases, the pharmaceutical formulations provided herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that substantially similar to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 150-fold of a dose of the pharmaceutical formulation administered by inhalation. In some cases, the pharmaceutical formulations provided herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that substantially similar to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 350-fold of a dose of the pharmaceutical formulation administered by inhalation. In some cases, the pharmaceutical formulations provided herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that substantially similar to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 700-fold of a dose of the pharmaceutical formulation administered by inhalation. In some cases, the pharmaceutical formulations provided herein, when administered to a subject by inhalation, exhibits an efficacy in reducing pulmonary fibrosis that substantially similar to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 3500-fold of the dose of the pharmaceutical formulation administered by inhalation.

In some cases, the efficacy in reducing pulmonary fibrosis is measured by modified Ashcroft score. In some cases, the efficacy in reducing pulmonary fibrosis is measured by quantitative morphometry of Masson’s Trichrome staining (%fibrosis area) in lung tissues of the subject. In some cases, the subject is Sprague-Dawley rat. In some cases, the subject is Sprague-Dawley rat with bleomycin-induced lung fibrosis.

In some cases, the administration of the pharmaceutical formulation to the subject is made via the inhalation device described herein. In some cases, the subject is human. In some cases, the subject is a human with IPF.

Inhibiting Lung Inflammation

In one aspect, pharmaceutical formulations provided herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation than an efficacy of a reference oral formulation of Compound A at a dose that is at least about 1-fold of the dose administered by inhalation.

In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in inhibiting lung inflammation that is at least about 0.5-fold, about 0.6-fold, about 0.7-fold, about 0.8-fold, about 0.9-fold, about 1-fold, about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 11-fold, about 12-fold, about 13-fold, about 14-fold, about 15-fold, about 18-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation.

In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in inhibiting lung inflammation that is at least about 0.5-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in inhibiting lung inflammation that is at least about 0.6-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in inhibiting lung inflammation that is at least about 0.7-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in inhibiting lung inflammation that is at least about 0.8-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in inhibiting lung inflammation that is at least about 0.9-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in inhibiting lung inflammation that is at least about 1-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits at least the same efficacy in inhibiting lung inflammation compared to an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits at least the same efficacy in inhibiting lung inflammation compared to an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 10-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits at least the same efficacy in inhibiting lung inflammation compared to an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1.5-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits at least the same efficacy in inhibiting lung inflammation compared to an efficacy of a reference oral formulation of Compound A administered at a dose that is from about 1.5-fold to about 1000-fold of the dose of the pharmaceutical formulation. [00231] In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 1.1-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 1.2-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 1.3-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 1.4-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 1.5-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 2-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 2.5-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 3-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 5-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 7-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 8-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 9-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 10-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 11-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 12-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 13-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 14-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 15-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 18-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 20-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 30-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 40-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a higher efficacy in inhibiting lung inflammation that is at least about 50-fold of an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation.

In some cases, the efficacy in inhibiting lung inflammation is measured by quantitative morphometry of Masson’s Trichrome staining (%inflammation area) of the subject. In some cases, the subject is Sprague-Dawley rat. In some cases, the subject is Sprague-Dawley rat with bleomycin-induced lung fibrosis.

In some cases, the efficacy in inhibiting lung inflammation is measured by a level of cytokines in lung tissues of the subject. In some cases, the cytokines comprises IL-1α, IL-1β, IL-4, IL-6, TNF-α, TGF-β, MCP-1, IL-17A, IL-7, MPO, or MIP-1α. In some cases, the cytokines comprises IL-1α. In some cases, the cytokines comprises IL-4. In some cases, the cytokines comprises TGF-β. In some cases, the cytokines comprises MPO. In some cases, the subject is mice. In some cases, the subject is mice with LPS-induced acute lung injury.

Improved Lung Function

In one aspect, provided herein is a method of improving lung function in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation described herein. In some cases, the lung function is measured by forced vital capacity (FVC in mL) , pulmonary compliance (Cdyn in mL/cmH₂O) , or airway resistance (RL or lung resistance in cmH₂O) of the subject. In some cases, the subject is Sprague-Dawley rat. In some cases, the subject is Sprague-Dawley rat with bleomycin-induced lung fibrosis.

In one aspect, pharmaceutical formulations provided herein, when administered to a subject by inhalation, exhibits a higher efficacy in improving lung function than an efficacy of a reference oral formulation of Pirfenidone. In some cases, the reference oral formulation of Pirfenidone is administered at a dose that is at least about 5-fold of a dose of the pharmaceutical formulation administered by inhalation. In some cases, the subject is Sprague-Dawley rat. In some cases, the subject is Sprague-Dawley rat with bleomycin-induced lung fibrosis.

In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 0.5-fold, about 0.6-fold, about 0.7-fold, about 0.8-fold, about 0.9-fold, about 1-fold, about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 5-fold, about 10-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, about 3500-fold of the dose of the pharmaceutical formulation for inhalation.

In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 0.5-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 0.6-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 0.7-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 0.8-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 0.9-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 1-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits at least the same efficacy in improving lung function compared to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is from about 20-fold to about 3500-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits at least the same efficacy in improving lung function compared to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is about 150-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits at least the same efficacy in improving lung function compared to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is about 150-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits at least the same efficacy in improving lung function compared to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is about 700-fold of the dose of the pharmaceutical formulation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 1.1-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 1.2-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 1.3-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 1.4-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 1.5-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 2-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 2.5-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 3-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 5-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is at least about 10-fold of an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 700-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation for inhalation.

In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is substantially similar to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 60-fold of a dose of the pharmaceutical formulation by inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is substantially similar to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 150-fold of the dose of the pharmaceutical formulation by inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is substantially similar to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 350-fold of the dose of the pharmaceutical formulation by inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is substantially similar to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 700-fold of the dose of the pharmaceutical formulation by inhalation. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits an efficacy in improving lung function that is substantially similar to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 3500-fold of the dose of the pharmaceutical formulation by inhalation.

In some cases, the efficacy in improving lung function is measured by forced vital capacity (FVC in mL) of the subject. In some cases, the efficacy in improving lung function is measured by pulmonary compliance (Cdyn in mL/cmH₂O) of the subject. In some cases, the efficacy in improving lung function is measured by airway resistance (RL or lung resistance in cmH₂O) of the subject.

Reduced Toxicity

In one aspect, provided herein is a method for administering 5′- (4-fluorophenyl) -3′-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H, 3′H- [2, 4′-biimidazole] -4-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof with reduced systemic or local toxicity to a subject in need thereof, the method comprising administering a pharmaceutical formulation described herein by inhalation.

In some cases, the reduced systemic or local toxicity is relative to a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A.

In one aspect, pharmaceutical formulations provided herein, when administered to a subject by inhalation, exhibits a higher toxicity safety margin as compared to a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A.

In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 11-fold, about 12-fold, about 13-fold, about 14-fold, about 15-fold, about 18-foldabout 20-fold, about 30-fold, about 40-fold, or about 50-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A.

In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 1.1-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold, about 120-fold, about 150-fold, or about 200-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin.

In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 1.1-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 1.2-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 1.3-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 1.4-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 1.5-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 2-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 2.5-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 3-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 5-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 7-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 8-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 9-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 10-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 11-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 12-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 13-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 14-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 15-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 18-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 20-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A.

In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 3-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 4-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 5-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 25-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 30-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 40-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 50-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 60-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 70-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 80-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 90-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 100-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 120-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least about 150-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin. In some cases, a pharmaceutical formulation described herein administered by inhalation exhibits a higher toxicity safety margin that is at least or about 200-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin.

In some cases, the toxicity safety margin is measured by systemic safety margin. In some cases, the toxicity safety margin is measured by local safety margin. The systemic safety margin can be determined on body surface area. The local safety margin can be determined on lung weight basis.

In some cases, the administration of the pharmaceutical formulation to the subject is made via the inhalation device described herein. In some cases, the subject is mice. In some cases, the subject is mice with LPS-induced acute lung injury. In some cases, the subject is Sprague-Dawley rat. In some cases, the subject is Sprague-Dawley rat with bleomycin-induced lung fibrosis. In some cases, the subject is dog. In some cases, the subject is human. In some cases, the subject is a human with IPF.

Reduced Dose

In one aspect, provided herein is a method for administering 5′- (4-fluorophenyl) -3′-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H, 3′H- [2, 4′-biimidazole] -4-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof with a reduced dose to a subject in need thereof, the method comprising administering a pharmaceutical formulation described herein by inhalation.

In some cases, the reduced dose is relative to a reference oral formulation of Compound A administered at a dose sufficient to reach a substantially similar lung Cmax and AUC of Compound A. In some cases, the reduced dose administered by inhalation is at most about 0.1%relative to the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 0.2%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 0.3%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 0.4%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 0.5%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 0.6%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 0.7%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 0.8%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 0.9%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 1%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 2%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 3%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 4%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 5%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 6%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 7%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 8%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 9%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 10%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 20%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 30%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 50%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 60%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 70%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most about 80%of the dose of the reference oral formulation of Compound A. In some cases, the reduced dose administered by inhalation is at most or about 90%of the dose of the reference oral formulation of Compound A.

