Inhalation formulations of 1'-cyano substituted carbocyclic nucleoside analogs

Abstract

The present disclosure provides compounds of Formula (I), Formula (la), or Formula (lb), or their pharmaceutically acceptable salts and aqueous solvent-containing pharmaceutical formulations. These pharmaceutical formulations of the present disclosure are useful for treating and preventing viral infections in a subject in need thereof, and are for administration by inhalation.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to the following U.S. provisional patent applications: U.S. Provisional Patent Application No. 63 / 005,724, filed April 6, 2020; U.S. Provisional Patent Application No. 63 / 022,290, filed May 8, 2020; U.S. Provisional Patent Application No. 63 / 033,679, filed June 2, 2020; and U.S. Provisional Patent Application No. 63 / 160,622, filed March 12, 2021. The entire contents of these applications are incorporated herein by reference. Technical Field

[0003] Inhalable drug formulations suitable for treating viral infections are provided, such as those from the Arenaviridae family (…). Arenaviridae Coronavirus family ( Coronaviridae Filoviridae ( Filoviridae ), Flaviviridae ( Flaviviridae Orthomyxoviridae ( Orthomyxoviridae ), Pulmonary Virology ( Pneumoviridae ) or Paramyxoviridae ( Paramyxoviridae Viral infection. In particular, this article provides inhaled formulations comprising compounds of formula I, Ia or Ib as described herein, or pharmaceutically acceptable salts thereof, and an aqueous solvent. Background Technology

[0004] Preventing or treating infections caused by some viruses in the families Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, Orthomyxoviruses, Pneumoviridae, and Paramyxoviridae presents challenges due to the lack of vaccines or post-exposure prophylaxis models for preventing or managing infections caused by viruses from these families. In some cases, patients receive only supportive care, such as electrolyte and fluid balance, oxygen, blood pressure maintenance, or treatment for secondary infections.

[0005] Compound (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionate, referred herein as compound Ia, is known to exhibit antiviral properties against several viral families, including Arenaviridae, Coronaviridae, Filoviridae, Paramyxoviridae, and Flaviviridae viruses (see, for example, Warren, T. et al.). Nature , 2016, Vol. 531, pp. 381-385; Lo MK et al., Sci.Reports , 2017 Year, the 7 Volume, No. 43395pages; Sheahan TP et al., Sci. Transl. Med.2017 , vol. 9 , vol. eaal3653 pages; Agostini ML et al., MBio , 2018 , vol. 9 , vol. 2 , vol. e00221-18 pages; Cell Research , 2020 , vol. 30 , vol. 269-271 pages; and WO 2017 / 184668). There is a need to develop inhalable pharmaceutical compositions comprising a compound of Formula la, or a pharmaceutically acceptable salt thereof. Such pharmaceutical formulations can be useful, especially in the treatment of respiratory infections.

[0006] There are several advantages to delivering a therapeutic agent directly to the affected respiratory tract. With delivery targeted to the respiratory tract, the drug reaches the target tissue without first entering the systemic circulation, where drug molecules are subject to dilution, metabolism, distribution, and excretion. High local drug concentrations can be achieved in the lung, while systemic concentrations are kept below levels that can lead to adverse side effects. Inhaled therapy can also be used to deliver drugs to the bloodstream and ultimately to the desired site of action. SUMMARY

[0007] Provided herein are pharmaceutical compositions comprising:

[0008] i. a compound of Formula I, Formula la, or Formula lb:

[0009] ,

[0010] ,

[0011] or a pharmaceutically acceptable salt thereof; and

[0012] ii. an aqueous vehicle;

[0013] wherein the pharmaceutical formulation is suitable for administration via inhalation.

[0014] In some embodiments, the present disclosure provides pharmaceutical formulations comprising:

[0015] i. a compound of Formula I:

[0016] or a pharmaceutically acceptable salt thereof; and

[0017] ii. an aqueous vehicle;

[0018] wherein the pharmaceutical formulation is suitable for administration via inhalation.

[0019] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising:

[0020] i. a compound of Formula la:

[0021] or a pharmaceutically acceptable salt thereof; and

[0022] ii. an aqueous vehicle;

[0023] wherein the pharmaceutical formulation is suitable for administration via inhalation.

[0024] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising:

[0025] i. a compound of Formula lb:

[0026] or a pharmaceutically acceptable salt thereof; and

[0027] ii. an aqueous vehicle;

[0028] wherein the pharmaceutical formulation is suitable for administration via inhalation.

[0029] Also provided herein are methods of treating or preventing a viral infection in a human in need thereof, wherein the methods comprise administering to the human a pharmaceutical formulation of the present disclosure, wherein the administration is by inhalation. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 . shows the suspension stability of exemplary pharmaceutical formulations of the present disclosure.

[0031] Figure 2 . shows the effect of particle size on the suspension stability of exemplary pharmaceutical formulations of the present disclosure.

[0032] Figure 3 . shows the microscope image of a pre-milled exemplary pharmaceutical formulation comprising 15 mg / mL of a compound of Formula la, PBS, and 0.1% HPMC.

[0033] Figure 4 . shows the microscope image of a post-milled exemplary pharmaceutical formulation comprising 15 mg / mL of a compound of Formula la, PBS, and 0.1% HPMC.

[0034] Figure 5 . shows the microscope image of a post-milled exemplary pharmaceutical formulation comprising 15 mg / mL of a compound of Formula la, 150 mM NaCl, 0.1% HPMC, and 0.5% poloxamer 237.

[0035] Figure 6 . Microscopy images of a post-milled exemplary pharmaceutical formulation comprising 15 mg / mL of the compound of Formula la, 150 mM NaCl, and 0.5% poloxamer 237 are shown.

[0036] Figure 7 . Plasma concentration-time profiles following intravenous injection of a 10 mg / Kg dose of Formula la in two exemplary formulations in cynomolgus monkey model are shown.

[0037] Figure 8 . Concentration-time profiles of Formula la and its metabolites in plasma following deposition dose of 0.168 mg / kg of Formula la inhaled by African green monkeys (mean ± SD, n=4) are shown.

[0038] Figure 9 . Concentration-time profiles of Formula la and its metabolites in plasma following deposition dose of 0.536 mg / kg of Formula la inhaled by African green monkeys (mean ± SD, n=4) are shown.

[0039] Figure 10 . Concentration-time profiles of Compound E in PBMC following deposition dose of 0.168 mg / kg or 0.536 mg / kg of Formula la inhaled by African green monkeys (mean ± SD, n=4) are shown.

[0040] Figure 11 . LC-MS / MS peak area ratios of Compound E to ATP in nasal and nasopharyngeal mucosa 24 hours after deposition dose of 0.168 mg / kg or 0.536 mg / kg of Formula la inhaled by African green monkeys (mean ± SD, n=4) are shown.

[0041] Figure 12 . Concentrations of Compounds C, D, and E in respiratory tissues 24 hours after deposition dose of 0.168 mg / kg of Formula la inhaled by African green monkeys (mean ± SD, n=4) are shown.

[0042] Figure 13 . Concentrations of Compounds C, D, and E in respiratory tissues 24 hours after deposition dose of 0.536 mg / kg of Formula la inhaled by African green monkeys (mean ± SD, n=4) are shown.

[0043] Figure 14 . Concentrations of total phosphorylated metabolites in liver and kidney 24 hours after deposition dose of 0.168 mg / kg or 0.536 mg / kg of Formula la inhaled by African green monkeys (mean ± SD, n=4) are shown.

[0044] Figure 15Plasma PK profiles of two exemplary cyclodextrin formulations (low cyclodextrin formulation: 75 mg / mL cyclodextrin, and high cyclodextrin formulation: 150 mg / mL) in AGM monkeys following inhalation administration are shown. As seen, the systemic exposures of the two formulations are comparable.