In some cases, the administration of the pharmaceutical formulation to the subject is made via the inhalation device described herein. In some cases, the subject is mice. In some cases, the subject is mice with LPS-induced acute lung injury. In some cases, the subject is Sprague-Dawley rat. In some cases, the subject is Sprague-Dawley rat with bleomycin-induced lung fibrosis. In some cases, the subject is human. In some cases, the subject is a human with IPF.

Improved Lung Exposure

In one aspect, provided herein is a method for administering 5′- (4-fluorophenyl) -3′-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H, 3′H- [2, 4′-biimidazole] -4-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof with improved lung exposure to a subject in need thereof, the method comprising administering a pharmaceutical formulation described herein by inhalation. In some cases, the improved lung exposure is relative to a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A.

In one aspect, pharmaceutical formulations provided herein, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A as compared to that of a reference oral formulation of Compound A administered at the same dose.

In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 0.5-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 0.6-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 0.7-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 0.8-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 0.9-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 1.1-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 1.2-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 1.3-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 1.4-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 1.5-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 2-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 2.5-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 3-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 5-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 7-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 10-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 15-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 20-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 30-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 40-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 50-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 60-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 80-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 100-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose.

In some cases, the lung exposure is measured by an AUC ratio of lung exposure/plasma level of Compound A in the subject. In some cases, the subject is rat or dog.

Reduced Systemic Exposure

In one aspect, pharmaceutical formulations provided herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A as compared to that of a reference oral formulation of Compound A administered at the same dose.

In some cases, the systemic exposure is measured by AUC of plasma level of Compound A in the subject.

In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 0.1%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 0.2%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 0.3%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 0.4%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 0.5%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 0.6%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 0.7%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 0.8%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 0.9%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 1%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 2%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 3%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 4%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 5%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 6%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 7%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 8%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 9%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 10%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 20%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 30%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 50%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 60%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 70%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 80%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 90%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, a pharmaceutical formulation described herein, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 95%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose. In some cases, the reference oral formulation of Compound A is a tablet or a capsule.

Prolonged in vivo half-life

In some cases, a Compound A suspension for inhalation described herein offers benefits of providing a prolonged in vivo half-life of Compound A or a pharmaceutically acceptable salt thereof as compared to a Compound A solution described herein administered at the same dose. The in vivo half-life can be measured by the mean plasma concentration of Compound A overtime after administration.

In some cases, a Compound A suspension for inhalation provides an in vivo half-life that is at least about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 5-fold, about 10-fold, about 15-fold, about 20-fold of an in vivo half-life of a Compound A solution described herein administered at the same dose. In some cases, a Compound A suspension provides an in vivo half-life that is at least about 1.1-fold of an in vivo half-life of a Compound A solution described herein administered at the same dose. In some cases, a Compound A suspension provides an in vivo half-life that is at least about 1.2-fold of an in vivo half-life of a Compound A solution described herein administered at the same dose. In some cases, a Compound A suspension provides an in vivo half-life that is at least about 1.3-fold of an in vivo half-life of a Compound A solution described herein administered at the same dose. In some cases, a Compound A suspension provides an in vivo half-life that is at least about 1.4-fold of an in vivo half-life of a Compound A solution described herein administered at the same dose. In some cases, a Compound A suspension provides an in vivo half-life that is at least about 1.5-fold of an in vivo half-life of a Compound A solution described herein administered at the same dose. In some cases, a Compound A suspension provides an in vivo half-life that is at least about 2-fold of an in vivo half-life of a Compound A solution described herein administered at the same dose. In some cases, a Compound A suspension provides an in vivo half-life that is at least about 2.5-fold of an in vivo half-life of a Compound A solution described herein administered at the same dose. In some cases, a Compound A suspension provides an in vivo half-life that is at least about 3-fold of an in vivo half-life of a Compound A solution described herein administered at the same dose. In some cases, a Compound A suspension provides an in vivo half-life that is at least about 5-fold of an in vivo half-life of a Compound A solution described herein administered at the same dose. In some cases, a Compound A suspension provides an in vivo half-life that is at least about 10-fold of an in vivo half-life of a Compound A solution described herein administered at the same dose. In some cases, a Compound A suspension provides an in vivo half-life that is at least about 15-fold of an in vivo half-life of a Compound A solution described herein administered at the same dose. In some cases, a Compound A suspension provides an in vivo half-life that is at least about 20-fold of an in vivo half-life of a Compound A solution described herein administered at the same dose.

Methods of treatment or administration

Provided herein, in one aspect, are methods of treating or preventing a disease or condition comprising administration of Compound A formulation for inhalation described herein to a subject in need thereof. In some embodiments, the pharmaceutical formulation is administered to the subject by inhalation. In some embodiments, the pharmaceutical formulation is administered to the subject via an inhalation device as described herein, such as a nebulizer or inhaler. In some embodiments, the pharmaceutical formulation is administered to the subject in a therapeutically effective amount.

Compound A formulations described herein can treat or prevent a disease or condition in a subject in need thereof.

In another aspect, provided herein is a method of treating or preventing a disease comprising inhibiting TNIK kinase by administering Compound A or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, Compound A formulations described herein are administered by inhalation.

In another aspect, provided herein is a method of treating pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation described herein.

In another aspect, provided herein is a method of treating lung injury in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation described herein.

In another aspect, provided herein is a method of treating respiratory inflammation in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation described herein. In some cases, the respiratory inflammation is evaluated by a level of cytokines in lungs of the subject; optionally wherein the cytokines comprises IL-1α, IL-1β, IL-6, TNF-α, TGF-β, MCP-1, IL-17A, IL-7, or MIP-1α.

In another aspect, provided herein is a Compound A pharmaceutical composition for use as a medicament.

In another aspect, provided herein is a Compound A pharmaceutical composition for use as a medicament for treating pulmonary fibrosis in a subject in need thereof.

In another aspect, provided herein is a Compound A pharmaceutical composition for use as a medicament for treating lung injury in a subject in need thereof.

In another aspect, provided herein is a Compound A pharmaceutical composition for use as a medicament for treating respiratory inflammation in a subject in need thereof. In some cases, the respiratory inflammation is evaluated by a level of cytokines in lungs of the subject; optionally wherein the cytokines comprises IL-1α, IL-1β, IL-6, TNF-α, TGF-β, MCP-1, IL-17A, IL-7, or MIP-1α.

The use of Compound A pharmaceutical composition for the preparation of a medicament for the therapeutic and/or prophylactic treatment of pulmonary fibrosis, lung injury, and/or respiratory inflammation.

In another aspect, provided herein is a method of inhibiting TNIK kinase, TGF-β induced expression of fibrotic proteins, or M2 macrophage polarization in a subject in need thereof, the method comprising administering to the subject a pharmaceutical formulation described herein.

In another aspect, provided herein is a method of pulmonary delivery of 5′- (4-fluorophenyl) -3′-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H, 3′H- [2, 4′-biimidazole] -4-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof to a subject in need thereof, the method comprising administering a pharmaceutical formulation described herein by inhalation.

Disease or Condition

In some embodiments, the disease is a fibrotic disease or condition. In some embodiments, the disease is a fibrotic disease or condition selected from pulmonary fibrosis, cystic fibrosis, CNS fibrosis, heart fibrosis, liver fibrosis, myocardial fibrosis, kidney fibrosis, brain fibrosis, arterial fibrosis, arthrofibrosis, intestinal fibrosis, Dupytren’s contracture fibrosis, keloid fibrosis, mediastinal fibrosis, myelofibrosis, peyronie’s disease fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma sclerosis fibrosis, and adhesive capsulitis fibrosis.

In some embodiments, the disease is an inflammatory disease or condition, for example, inflammation in the lung, heart, kidney, liver, eye and CNS.

In some embodiments, the disease is a fibrotic disease or condition selected from liver cirrhosis, pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction, systemic sclerosis (SSc) , and graft-versus-host disease (GVHD) .

In some embodiments, the disease is idiopathic pulmonary fibrosis (IPF) . In some embodiments, the disease is lung inflammation.

In some embodiments, the disease is kidney fibrosis.

In some embodiments, the disease is skin fibrosis.

In some embodiments, the disease is associated with TNIK kinase.

In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from colorectal cancer, gastric cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, multiple myeloma, chronic myelogenous leukemia, cancer metastasis, fibrosis, and psychiatric disorders.

Subject

A subject (or a patient or host) can comprise a to living organism such as a mammal. Examples of subjects and hosts can comprise horses, cows, camels, sheep, pigs, goats, dogs, cats, rabbits, guinea pigs, rats (e.g., with bleomycin-induced lung fibrosis) , mice (e.g., with LPS-induced lung injury) , gerbils, non-human primates (e.g., macaques) , humans and the like, non-mammals, including, e.g., non-mammalian vertebrates, such as birds (e.g., chickens or ducks) fish (e.g., sharks) or frogs, and non-mammalian invertebrates, as well as transgenic species thereof. In some cases, a subject refers to a single organism (e.g., human) . In some cases, a subject refers to a group of individuals composing a small cohort having either a common immune factor to study and/or disease, and/or a cohort of individuals without the disease (e.g., negative/normal control) are provided. A subject from whom samples are obtained can either be inflicted with a disease and/or disorder (e.g., one or more allergies, infections, cancers or autoimmune disorders or the like) and can be compared against a negative control subject which is not affected by the disease.