[0045] Figure 16 PBMC triphosphate levels of two exemplary cyclodextrin formulations (low cyclodextrin formulation: 75 mg / mL cyclodextrin, and high cyclodextrin formulation: 150 mg / mL) in AGM monkeys following inhalation administration are shown. As seen, the plasma PK profiles of the two formulations are comparable.

[0046] Figure 17 Respiratory tissue levels of compounds C, D, and E of two exemplary cyclodextrin formulations (low cyclodextrin formulation: 75 mg / mL cyclodextrin, and high cyclodextrin formulation: 150 mg / mL) in AGM monkeys following inhalation administration are shown. As seen, the tissue levels are similar between the two formulations.

[0047] Figure 18 Total nucleotide levels in the liver and kidney 24 hours after AGM monkeys inhaled two exemplary cyclodextrin formulations (low cyclodextrin formulation: 75 mg / mL cyclodextrin, and high cyclodextrin formulation: 150 mg / mL) are shown. As seen, these nucleotide levels are comparable for the two formulations. The inhalation route also resulted in lower liver and kidney concentrations relative to IV dosing.

[0048] Figure 19 Mucosal compound E / ATP ratios of two exemplary cyclodextrin formulations (low cyclodextrin formulation: 75 mg / mL cyclodextrin, and high cyclodextrin formulation: 150 mg / mL) in AGM monkeys following inhalation administration are shown. Compound E was detected in the mucosal samples in the low cyclodextrin group, but the TP / ATP ratios can be lower due to blood contamination in the samples.

[0049] Figure 20 Plasma PK profiles of two exemplary formulations (cyclodextrin solution formulation and 0.1% HPMC suspension formulation) in AGM monkeys following inhalation administration are shown. As seen, the suspension and suspension formulation show similar AUCs, but the suspension formulation shows prolonged exposure of the compound of Formula la and Compound B relative to the solution formulation.

[0050] Figure 21 PBMC triphosphate levels of two exemplary cyclodextrin formulations (75 mg / mL cyclodextrin solution formulation and 0.1% HPMC suspension formulation) in AGM monkeys following inhalation administration are shown. As seen, the two formulations show similar PBMC triphosphate levels.

[0051] Figure 22Respiratory tissue metabolite levels of compounds C, D, and E in AGM monkeys following inhalation administration of two exemplary cyclodextrin formulations (75 mg / mL cyclodextrin solution formulation and 0.1% HPMC suspension formulation). Tissue samples were collected 24 h post-dose. As seen, while lung levels were similar, the suspension formulation had slightly lower levels in other tissues.

[0052] Figure 23 Total nucleotide levels in the liver and kidney at 24 h post-inhalation administration of two exemplary formulations (75 mg / mL cyclodextrin solution formulation and 0.1% HPMC suspension formulation) in AGM monkeys are shown. As seen, these nucleotide levels were comparable for both formulations. The inhalation route also resulted in lower liver and kidney concentrations relative to IV dosing.

[0053] Figure 24 Mucosal compound E / ATP ratios in AGM monkeys following inhalation administration of two exemplary formulations (75 mg / mL cyclodextrin solution formulation and 0.1% HPMC suspension formulation) are shown. Triphosphate (compound E) was detected in both groups, but the TP / ATP ratio was lower for the suspension formulation. Blood contamination noted in the mucosal samples can have affected the bioanalysis. DETAILED DESCRIPTION

[0054] I. SUMMARY

[0055] The present application includes a pharmaceutical formulation comprising a compound of Formula I, Formula la, or Formula lb and an aqueous solvent, wherein the pharmaceutical formulation is for administration via inhalation.

[0056] II. DEFINITIONS

[0057] A "compound of Formula I" means the following compound:

[0058]

[0059] A compound of Formula I is disclosed in WO 2012 / 012776. The IUPAC name of the compound of Formula I is (((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester

[0060] A "compound of Formula la" means the following compound:

[0061]

[0062] The compound of Formula Ia is disclosed in WO 2016 / 069826. The IUPAC name of the compound of Formula Ia is S )-2-ethylbutyl 2-((( S )-(((2 R ,3 S ,4 R ,5 R )-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate and has a CAS Registry Number of 1809249-37-3. The compound of Formula Ia is also known as remdesivir and GS-5734.

[0063] A "compound of Formula Ib" refers to the following compound:

[0064]

[0065] The compound of Formula Ib is disclosed in WO 2016 / 069826. The IUPAC name of the compound of Formula Ib is R )-2-ethylbutyl 2-((( S )-(((2 R ,3 S ,4 R ,5 R )-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate.

[0066] The compounds of the present disclosure exemplified by Formula I, Formula Ia, and Formula Ib have chiral centers, e.g., chiral carbon or phosphorus atoms. Accordingly, the compounds of the present disclosure include racemic mixtures of all stereoisomers, including enantiomeric, diastereomeric, and atropisomeric forms. In addition, the compounds of the present invention include optically active isomers that are enriched or resolved at any or all of the asymmetric, chiral atoms. In other words, chiral centers apparent from the description are provided as chiral isomers or racemic mixtures. Both racemic mixtures and diastereomeric mixtures, as well as separated or synthetic individual optical isomers (substantially free of their enantiomeric or diastereomeric partners), are within the scope of the present invention. Racemic mixtures are separated into their individual, substantially optically pure isomers by appropriate techniques, such as, for example, separation of diastereomeric salts formed with an optically active base (e.g., acid or base), followed by conversion back to the optically active compounds. In most cases, the desired optical isomer is synthesized by a stereospecific reaction that

[0067] The stereochemical definitions and conventions used in this article generally follow those edited by SP Parker. "McGraw-Hill Dictionary of Chemical Terms” (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds” (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in an optically active form, meaning they possess the ability to rotate the plane of polarization of light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l, D and L, or (+) and (-) are used to indicate the plane-polarized rotation symbol of a compound, where S, (-), or 1 indicates that the compound is levorotatory, while compounds prefixed with R, (+), or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical, differing only in that they are mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of such isomers are generally referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur in chemical reactions or processes without stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.

[0068] In some cases, the compounds of the present invention may also exist as tautomers. Although only one delocalized resonance structure can be described, all such forms are considered within the scope of the present invention. For example, for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazolium systems, olefin-amine tautomers may exist, and all their possible tautomer forms are within the scope of the present invention.

[0069] Any formula or structure given herein, including compounds of formula I, Ia, or Ib, is also intended to represent the unlabeled form and isotopically labeled form of the compound. Isotopically labeled compounds have the structure described by the formula given herein, except that one or more atoms are replaced by atoms having selected atomic masses or mass numbers. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, isotopes of these elements. 2 H (deuterium, D) 3 H (tritium) 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl and125 I. Various isotopically labeled compounds of the disclosure, e.g., wherein a radioisotope such as 3 H, 13 C and 14 C incorporation. Such isotopically labeled compounds are useful in metabolic studies, receptor binding assays, detection or imaging techniques, such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radioactive treatment of patients.

[0070] The disclosure also includes compounds of Formula I, Formula la, or Formula lb, wherein 1 to n hydrogens attached to a carbon atom are replaced with deuterium, wherein n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and, therefore, can be useful in prolonging the half-life of any compound of Formula I, Formula la, or Formula lb when administered to a mammal, especially a human. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. Vol. 5 (No. 12): pp. 524-527 (1984). Such compounds are synthesized by methods known in the art, e.g., by employing starting materials in which one or more hydrogens have been replaced by deuterium, in light of the present disclosure.