Subjects can be, for example, mammal, rodents, dogs, humans, pregnant women, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, newborn, or neonates. A subject can be a patient. In some cases, a subject can be a human. In some cases, a subject can be a child (e.g., a young human being below the age of puberty) . In some cases, a subject can be an infant. In some cases, the subject can be a formula-fed infant. In some cases, a subject can be an individual enrolled in a clinical study. In some cases, a subject can be a laboratory animal, for example, a mammal, or a rodent. In some cases, the subject can be a mouse. In some cases, the subject can be a rat. In some cases, the subject can be a dog. In some cases, the is human. In some cases, the subject is an adult male. In some cases, the subject is an adult female.

A subject can have a disease or condition described herein or a risk of developing a disease or condition described herein. For prophylactic treatments, in some cases, the subject may not have the disease condition or the risk of developing thereof. In some cases, the subject may not be diagnosed with a disease or condition or the risk of developing thereof. In some cases, the subject has fibrosis in lung, kidney, skin, systemic sclerosis. In some cases, the subject has a pulmonary disease. In some cases, the subject has less than normal lung function. In some cases, the subject has acute lung injury. In some cases, the subject has pulmonary fibrosis. In some cases, the subject has lung inflammation. In some cases, the subject has IPF. In some cases, the subject has a disease associated with TNIK kinase.

In some embodiments, the subject has previously been treated with one or more different cancer treatment or fibrotic treatment. In some embodiments, the subject has previously been treated with one or more of radiotherapy, chemotherapy, or immunotherapy. In some embodiments, the subject has been treated with one, two, three, four, or five lines of prior therapy.

Administration

In some embodiments, administration of a pharmaceutical formulation described herein to the subject is made via an inhalation device described herein.

In certain therapeutic applications, the formulations of Compound A or pharmaceutically acceptable salts thereof are administered to a patient already suffering from a disease, e.g., IPF, in an amount sufficient to cure the disease or at least partially arrest or ameliorate the symptoms, e.g., reduce fibrosis, anti-inflammation, improved lung functions. Amounts effective for this use depend on the severity of the disease, previous therapy, the patient's health status, weight, and response to the formulations of Compound A or pharmaceutically acceptable salts thereof for inhalation, and the judgment of the treating physician. In some embodiments, the pharmaceutical formulation are administered in a therapeutically effective amount. Therapeutically effective amounts for each use described herein can optionally be determined by methods including, but not limited to, a dose escalation clinical trial. The precise therapeutically effective amounts for each use described herein can also depend on the patient's state of health, weight, and the like. When used in a patient, the therapeutically effective amounts for each use described herein can depend on the risk or susceptibility of developing the particular disease, previous therapy, the patient's health status and response to the Compound A formulations, and the judgment of the treating physician.

In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of a Compound A pharmaceutical formulation described herein are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life, if needed, in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease. In other embodiments, administration of a Compound A pharmaceutical formulation continues until complete or partial response of a disease.

In certain embodiments wherein a patient’s status does improve, the dose of a Compound A formulation being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday” ) . In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. The dose reduction during a drug holiday is, by way of example only, by 10 %-100 %, including by way of example only 10 %, 15 %, 20 %, 25 %, 30 %, 35 %, 40 %, 45 %, 50 %, 55 %, 60 %, 65 %, 70 %, 75 %, 80 %, 85 %, 90 %, 95 %, and 100 %.

In some embodiments, the method of treating a disease or disorder, or a symptom thereof comprises administering by inhalation to a subject in need thereof Compound A pharmaceutical formulations described herein. In some embodiments, the disease or disorder, or symptom thereof is one described herein. In some embodiments, the disease or disorder, or symptom thereof is IPF. In some embodiments, the method comprises by inhalation administering to a subject in need thereof Compound A pharmaceutical formulations described herein, wherein the Compound A pharmaceutical formulations are administered to the subject from an inhalation device described herein. In some embodiments, the inhalation device is a nebulizer or inhaler. In some embodiments, the method further comprises the step of filling the inhalation device with Compound A pharmaceutical formulations described herein. In some embodiments, the amount of the pharmaceutical composition administered to the subject is sufficient to provide from about 0.1 mg to about 20 mg of Compound A free base or a pharmaceutically acceptable salt thereof (e.g., acetate salt, hydrochloride salt, citrate salt, or fumarate salt) to the subject.

The present disclosure also provides the use of a composition (e.g., a pharmaceutical formulation) as described herein in the preparation of a medicament for the treatment of any of the disease or disorders, or symptom thereof, as disclosed herein.

Dosing

In one aspect, Compound A formulation for inhalation described herein are used for the treatment of diseases and conditions described herein. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of Compound A formulation in therapeutically effective amounts to said subject.

Dosages of Compound A formulation described can be determined by any suitable method. In various embodiments, a patient in need of Compound A or a pharmaceutically acceptable salt thereof (e.g., free base, acetate salt, hydrochloride salt, citrate salt, or fumarate salt) is monitored for improvement of symptoms, and the dose is individually adjusted to their optimum therapeutic dose. Maximum tolerated doses (MTD) and maximum response doses (MRD) for Compound A or a pharmaceutically acceptable salt thereof can be determined via established animal and human experimental protocols as well as in the examples described herein. For example, toxicity and therapeutic efficacy of Compound A or a pharmaceutically acceptable salt thereof can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD50 (the dose lethal to 50 %of the population) and the ED50 (the dose therapeutically effective in 50 %of the population) . The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compound A or a pharmaceutically acceptable salt thereof dosages exhibiting high therapeutic indices are of interest. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Additional relative dosages, represented as a percent of maximal response or of maximum tolerated dose, are readily obtained via the protocols.

In some embodiments, the amount of a given Compound A formulation that corresponds to such an amount varies depending upon factors such as the particular Compound A salt or form, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the composition type, the condition being treated, and the subject or host being treated. In many instances, the dose of the Compound A formulation can be adjusted based on any change or lack thereof of the symptoms in a patient, such as an improvement, no change or effect, or deterioration of a symptom or a condition. In some instances, the Compound A formulation can be discontinued if there is a lack of satisfactory response is noted.

In further embodiments, the dosages appropriate for the formulation for inhalation of Compound A or a pharmaceutically acceptable salt thereof described herein are from about 0.01 mg/kg to about 100 mg/kg, from about 0.05 mg/kg to about 80 mg/kg, from about 0.1 mg/kg to about 50 mg/kg, from about 0.25 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 20 mg/kg, from about 1 mg/kg to about 15 mg/kg, from about 1.5 mg/kg to about 10 mg/kg Compound A per body weight. In one embodiment, the dosages appropriate for the formulation of Compound A or a pharmaceutically acceptable salt thereof are from about 0.01 mg/kg to about 0.1 mg/kg Compound A per body weight. In another embodiment, the dosage appropriate for the Compound A formulation are from about 0.1 mg/kg to about 1 mg/kg Compound A per body weight. In another embodiment, the dosage appropriate for the Compound A formulation are from about 1 mg/kg to about 5 mg/kg Compound A per body weight. In yet another embodiment, the dosage appropriate for the Compound A formulation are from about 1 mg/kg to about 10 mg/kg Compound A per body weight. In yet another embodiment, the dosage appropriate for the Compound A formulation are from about 10 mg/kg to about 20 mg/kg Compound A per body weight. In yet another embodiment, the dosage appropriate for the Compound A formulation are from about 20 mg/kg to about 40 mg/kg Compound A per body weight. In yet another embodiment, the dosage appropriate for the Compound A formulation are from about 40 mg/kg to about 60 mg/kg Compound A per body weight. In yet another embodiment, the dosage appropriate for the Compound A formulation are from about 60 mg/kg to about 80 mg/kg Compound A per body weight. In yet another embodiment, the dosage appropriate for the Compound A formulation are from about 80 mg/kg to about 100 mg/kg Compound A per body weight. In some embodiments, the dosage appropriate for the Compound A formulation are from about 1.5 mg/kg Compound A per body weight. In some embodiments, the dosage appropriate for the Compound A formulation are from about 3 mg/kg Compound A per body weight. In some embodiments, the dosage appropriate for the Compound A formulation are from about 10 mg/kg Compound A per body weight. In one embodiment, the foregoing doses is the appropriate dose given per day. In another embodiment, the foregoing doses is the appropriate dose given every other day, every third day, every fourth day, every fifth day, every sixth day, weekly, biweekly, monthly or bimonthly. Dose per day can be given once per day or multiple times per day in the form of sub-doses given b.i.d., t.i.d., q.i.d., or the like where the number of sub-doses equal the dose per day. In some embodiments, the appropriate dose given per day is from about 0.1 mg to about 100 mg, from about 0.5 mg to about 80 mg, from about 1 mg to about 50 mg, from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1.5 mg to about 10 mg, or about 1.5 mg, about 3.0 mg, or about 10 mg.