[0071] Deuterium labeled or substituted therapeutic compounds of the disclosure can have improved DMPK (drug metabolism and pharmacokinetics) properties, which relate to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, and / or an improvement in therapeutic 18 F labeled compounds can be used in PET or SPECT studies. Isotopically labeled compounds of the disclosure and prodrugs thereof can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent in a

[0072] The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the disclosure, any atom not specifically designated as a particular isotope means that the atom has its natural abundance isotope composition. Thus, in the compounds of the disclosure, any atom specifically designated as deuterium (D) means that the atom is deuterium.

[0073] “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying worsening or progression of the disease or condition, and / or preventing or delaying spread (e.g., metastasis) of the disease or condition; and / or c) relieving the disease, i.e., causing regression of clinical symptoms (e.g., improving a disease state, providing partial or total relief from the disease or condition, enhancing the effect of another drug, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival).

[0074] As used herein, the term “polyethylene glycol” or “PEG” refers to a polymer of the general chemical formula H(OCH2CH2) n OH, also known as (alpha-hydro-omega-hydroxypoly-(oxy-1,2-ethanediyl), wherein “n” is greater than or equal to 4. The term encompasses any substituted or unsubstituted PEG. PEGs are commercially available from a number of suppliers (e.g., Carbowax ™ (Dow Chemical, Midland, Mich.) and Poly-G ® (Arch Chemicals, Norwalk, Conn.).

[0075] “Prevention” or “preventing” means any treatment of a disease or condition that results in the non-development of clinical symptoms of the disease or condition. In some embodiments, the composition can be administered to a subject (including a human) at risk or with a family history of the disease or condition.

[0076] “DI water” (also known as deionized water, DIW, de-ionized water, demineralized water, or DM water) is water that has had substantially all of its mineral ions, such as cations including sodium, calcium, iron and copper, and anions such as chloride and sulfate, removed.

[0077] As used herein, “volume average diameter” or VMD refers to the diameter of a hypothetical particle that has the same average volume as the given sample.

[0078] The term “hypertonic saline” means an aqueous solution containing greater than 0.9% (w / v) NaCl. For example, 3% hypertonic saline contains 3% (w / v) NaCl.

[0079] III. PHARMACEUTICAL FORMULATIONS

[0080] All pharmaceutical formulations described herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, and an aqueous vehicle. In some embodiments, the pharmaceutical formulations provided herein comprise a compound of Formula I, or a pharmaceutically acceptable salt thereof, and an aqueous vehicle. In some embodiments, the pharmaceutical formulations provided herein comprise a compound of Formula la, or a pharmaceutically acceptable salt thereof, and an aqueous vehicle. In some embodiments, the pharmaceutical formulations provided herein comprise a compound of Formula lb, or a pharmaceutically acceptable salt thereof, and an aqueous vehicle. The aqueous vehicle comprises water and optionally one or more components selected from a cosolvent, a surfactant, a suspending agent, a tonicity agent, a buffer, a cyclodextrin, and an antimicrobial agent or preservative. The pharmaceutical formulations disclosed herein are for administration to a subject (for example, a human) by inhalation, for example, the pharmaceutical formulations are for administration by inhalation in the form of a mist or aerosol.