In other embodiments the Compound A formulation for inhalation are provided at the maximum tolerated dose (MTD) for Compound A or a pharmaceutically acceptable salt thereof. In other embodiments, the amount of the Compound A formulation administered is from about 10 %to about 90 %of the maximum tolerated dose (MTD) , from about 25 %to about 75 %of the MTD, or about 50 %of the MTD. In particular embodiments, the amount of the Compound A formulation administered is from about 5 %to about 10 %, about 10 %to about 20 %, about 20 %to about 30 %, about 30 %to about 40 %, about 40 %to about 50 %, about 50 %to about 60 %, about 60 %to about 70 %, about 70 %to about 80 %, about 80 %to about 90 %, about 90 %to about 99 %or higher, of the MTD for Compound A or a pharmaceutically acceptable salt thereof.

In some embodiments, the Compound A formulation for inhalation are provided in a dosage that is lower than a dosage of Compound A oral formulation (e.g., the amount needed to reach a substantially similar lung Cmax or AUC of Compound A) as described herein.

Further Combinations

The treatment of certain diseases or conditions (e.g., IPF) in a subject with a Compound A pharmaceutical formulation for inhalation described herein encompass additional therapies and treatment regimens with other agents in some embodiments. Such additional therapies and treatment regimens can include another therapy, e.g., anti-inflammatory medication or antifibrotic medication, such as dexamethasone, pirfenidone for treatment of the particular disease or condition in some embodiments. In one instance, Compound A formulation can be used in conjunction with anti-inflammatory medication, such as dexamethasone to treat lung inflammation where applicable. Alternatively, in other embodiments, additional therapies and treatment regimens include other agents used to treat adjunct conditions associated with the disease or condition or a side effect from the Compound A formulation in the therapy.

Preparation of liquid formulations of Compound A or pharmaceutically acceptable salts thereof

Preparation of the Compound A liquid formulation for inhalation described herein includes any known pharmaceutical method.

In one embodiment, the Compound A liquid formulation described herein is prepared by first dissolving excipients, such as a buffer (e.g., citrate buffer) , pH-adjusting agents (e.g., citric acid) , or osmolarity adjusting agents in liquid vehicle (e.g., water) , thereby forming a solution comprising excipients. In some cases, the solution comprising excipients is prepared in an amount more than the final volume of the liquid formulation of Compound A or a pharmaceutically acceptable salt thereof. In some cases, the solution comprising excipients is prepared to reach a concentration of the excipients that is the same as the desired excipient concentration in the liquid formulation of Compound A or pharmaceutically acceptable salts thereof. In some cases, the solution comprising excipients is prepared having a concentration of the excipient that is higher than the desired concentration. In some cases, Compound A free base or a pharmaceutically acceptable salt thereof (e.g., acetate salt, hydrochloride salt, citrate salt, or fumarate salt) can be dissolved in a desired amount of the solution comprising excipients in a compounding container. The desired amount of the solution comprising excipients can be less than the desired final volume. Additional excipients, such as preservatives or surfactants can be added before or after Compound A is dissolved. The method can further comprise adding additional liquid vehicle or the solution comprising excipients to the compounding container to make up the desired final volume.

In some embodiments, Compound A or a pharmaceutically acceptable salt thereof and the excipients such as a buffer (e.g., citrate buffer) , an osmolarity adjusting agent (e.g., Sodium chloride) and optionally a preservative, and optionally a surfactant, can be combined in any order of addition.

In some embodiments, excipients such as a buffer (e.g., citrate buffer) , an osmolarity adjusting agent (e.g., Sodium chloride) and optionally a preservative (e.g., EDTA) are first dissolved in water to prepare a blank solvent. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is dissolved in the blank solvent and adjusted to desired volume or concentration, thereby obtaining the Compound A liquid formulation for inhalation described herein. In some embodiments, after Compound A or a pharmaceutically acceptable salt thereof is dissolved in the blank solvent and adjust to desired volume or concentration, a pH adjusting agent (e.g., HCl or NaOH) is added. In some embodiments, the obtained Compound A liquid formulation is packaged in a vial (e.g., LDPE vial) . In some embodiments, the obtained Compound A liquid formulation is packaged in a bottle (e.g., sodium-calcium glass bottle) . In some embodiments, the obtained Compound A liquid formulation is first packaged in a vial (e.g., LDPE vial) and then the vial is packed into an aluminum foil bag. In some embodiments, nitrogen-purging is used during the packaging. In some embodiments, the obtained Compound A liquid formulation is first packaged in a vial (e.g., LDPE vial) and then the vial is packed into an aluminum foil bag with nitrogen-purging before sealing.

In some embodiments, the method comprises testing pH of the composition and adjusting the pH by adding an additional amount of buffer or pH-adjusting agent (e.g., citric acid) to about 4.0 to about 5.5, such as about 4.0, about 4.5, about 5.0, or to about 5.5. In some embodiments, the testing and adjusting the pH is performed before adding Compound A free base or a pharmaceutically acceptable salt thereof. In some embodiments, the testing and adjusting the pH is performed after adding Compound A free base or a pharmaceutically acceptable salt thereof.

Kits and Articles of Manufacture

Kits and articles of manufacture are also described for Compound A pharmaceutical formulations for inhalation described herein, Compound A pharmaceutical compositions for preparation of pharmaceutical formulations for inhalation described herein, or inhalation devices described herein. In some aspects, provided herein is a kit comprising a package enclosing Compound A pharmaceutical compositions for preparation of pharmaceutical formulations described herein. In some aspects, provided herein is a kit comprising a package enclosing Compound A pharmaceutical formulations described herein. In some aspects, provided herein is a kit comprising a package enclosing an inhalation device described herein. In some aspects, provided herein is a kit comprising a package enclosing Compound A pharmaceutical formulation described herein and an inhalation device described herein. In some aspects, provided herein is a kit comprising a package enclosing Compound A pharmaceutical composition for preparation of pharmaceutical formulation described herein and an inhalation device described herein. The inhalation device can comprise the liquid pharmaceutical formulations described herein.

Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as inhalation devices described herein, bottles, vials, tubes, and the like, each of the container (s) comprising one of the separate elements to be used in a method described herein including a Compound A pharmaceutical formulation for inhalation or a Compound A pharmaceutical composition for preparation of a pharmaceutical formulation for inhalation described herein. Suitable containers include, for example, tanks, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic. The containers can further comprise a light protection mechanism, for example, an amber glass bottle. The containers can have different sizes, such as about 12 oz, about 10 oz, about 8 oz, about 6 oz, about 4 oz, about 2 oz, about 1 oz, or about 0.5 oz. The containers can have seal, such as induction seal. In some embodiments, the kit comprises a package enclosing a pharmaceutical formulation or the pharmaceutical composition for preparation of the pharmaceutical formulation described herein. In some embodiments, the package is a bottle. In some embodiments, the package comprises a vial, such as an LDPE vial. In some embodiments, the package comprises an aluminum foil bag. In some embodiments, the primary package comprises an LDPE vial and a secondary package comprises an aluminum foil bag. In some embodiments, the package is a sodium-calcium glass bottle. In some embodiments, the package is a borosilicate glass bottle. In some cases, the package has a light-protein mechanism, such as ambler glass. In some embodiments, the kit comprises a package enclosing a pharmaceutical formulation described herein and further comprises an inhalation device described herein (e.g., a nebulizer or inhaler) .

A kit can comprise one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for Compound A pharmaceutical formulation described herein. Non-limiting examples of such materials include, but not limited to, inhalation device described herein (e.g., a nebulizer) carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use associated with a Compound A pharmaceutical formulation described herein. A set of instructions can also be included. In some embodiments, the kit comprises instructions for use of a pharmaceutical formulation described herein.

A label can be on or associated with the container. A label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. A label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein.

Certain Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments described herein, certain preferred methods, devices, and materials are now described.

As used herein and in the appended claims, the singular forms “a” , “an” , and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" is a reference to one or more excipients and equivalents thereof known to those skilled in the art, and so forth.

Unless specifically stated or obvious from context, as used herein, the term “about” in reference to a number or range of numbers is understood to mean the stated number and numbers +/-10 %thereof, or 10 %below the lower listed limit and 10 %above the higher listed limit for the values listed for a range.

Unless specifically stated or obvious from context, as used herein, the term “substantially” or “substantially similar” in reference to a number or range of numbers is understood to mean the stated number and numbers +/-20 %thereof, or 20 %below the lower listed limit and 20 %above the higher listed limit for the values listed for a range.

The use of the term "or" in the claims is used to mean "and/or" unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and to "and/or. " The terms "comprise, " "have" and "include" are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as "comprises, " "comprising, " "has, " "having, " "includes" and "including, " are also open-ended. For example, any method that "comprises, " "has" or "includes" one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps.

“Optional” or “optionally” may be taken to mean that the subsequently described structure, event or circumstance may or may not occur, and that the description includes instances where the events occurs and instances where it does not.

As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient. In some embodiments, a therapeutic agent such as Compound A or a pharmaceutically acceptable salt thereof is directed to the treatment and/or the amelioration of, reversal of, or stabilization of the symptoms of IPF or other conditions described herein.