[0081] 1. A compound of Formula I, Formula la, or Formula lb

[0082] A compound of Formula I, Formula la, or Formula lb can be used in any suitable amount to achieve the desired concentration in a pharmaceutical formulation. For example, a compound of Formula I, Formula la, or Formula lb can be present in an amount of 0.1 mg to 1000 mg per mL of the pharmaceutical formulation, or 0.1 mg to 800 mg, 0.1 mg to 600 mg, 0.1 mg to 400 mg, 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 30 mg, 0.5 mg to 1000 mg, 0.5 mg to 800 mg, 0.5 mg to 600 mg, 0.5 mg to 500 mg, 0.5 mg to 400 mg, 0.5 mg to 200 mg, 0.5 mg to 100 mg, 0.5 mg to 50 mg, 0.5 mg to 30 mg, 1 mg to 800 mg, 1 mg to 600 mg, 1 mg to 400 mg, 1 mg to 200 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 30 mg, 10 mg to 1000 mg, 10 mg to 800 mg, 10 mg to 600 mg, 10 mg to 500 mg, 10 mg to 400 mg, 10 mg to 200 mg, 10 mg to 100 mg, 10 mg to 50 mg, 10 mg to 30 mg, 50 mg to 1000 mg, 50 mg to 800 mg, 50 mg to 600 mg, 50 mg to 400 mg, 50 mg to 200 mg, 50 mg to 100 mg, 100 mg to 1000 mg, 100 mg to 800 mg, 100 mg to 600 mg, 100 mg to 400 mg, 100 mg to 200 mg, 200 mg to 1000 mg, 200 mg to 800 mg, 200 mg to 600 mg, 200 mg to 400 mg, 300 mg to 1000 mg, 300 mg to 800 mg, 300 mg to 600 mg, 300 mg to 400 mg, 400 mg to 1000 mg, 400 mg to 800 mg, 400 mg to 600 mg, 400 mg to 500 mg, 500 mg to 1000 mg, 500 mg to 800 mg, 500 mg to 600 mg, 600 mg to 1000 mg, 600 mg to 900 mg, 600 mg to 800 mg, 600 mg to 700 mg, 700 mg to 1000 mg, 700 mg to 900 mg, 700 mg to 800 mg, 800 mg to 1000 mg, 800 mg to 900 mg, 900 mg to 100 mg per mL of the pharmaceutical formulation. In some embodiments, a compound of Formula I, Formula la, or Formula lb is present in an amount of about 10 mg to about 500 mg per mL of the pharmaceutical formulation, for example, about 10 mg to about 400 mg or about 10 mg to about 200 mg per mL of the pharmaceutical formulation.In some embodiments, the compound of Formula I, Formula la, or Formula lb is present in an amount of about 10 mg to about 40 mg per mL of the pharmaceutical formulation.

[0083] In some embodiments, the compound of Formula I, Formula la, or Formula lb is present in an amount of about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 5 mg to about 50 mg, about 5 mg to about 40 mg, about 5 mg to about 30 mg, about 5 mg to about 20 mg, or about 5 mg to about 10 mg per mL of the pharmaceutical formulation. In some embodiments, the compound of Formula I, Formula la, or Formula lb is present in an amount of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg per mL of the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises about 15 mg of the compound of Formula I, Formula la, or Formula lb per mL of the pharmaceutical formulation.

[0084] The compound of Formula I, Formula la, or Formula lb can be used in any suitable form. For example, the compound of Formula I, Formula la, or Formula lb can be amorphous or crystalline. In some embodiments, the compound of Formula I, Formula la, or Formula lb is amorphous. In some embodiments, the compound of Formula I, Formula la, or Formula lb is crystalline.

[0085] Crystalline forms of the compound of Formula la that can be used in the methods and compositions of the present application are described in U.S. Patent Application Publication No. 20180346504. For example, the compound of Formula la can be crystalline Form I, Form II, Form III, Form IV, as described in U.S. Patent Application Publication No. 20180346504, or a combination thereof. In some embodiments, the compound of Formula la is crystalline.

[0086] In some embodiments, the compound of Formula la is crystalline Form II. In some embodiments, the crystalline compound of Formula la is characterized by an X-ray powder diffraction (XRPD) pattern having at least three peaks selected from the group consisting of 22.3°, 16.2°, 22.5°, 13.8°, 12.7°, 16.9°, 10.6°, 14.5°, 24.3°, 24.0°, 17.6°, 23.4°, 8.1°, 11.0°, 26.8°, 28.9°, 19.6°, 27.8°, 26.4°, 28.7°, 29.8°, 33.0°, 18.8°, 18.3°, 32.1°, 25.3°, 32.6°, 8.6°, 34.2°, 35.9°, 27.2°, 28.1°, 38.9°, 34.6°, 17.1°, 35.2°, 21.4°, 30.6°, 25.6°, 18.5°, 31.7°, 36.5°, and 37.1° ± 0.2° 2-theta.