“Administering” when used in conjunction with a therapeutic means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering” , when used in conjunction with a Compound A formulation, can include, but is not limited to providing a Compound A formulation systemically to a patient by, e.g., administration by inhalation whereby the therapeutic reaches the target tissue or cells. “Administering” a formulation may be accomplished by administration by inhalation, injection, topical administration, or by other methods alone or in combination with other known techniques.

The term “animal” as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals. As used herein, the terms "patient, " "subject" and "individual" are intended to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In a preferred embodiment, the patient is a primate. In certain embodiments, the primate or subject is a human. In certain instances, the human is an adult. In certain instances, the human is child. In further instances, the human is 12 years of age or younger. In certain instances, the human is elderly. In other instances, the human is 60 years of age or older. Other examples of subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The experimental animal can be an animal model for a disorder, e.g., a rat or mouse with IPF or other conditions described herein. A patient can be a human suffering from IPF or other conditions described herein.

By “pharmaceutically acceptable” , it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The term “pharmaceutical composition” shall mean a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human) . Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

“Effective amount, ” and “sufficient amount” may be used interchangeably, and refer to an amount of a substance that is sufficient to achieve an intended purpose or objective.

A “therapeutically effective amount” when used in connection with a pharmaceutical composition described herein is an amount of one or more pharmaceutically active agent (s) sufficient to produce a therapeutic result in a subject in need thereof.

“Therapeutically equivalent” when used in connection with a pharmaceutical composition de-scribed herein refers to an amount or quantity of a pharmaceutically acceptable salt or ester of a pharmaceutically active agent that is equivalent to the therapeutically effective amount of the free base or alcohol of the pharmaceutically active agent.

The terms “treat, ” “treated, ” “treatment, ” or “treating” as used herein refers to therapeutic treatment, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total) , whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

EXAMPLES

The following examples are provided to further illustrate some embodiments of the present disclosure, but are not intended to limit the scope of the disclosure; it will be understood by their exemplary nature that other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.

Example A: Liquid formulations of Compound A for inhalation

Liquid formulations for inhalation were prepared using the ingredients described in Tables A-1 and A-2. Briefly, all excipients were dissolved in purified water that is in an amount of about 50%of the final volume, Compound A was then added to the solution, and purified water was added until a desirable volume was achieved. Alternatively method of preparation can be used to achieve the same. Stability of the formulations can be measured using the HPLC method described in Table A-3 (e.g., assay of Compound A and the amount of impurity of related substance) and visual examination, at different time points under various conditions, for example, after 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, and/or 36 months of storage at refrigerated conditions, ambient conditions, accelerated conditions, and/or other conditions that simulate controlled room temperature.

Table A-1. Exemplary liquid formulation of Compound A acetate salt for inhalation

Table A-2. Exemplary liquid formulation of Compound A acetate salt for inhalation

Table A-3. Exemplary HPLC method for Compound A acetate salt

Additional three liquid formulations for inhalation were prepared using the ingredients described in Table A-4.

Table A-4. Exemplary liquid formulations of Compound A free base for inhalation

Formulation 1 was prepared and packaged as follows. Blank solvent 1 was prepared by weighing 8.0030g of citric acid, 8.0054g of sodium citrate, and 15.0620g of sodium chloride, all of which were dissolve in approximately 1000mL of purified water, and was then made up to 2000mL with purified water. 5.3276g of Compound A free base was weighed, placed into a 1000mL volumetric flask, dissolved with the aforementioned blank solvent 1, and adjusted to volume to obtain Formulation 1. A syringe was used to draw up 2mL of the Formulation 1 into a 2.5mL LDPE vial. A pipette was used to transfer 10mL of the Formulation 1 into a 15mL sodium-calcium glass bottle. All vial samples were packed into aluminum foil bags, with half being nitrogen-purged and sealed, and the other half sealed directly. Half of the sodium-calcium glass bottle samples were first purged with nitrogen through a fine tube for 5 seconds and then immediately sealed; the other half were sealed directly.

Formulation 2 was prepared and packaged as follows. Blank solvent 2 was prepared by weighing 8.0082g of citric acid and 8.0024g of sodium citrate, both of which were dissolve in approximately 1000mL of purified water, and the volume was adjusted to 2000mL with purified water. 5.3238g of Compound A free base was weighed, placed into a 1000mL volumetric flask, dissolved with the aforementioned blank solvent 2, and adjusted to volume to obtain Formulation 2. A syringe was used to draw up 2mL of the Formulation 2 into a 2.5mL LDPE vial. A pipette was used to transfer 10mL of the Formulation 2 into a 15mL sodium-calcium glass bottle. All vial samples were packed into aluminum foil bags, with half being nitrogen-purged and sealed, and the other half sealed directly. Half of the sodium-calcium glass bottle samples were first purged with nitrogen through a fine tube for 5 seconds and then immediately sealed; the other half were sealed directly.

Formulation 3 was prepared and packaged as follows. Blank solvent 3 was prepared by weighing 8.0051g of citric acid, 8.0013g of sodium citrate, 15.0645g of sodium chloride, and 1.0077g of disodium edetate, all of which were dissolve in approximately 1000mL of purified water, and was then made up to 2000mL with purified water. 5.3214g of Compound A free base was weighed, placed into a 1000mL volumetric flask, dissolved with the aforementioned blank solvent 3, and adjusted to volume to obtain Formulation 3. A syringe was used to draw up 2mL of the Formulation 3 into a 2.5mL LDPE vial. A pipette was used to transfer 10mL of the Formulation 3 into a 15mL sodium-calcium glass bottle. All vial samples were packed into aluminum foil bags, with half being nitrogen-purged and sealed, and the other half sealed directly. Half of the sodium-calcium glass bottle samples were first purged with nitrogen through a fine tube for 5 seconds and then immediately sealed; the other half were sealed directly.

Additionally, HCl or NaOH can be added to adjust pH of any one of the liquid formulations for inhalation described herein as needed after Compound A or a pharmaceutically acceptable salt thereof was dissolved in the solution. Citric acid may not be used for adjusting pH as it was found to cause precipitation.

Each of the Formulations 1-3 packaged in LDPE vial or sodium-calcium glass bottle, with or without nitrogen purging, were tested for stability at initial time point (T0) , at 5 days (5d) , 10 days (10d) and 30 days (30d) under 40℃, at 5 days, 10 days and 30 days under 60℃, and at 5 days and 10 days under light exposure, respectively. The light exposure condition requires an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter. The individual impurities and total impurities were measured using HPLC. Stability results were summarized in Table A-5. Formulation 3 showed better stability than Formulation 1 and Formulation 2. LDPE vial as the primary package and foil bag as secondary package are considered better packaging than sodium-calcium glass bottles. Formulations that were packaged with nitrogen purging generally showed lower impurities than those without nitrogen purging.

Additional liquid formulations for inhalation were prepared using the ingredients described in Tables A-6 to A-9. The formulations can be prepared using a similar method as described above.

Table A-6. Exemplary liquid formulation of Compound A acetate salt for inhalation

Table A-7. Exemplary liquid formulation of Compound A free base for inhalation

Table A-8. Exemplary liquid formulation of Compound A HCl salt for inhalation

Table A-9. Additional liquid formulations of Compound A free base for inhalation

Example B: Efficacy study using mice with LPS-induced acute lung injury as a model

Lipopolysaccharide (LPS) was used to induce acute lung injury in C57BL/6 male mice, and the efficacy of Compound A acetate salt by intratracheal delivery (i. t) for inhibiting LPS-induced lung inflammation was evaluated, using dexamethasone (Dex) as a control. Figure 1 depicts the workflow of the efficacy study. Mice were divided into control groups and treatment groups. For the sham vehicle group (G1) , mice received saline instead of LPS and thus does not have any lung injury. For the model vehicle group (G2) , mice received LPS and later received vehicle treatment without an active pharmaceutical ingredient. For G3 group, mice received LPS and were administered Compound A acetate liquid formulation by intratracheal delivery (i.t. ) at 0.1 mg/kg once a day. For G4 group, mice received LPS and were administered Compound A acetate liquid formulation by intratracheal delivery (i.t. ) at 0.3 mg/kg one a day. For G5 group, mice received LPS and were administered Compound A acetate liquid formulation by intratracheal delivery (i.t. ) at 1 mg/kg once a day (Q.D. ) . For G6 group, mice received LPS and were administered orally administered (P.O. ) Dexamethasone (Dex) at 10 mg/kg twice a day (B.I.D. ) . For G7 group, mice received LPS and were orally administered Compound A acetate liquid formulation at 10 mg/kg once a day. Dose administered was calculated based on Compound A free base. Bronchoalveolar lavage fluid (BALF) , plasma, and lung were collected after 24 hours for analysis. Different endpoints, including the level of IL-1α, IL-4, MPO, and TGF-β, are measured for each treatment group, and the results are summarized in Figures 2A-2D. The results suggested that Compound A acetate liquid formulation delivered at 0.1, 0.3 and 1 mg/kg once a day by inhalation inhibited LPS-induced lung inflammation dose-dependently. Furthermore, the efficacy of Compound A acetate delivered by inhalation at 1 mg/kg once daily is comparable to Compound A acetate administered orally at 10 mg/kg once daily.

Example C: Efficacy study using rats with bleomycin-induced lung fibrosis as a model

Bleomycin was used to induce lung fibrosis in Sprague-Dawley male rats, and the efficacy of Compound A acetate salt delivered by inhalation for inhibiting lung fibrosis was evaluated, using Pirfenidone as a control. Figure 3 depicts the workflow of the efficacy study. Rats were divided into seven groups and received different treatment as described in Table C-1.

Table C-1. Treatment groups for efficacy study using rats with bleomycin-induced lung fibrosis as a model

Doses were calculated based on Compound A free base. The inhalation solution for Compound A administered to Groups 3-6 contains 0.1 mg/mL, 0.3 mg/mL, 1.0 mg/mL, and 6.0 mg/mL of Compound A free base, prepared according to the formulations described in Example A. At the end of the study, the lung functions were evaluated based on forced vital capacity, pulmonary compliance, and airway resistance for each group. The results for forced vital capacity, pulmonary compliance, and airway resistance are shown in Figures 4A-4C, respectively, showing that lung functions were improved in all treatment groups as compared to the vehicle control.

The degree of pulmonary fibrosis was also evaluated using modified Ashcroft score and quantitative Morphometry of Masson’s Trichrome staining. Masson's Trichrome (M&T) Staining Protocol: Lung sections were cut at 4 μm in thickness, dried in an oven for 1 hour, and stained with M&T by a standard staining protocol. The sections were briefly stained with Weigert's iron hematoxylin working solution for 10 minutes. This was followed by staining in Biebrich scarlet-acid fuchsin solution for 10 minutes and differentiation in phosphomolybdic-phosphotungstic acid solution for 5 minutes or until collagen is not red. The sample was then transferred to aniline blue solution and stained for 1 minute followed by dedifferentiation in 1%acetic acid solution. This was followed by dehydration and placement of a cover-slip for the subsequent image analysis. For image analysis of collagen deposition, Masson's trichrome stained slides were scanned using Aperio Scan Scope Model: CS2 (Leica) , at 200×magnification. The area of fibrosis stained with Masson's trichrome stain was quantified with the image analysis platform from Indica Labs. The whole left lung section was selected as an annotation layer. Fibrotic modifications were assessed morphologically and semi-quantitatively graded according to the scale of 0-8 defined by Ashcroft et al. and modified by Hübner et al. as described in the Table C-2 below. The final score was expressed as a mean of individual scores observed across all microscopic fields.

Table C-2. Modified Ashcroft Score

The results of modified Ashcroft score and Quantitative Morphometry of Masson’s Trichrome Staining (%fibrosis area) are summarized in Figures 4D and 4E, respectively. The results of Masson’s Trichrome staining for each group are shown in Figures 5A-5G. The degree of pulmonary fibrosis was reduced in Compound A 1.0 mg/mL treatment group (actual dose 0.489 mg/kg by inhalation, Q.D. ) and Compound A 6.0 mg/mL (actual dose 2.311 mg/kg by inhalation, Q.D. ) as compared to the vehicle control group. Furthermore, the reduction of pulmonary fibrosis from test articles from Compound A 1.0 mg/mL treatment group (actual dose 0.489 mg/kg by inhalation, Q.D. ) appeared to be greater than that of pirfenidone 350 mg/kg treatment group. The results in Figures 7A-7B also suggest that inhalation of Compound A at about 0.5mg/kg q.d. has comparable efficacy as oral administration of Compound A at about 10 mg/kg b.i.d.

The anti-inflammatory effects were also evaluated using H&E staining and the measurement of %inflammation in different groups. The quantitative morphometry of H&E staining is summarized in Figure 4F and the H&E staining for each group was shown in Figures 6A-6G. The Compound A 1.0 mg/mL treatment group (actual dose 0.489 mg/kg by inhalation, Q.D. ) and Compound A 6.0 mg/mL (actual dose 2.311 mg/kg by inhalation, Q.D. ) show clear effects of anti-inflammation as compared to the vehicle control group. Anti-inflammation effects from 1.0 mg/mL treatment group (actual dose 0.489 mg/kg by inhalation, Q.D. ) was greater than that of pirfenidone 350 mg/kg treatment group. Furthermore, the anti-inflammatory effect of inhalation of Compound A at 0.5 mg/kg, q.d., is comparable to oral dose of Compound A at 10 mg/kg, b.i.d. as indicated in Figures 8A-8B.

Example D: Rat PK Study for comparison of Compound A solution and Compound A suspension

A PK study comparing Compound A solution and suspension by single dose was conducted using male rat (strain: SD, approximately 300 g) as a model. The dose was given by nebulization. The treatment group information is shown in Table D-1. Compound A solution and Compound A suspension described in Table D-1 is administered once. Blood samples were collected at 0 min, 15min, 30min, 45min, 1h, 2h, 4h, 6h, 8h, and 24h for PK analysis. The mean plasma concentration of Compound A after Group 3 and Group 6 dosing was plotted in Figure 7. It was found that the suspension for inhalation can significantly prolong the in vivo half-life of Compound A.

Preparation of suspension: appropriate amount of Compound A acetate salt was added in Phosphate-buffered saline (PBS, pH = 6.8) and was stirred for 24 hours to form a suspension with Compound A at 0.1mg/mL.

Table D-1. Treatment groups

While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be employed in practicing the invention.

Claims

A pharmaceutical formulation for inhalation, wherein the formulation comprises

(a) Compound A or a pharmaceutically acceptable salt thereof, wherein the Compound A has a structure of

(b) a liquid vehicle;

wherein the Compound A is present in an amount of from about 0.001 mg/mL to about 200 mg/mL.
A pharmaceutical formulation for inhalation, wherein the formulation comprises

(a) Compound A or a pharmaceutically acceptable salt thereof, wherein the Compound A has a structure of

(b) a liquid vehicle;

wherein the pharmaceutical formulation has pH of from about 1.0 to about 11.0.
A pharmaceutical formulation for inhalation, wherein the formulation comprises

(a) Compound A or a pharmaceutically acceptable salt thereof, wherein the Compound A has a structure of

(b) a liquid vehicle;

wherein the pharmaceutical formulation is stable after stored at room temperature for at least 2 weeks.
The pharmaceutical formulation of any one of claims 1-3, wherein the formulation is a solution or a suspension.
A pharmaceutical formulation for inhalation, wherein the formulation comprises

(a) Compound A or a pharmaceutically acceptable salt thereof, wherein the Compound A has a structure of

(b) a liquid vehicle;

wherein the pharmaceutical formulation is a clear solution.
The pharmaceutical formulation of any one of claims 1-5, wherein the Compound A or a pharmaceutically acceptable salt thereof is an acetate salt of Compound A, a hydrochloride salt of Compound A, a fumarate salt of Compound A, or a citrate salt of Compound A.
The pharmaceutical formulation of any one of claims 1-6, wherein the Compound A or a pharmaceutically acceptable salt thereof is present in the pharmaceutical formulation in an amount of from about 0.001 mg/mL to about 120 mg/mL, about 0.001 mg/mL to about 60 mg/mL, from about 0.001 mg/mL to about 30 mg/mL, from about 1 mg/mL to about 30 mg/mL, from about 1 mg/mL to about 10 mg/mL, or about 15 mg/mL to about 25 mg/mL; optionally wherein the Compound A or a pharmaceutically acceptable salt thereof is present in the pharmaceutical formulation in an amount of about 0.5 mg/mL, about 1.0 mg/mL, about 2.0 mg/mL, about 3.0 mg/mL, about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL, about 60 mg/mL, or about 120 mg/mL.
The pharmaceutical formulation of any one of claims 1-7, wherein the pharmaceutical formulation is a liquid formulation for inhalation.
The pharmaceutical formulation of any one of claims 1-8, wherein the pharmaceutical formulation has a pH of from about 1.0 to about 11.0, from about 3.0 to about 11.0, from about 2.5 to about 8.0, from about 2.5 to about 7.5, from about 3.0 to about 7.0, from about 3.0 to about 6.5, from about 3.5 to about 6.0, or from about 4.0 to about 5.5.
The pharmaceutical formulation of any one of claims 1-9, wherein the liquid pharmaceutical formulation, when administered to a subject by inhalation, exhibits a higher toxicity safety margin that is at least about 1.1-fold of a toxicity safety margin of a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A, wherein the toxicity safety margin is measured by systemic safety margin or systemic safety margin.
The pharmaceutical formulation of any one of claims 1-10, wherein the pharmaceutical formulation, when administered to a subject by inhalation, exhibits at least the same efficacy in inhibiting lung inflammation compared to an efficacy of a reference oral formulation of Compound A administered at a dose that is at least about 1-fold, about 3-fold, about 5-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, or about 50-fold of the dose of the pharmaceutical formulation, wherein the efficacy in inhibiting lung inflammation is measured by quantitative morphometry of H&E staining (%inflammation area) or a level of cytokines in lung tissues of the subject; optionally wherein the subject is a mice or Sprague-Dawley rat; optionally wherein the cytokines comprises IL-1α, IL-1β, IL-4, IL-6, TNF-α, TGF-β, MCP-1, IL-17A, IL-7, Myeloperoxidase (MPO) , or MIP-1α.
The pharmaceutical formulation of any one of claims 1-11, wherein the pharmaceutical formulation, when administered to a subject by inhalation, exhibits at least the same efficacy in improving lung function compared to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation, wherein the efficacy in improving lung function is measured by forced vital capacity (FVL in mL) , pulmonary compliance (Cdyn in mL/cmH2O) , or airway resistance (RL or lung resistance in cmH2O) of the subject; optionally wherein the subject is a Sprague-Dawley rat.
The pharmaceutical formulation of any one of claims 1-12, wherein the pharmaceutical formulation, when administered to a subject by inhalation, exhibits at least the same efficacy in reducing pulmonary fibrosis compared to an efficacy of a reference oral formulation of Pirfenidone administered at a dose that is at least about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 80-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 350-fold, about 500-fold, about 800-fold, about 1000-fold, about 2000-fold, about 3000-fold, or about 3500-fold of the dose of the pharmaceutical formulation, wherein the efficacy in reducing pulmonary fibrosis is measured by modified Ashcroft score or quantitative morphometry of Masson’s Trichrome staining (%fibrosis area) in lung tissues of the subject; optionally wherein the subject is Sprague-Dawley rat.
The pharmaceutical formulation of any one of claims 1-13, wherein the pharmaceutical formulation, when administered to a subject by inhalation, exhibits an improved lung exposure of Compound A that is at least about 20-fold of a lung exposure of a reference oral formulation of Compound A administered at the same dose, wherein the lung exposure is measured by an AUC ratio of lung exposure/plasma level of Compound A in the subject; optionally wherein the subject is rodents or dog.
The pharmaceutical formulation of any one of claims 1-14, wherein the pharmaceutical formulation, when administered to a subject by inhalation, exhibits a reduced systemic exposure of Compound A that is at most about 5%relative to a systemic exposure of a reference oral formulation of Compound A administered at the same dose, wherein the systemic exposure is measured by AUC of plasma level of Compound A in the subject.
The pharmaceutical formulation of any one of claims 1-15, wherein the liquid vehicle is aqueous, optionally wherein the liquid vehicle comprises water and wherein water is present in the pharmaceutical formulation in an amount of from about 1%to about 99.9%w/v, from about 10%to about 90%w/v, 10%to about 99.9%w/v, from about 20%to about 99.9%w/v, from about 40%to about 99.9%w/v, about 60%to about 99.9%w/v, from about 80%to about 99.9%w/v, from about 90%to about 99.9%w/v, or from about 95%to about 99.9%w/v, and optionally wherein the liquid vehicle is water.
The pharmaceutical formulation of any one of claims 1-15, wherein the liquid vehicle is non-aqueous.
The pharmaceutical formulation of any one of claims 1-17, wherein the liquid vehicle is present in an amount of from about 50%w/v to about 99.9%w/v, from about 60%w/v to about 99.9%w/v, from about 75%w/v to about 99.9%w/v, from about 90%w/v to about 99.9%w/v, from about 95%w/v to about 99.9%w/v, or from about 98%w/v to about 99.9%w/v.
The pharmaceutical formulation of any one of claims 1-18, wherein the pharmaceutical formulation comprises a buffer and wherein the buffer comprises a buffering agent.
The pharmaceutical formulation of claim 19, wherein the buffering agent comprises citrate, tartrate, acetate, carbonate, phosphate, metaphosphate, glycerophosphate, polyphosphate, pyrophosphate, oxide, lactate, fumarate, or a combination thereof.
The pharmaceutical formulation of claim 19 or 20, wherein the buffer is a citrate buffer and wherein the buffering agent comprises citric acid and sodium citrate; optionally wherein the citric acid is present in the pharmaceutical formulation in an amount of from about 0.05%w/v to about 5.0%w/v, from about 0.05%w/v to about 3.5%w/v, from about 0.1%w/v to about 2.0 %w/v, from about 0.1%w/v to about 1.0 %w/v, from about 0.1%w/v to about 0.8 %w/v, from about 0.2%w/v to about 0.6 %w/v, about 0.25%w/v, about 0.3%w/v, about 0.35%w/v, about 0.4%w/v, about 0.45%w/v, about 0.5%w/v, about 0.55%w/v, or about 0.6%w/v; optionally wherein the sodium citrate is present in the pharmaceutical formulation in an amount of from about 0.05%w/v to about 5%w/v, from about 0.1%w/v to about 3.0 %w/v, from about 0.2%w/v to about 2.0 %w/v, from about 0.3%w/v to about 1.0 %w/v, from about 0.4%w/v to about 0.8 %w/v, about 0.4%w/v, about 4.5%w/v, about 0.5%w/v, about 0.55%w/v, about 0.6%w/v, about 0.65%w/v, about 0.7%w/v, about 0.75%w/v, about 0.8%w/v, about 0.9%w/v, or about 1.0%w/v.
The pharmaceutical formulation of any one of claims 19-21, wherein the buffer is configured to provide a pH of from about 1.0 to about 11.0 from about 2.5 to about 7.5, from about 3.0 to about 7.0, or from about 3.0 to about 5.5.
The pharmaceutical formulation of any one of claims 1-22, wherein the pharmaceutical formulation comprises a pH-adjusting agent.
The pharmaceutical formulation of any one of claims 1-23, wherein the pharmaceutical formulation comprises a surfactant, optionally wherein the surfactant comprises an ionic surfactant (e.g., a cationic surfactant, an anionic surfactant, or a zwitterionic surfactant) , and optionally wherein the surfactant is present in the pharmaceutical formulation in an amount of from about 0.01%w/v to about 30%w/v, from 0.1%w/v to about 5%w/v, from 0.5%w/v to about 5%w/v, from 1%w/v to about 10%w/v, from 1%w/v to about 4%w/v, from about 0.5%w/v to about 25%w/v, or from about 1%w/v to about 20%w/v.
The pharmaceutical formulation of any one of claims 1-24, wherein the pharmaceutical formulation comprises a preservative, optionally wherein the preservative comprises an antimicrobial agent, a chelating agent, an antioxidant, or any combinations thereof.
The pharmaceutical formulation of claim 25, wherein the preservative comprises a paraben or a mixture of parabens, benzoic acid or a pharmaceutically acceptable salt thereof, sorbic acid or a pharmaceutically acceptable salt thereof, phenoxyethanol, benzyl alcohol, propionic acid, disodium ethylenediaminetetraacetic acid, polyphosphates, calcium disodium edetate, ethylenediaminetetraacetic acid (EDTA) , vitamin A, monothioglycerol, ascorbic acid, sodium bisulfite, sodium sulfite, α-Tocopherol acetate (vitamin E) , butylated hydroxyanisole (BHA) , butylated hydroxytoluene (BHT) , or any combinations thereof, optionally wherein the preservative is present in an amount of from about 0.001%w/v to about 1%w/v, from about 0.001%w/v to about 0.5%w/v, from about 0.005%w/v to about 0.2%w/v, from about 0.005%w/v to about 0.1%w/v, from about 0.005%w/v to about 0.01%w/v, from about 0.01%w/v to about 0.05%w/v, from about 0.01%w/v to about 0.1%w/v, from about 0.1%w/v to about 2%w/v, from about 0.01%w/v to about 0.2%w/v, from about 0.01%w/v to about 0.3%w/v, from about 0.01%w/v to about 0.4%w/v, from about 0.01%w/v to about 0.5%w/v, from about 0.05%w/v to about 0.2%w/v, or from about 0.1 %w/v to about 0.5%w/v.
The pharmaceutical formulation of any one of claims 1-26, wherein the pharmaceutical formulation comprises an osmolarity adjusting agent, optionally wherein the osmolarity adjusting agent comprises potassium chloride, magnesium chloride, sodium chloride, sodium bromide, magnesium bromide, calcium chloride or calcium bromide; optionally wherein the osmolarity adjusting agent is sodium chloride; optionally wherein the osmolarity adjusting agent is present in the pharmaceutical formulation in an amount of from about 0.01%w/v to about 10%w/v, from about 0.05%w/v to about 5%w/v, from about 0.1%w/v to about 2.5 %w/v, from about 0.2%w/v to about 2 %w/v, from about 0.5%w/v to about 1.5 %w/v, about 0.5%w/v, about 0.75%w/v, about 0.9%w/v, about 1 %w/v, about 1.5%w/v, or about 2 %w/v.
The pharmaceutical formulation of any one of claims 1-27, wherein the pharmaceutical formulation comprises Compound A or a pharmaceutically acceptable salt thereof in an amount of from about 0.001 mg/mL to about 60 mg/mL and the osmolality of the pharmaceutical formulation is from about 250 mOsmol/kg to about 400 mOsmol/kg; optionally wherein the pharmaceutical formulation comprises a citrate buffer that is configured to maintain a pH of the pharmaceutical formulation from about 3.0 to about 5.5.
The pharmaceutical formulation of any one of claims 1-28, wherein the pharmaceutical formulation contains (a) no more than 10%wt of total impurities after stored at about 2℃ to about 8℃ for 3 months; (b) no more than 10%wt of total impurities after stored at room temperature for 1 month; and/or (c) no more than 10%wt of total impurities after stored at about 40℃ ± 2℃ for 1 month, optionally wherein the total impurities is determined according to High-performance liquid chromatography (HPLC) method.
The pharmaceutical formulation of any one of claims 1-29, wherein the pharmaceutical formulation (a) retains at least 90 %wt of initial Compound A amount after stored at about 2℃to about 8℃ for 3 months; (b) retains at least 90 %wt of initial Compound A amount after stored at room temperature for 1 month; and/or (c) retains at least 90 %wt of initial Compound A amount after stored at about 40℃ ± 2℃ for 1 month, optionally wherein Compound A amount is determined according to High-performance chromatography (HPLC) method.
The pharmaceutical formulation of any one of claims 1-30, wherein the pharmaceutical formulation is (a) a clear solution after stored at about 2℃ to about 8℃ for 3 month; (b) is a clear solution after stored at room temperature for 1 month; and/or (c) is a clear solution after stored at about 40℃ ± 2℃ for 1month.
The pharmaceutical formulation of any one of claims 1-31, wherein the pharmaceutical formulation (a) remains stable after stored at about 2℃ to about 8℃ for at least 3 months; (b) remains stable after stored at room temperature for 1 month; and/or (c) remains stable after stored at about 40℃ ± 2℃ for 1 month.
A pharmaceutical composition for preparation of the pharmaceutical formulation of any one of claims 1-32, the pharmaceutical composition comprising:

(a) Compound A or a pharmaceutically acceptable salt thereof, wherein the Compound A has a structure of

(b) a buffering agent, a pH-adjusting agent, or both; and

(c) optionally, an osmolarity adjusting agent, a sweetener, a surfactant, a chelating agent, an anti-oxidant, a preservative, or a combination thereof.
The pharmaceutical composition of claim 33, wherein the pharmaceutical composition is a lyophilized formulation.
A pharmaceutical composition for reconstitution, the pharmaceutical composition comprising:

(a) Compound A or a pharmaceutically acceptable salt thereof, wherein the Compound A has a structure of

(b) a buffering agent, a pH-adjusting agent, or both; and

(c) optionally, an osmolarity adjusting agent, a sweetener, a surfactant, a chelating agent, an anti-oxidant, a preservative, or a combination thereof.
The pharmaceutical composition of any one of claims 33-35, wherein the pharmaceutical formulation is prepared by dispersing the pharmaceutical composition in a liquid vehicle.
An inhalation device comprising the pharmaceutical formulation of any one of claims 1-32 or the pharmaceutical composition of any one of claims 33-36, optionally wherein the inhalation device is an inhaler or a nebulizer.
The inhalation device of claim 37, wherein

(a) the inhalation device is configured to convert the pharmaceutical formulation into emitted droplets when administering to a subject; optionally wherein the inhalation device nebulizes the pharmaceutical formulation, optionally wherein

(i) the emitted droplets have a mass median aerodynamic diameter (MMAD) of droplet size of from about 0.1 μm to about 10 μm, about 0.5 μm to about 7 μm, about 1 μm to about 5 μm, about 1 μm to about 4 μm, or about 2 μm to about 3 μm,

(ii) the emitted droplets have a Geometric Standard Deviation (GSD) of droplet size distribution of from about 0.5 μm to about 5 μm, about 0.7 μm to about 3 μm, about 0.8 μm to about 2.5 μm, about 1.0 μm to about 3.0 μm, or about 1 μm to about 2 μm,

(iii) the emitted droplets have a volumetric mean diameter (VMD) of from about 1 μm to about 5 μm,

(iv) the emitted droplets have a mass median diameter (MMD) of from about 1 μm to about 5 μm, and/or

(v) a fine particle fraction (FPF) provided by the inhalation device is at least about 10%;

(b) the inhalation device is configured to deliver a dose for inhalation by a subject of from about 0.01 mL to 50 mL of the pharmaceutical formulation of any one of claims 1-32;

(c) the inhalation device is configured to achieve lung deposition of at least 5 %of Compound A or a pharmaceutically acceptable salt administered to a subject; and/or

(d) the inhalation device is configured to provide an output rate of at least about 0.1 mL/min.
A method of treating or preventing a disease or a condition in a subject in need thereof, the method comprising administering to the subject the pharmaceutical formulation of any one of claims 1-32.
The method of claim 39, wherein the disease or condition is a fibrotic disease or condition selected from pulmonary fibrosis, cystic fibrosis, CNS fibrosis, heart fibrosis, liver fibrosis, myocardial fibrosis, kidney fibrosis, brain fibrosis, arterial fibrosis, arthrofibrosis, intestinal fibrosis, Dupytren’s contracture fibrosis, keloid fibrosis, mediastinal fibrosis, myelofibrosis, peyronie’s disease fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma sclerosis fibrosis, and adhesive capsulitis fibrosis, optionally wherein the disease or condition is a fibrotic disease or condition selected from liver cirrhosis, pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction, systemic sclerosis (SSc) , and graft-versus-host disease (GVHD) .
The method of claim 39, wherein the disease or condition is associated with TNIK kinase.
The method of claim 39, wherein the disease or condition is idiopathic pulmonary fibrosis or lung inflammation.
A method of treating pulmonary fibrosis in a subject in need thereof, the method comprising administering to the subject the pharmaceutical formulation of any one of claims 1-32.
A method of treating lung injury in a subject in need thereof, the method comprising administering to the subject the pharmaceutical formulation of any one of claims 1-32.
A method of treating respiratory inflammation in a subject in need thereof, the method comprising administering to the subject the pharmaceutical formulation of any one of claims 1-32, optionally wherein the respiratory inflammation is evaluated by a level of cytokines in lungs of the subject; optionally wherein the cytokines comprises IL-1α, IL-1β, IL-6, TNF-α, TGF-β, MCP-1, IL-17A, IL-7, or MIP-1α.
A method of improving lung function in a subject in need thereof, the method comprising administering to the subject the pharmaceutical formulation of any one of claims 1-32, optionally wherein the lung function is measured by forced vital capacity (FVL in mL) , pulmonary compliance (Cdyn in mL/cmH₂O) , or airway resistance (RL or lung resistance in cmH₂O) of the subject.
A method of inhibiting TNIK kinase, TGF-β induced expression of fibrotic proteins, or M2 macrophage polarization in a subject in need thereof, the method comprising administering to the subject the pharmaceutical formulation of any one of claims 1-32.
The method of any one of claims 39-47, wherein the pharmaceutical formulation is administered to the subject by inhalation.
A method of pulmonary delivery of 5′- (4-fluorophenyl) -3′-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H, 3′H- [2, 4′-biimidazole] -4-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof to a subject in need thereof, the method comprising administering the pharmaceutical formulation of any one of claims 1-32 by inhalation.
A method for administering 5′- (4-fluorophenyl) -3′-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H, 3′H- [2, 4′-biimidazole] -4-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof with reduced systemic or local toxicity to a subject in need thereof, the method comprising administering the pharmaceutical formulation of any one of claims 1-32 by inhalation, optionally wherein the reduced systemic or local toxicity is relative to a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A.
A method for administering 5′- (4-fluorophenyl) -3′-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H, 3′H- [2, 4′-biimidazole] -4-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof with a reduced dose to a subject in need thereof, the method comprising administering the pharmaceutical formulation of any one of claims 1-32 by inhalation, optionally wherein the reduced dose is relative to a reference oral formulation of Compound A administered at a dose sufficient to reach a substantially similar lung Cmax and AUC of Compound A; optionally wherein the reduced dose administered by inhalation is at most about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 20%, about 30%, about 50%, about 60%, about 70%, about 80%, or about 90%of the dose of the reference oral formulation of Compound A.
A method for administering 5′- (4-fluorophenyl) -3′-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H, 3′H- [2, 4′-biimidazole] -4-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof with improved lung exposure to a subject in need thereof, the method comprising administering the pharmaceutical formulation of any one of claims 1-32 by inhalation, optionally wherein the improved lung exposure is relative to a reference oral formulation of Compound A administered at a level sufficient to reach a substantially similar lung Cmax and AUC of Compound A.
The method of any one of claims 39-52, wherein the administration of the pharmaceutical formulation to the subject is made via the inhalation device of claims 37 or 38; optionally wherein the pharmaceutical formulation is delivered less than 5 times a day; optionally wherein the pharmaceutical formulation is delivered in less than 30 min.
A kit comprising a package enclosing the pharmaceutical formulation of any one of claims 1-32, the pharmaceutical composition of any one of claims 33-36, or the inhalation device of claims 37 or 38, optionally wherein the kit comprises instructions for use of the liquid pharmaceutical formulation.
A kit comprising the pharmaceutical formulation of any one of claims 1-32 or the pharmaceutical composition of any one of claims 33-36, and an inhalation device.