[0087] In some embodiments, the crystalline Form II of the compound of Formula la has an XRPD pattern comprising degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 22.3°, 16.9°, and 16.2°. In some embodiments, the crystalline Form II of the compound of Formula la has an XRPD pattern comprising degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 22.3°, 16.9°, and 16.2° and one or more of 13.8° and 12.7°. In some embodiments, the crystalline Form II of the compound of Formula la has an XRPD pattern comprising degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 22.3°, 16.9°, and 16.2° and one of 13.8° and 12.7°. In some embodiments, the crystalline Form II of the compound of Formula la has an XRPD pattern comprising degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 22.3°, 16.9°, and 16.2° and two of 13.8° and 12.7°. In some embodiments, the crystalline Form II of the compound of Formula la has an XRPD pattern comprising degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 22.3°, 16.9°, 16.2°, 13.8°, and 12.7°. In some embodiments, the crystalline Form II of the compound of Formula la has an XRPD pattern comprising any three degree 2-theta reflections (+ / - 0.2 degree 2-theta) selected from the group consisting of 22.3°, 16.9°, 16.2°, 13.8°, and 12.7°.

[0088] In some embodiments, the crystalline Form II of the compound of Formula la has an XRPD pattern including degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 22.5°, 10.6°, and 14.5°. In some embodiments, the crystalline Form II of the compound of Formula la has an XRPD pattern including one or more of degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 22.3°, 16.9°, 16.2°, 13.8°, and 12.7° and at 22.5°, 10.6°, and 14.5°. In some embodiments, the crystalline Form II of the compound of Formula la has an XRPD pattern including one of degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 22.3°, 16.9°, 16.2°, 13.8°, and 12.7° and at 22.5°, 10.6°, and 14.5°. In some embodiments, the crystalline Form II of the compound of Formula la has an XRPD pattern including two of degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 22.3°, 16.9°, 16.2°, 13.8°, and 12.7° and at 22.5°, 10.6°, and 14.5°. In some embodiments, the crystalline Form II of the compound of Formula la has an XRPD pattern including degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 22.3°, 16.9°, 16.2°, 13.8°, 12.7°, 22.5°, 10.6°, and 14.5°. In some embodiments, the crystalline Form II of the compound of Formula la has an XRPD pattern including any three degree 2-theta reflections (+ / - 0.2 degree 2-theta) selected from the group consisting of 22.3°, 16.9°, 16.2°, 13.8°, 12.7°, 22.5°, 10.6°, and 14.5°.

[0089] In some embodiments, the compound of Formula la is a mixture of crystalline Form II and crystalline Form IV. In some embodiments, the compound of Formula la is Mixture I, Mixture II, or Mixture III as described in U.S. Patent Application Publication No. 20180346504.

[0090] In some embodiments, the compound of Formula la is Mixture I having an XRPD pattern including degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 15.9°, 22.6°, and 14.1°. In some embodiments, Mixture I has an XRPD pattern including degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 15.9°, 22.6°, and 14.1° and at 12.5°. In some embodiments, Mixture I has an XRPD pattern including degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 15.9°, 22.6°, 14.1°, and 12.5°. In some embodiments, Mixture I has an XRPD pattern including any three degree 2-theta reflections (+ / - 0.2 degree 2-theta) selected from the group consisting of 15.9°, 22.6°, 14.1°, and 12.5°.

[0091] In some embodiments, the compound of Formula la is Mixture II having an XRPD pattern including degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 16.1°, 22.4°, and 12.7°. In some embodiments, Mixture II has an XRPD pattern including degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 16.1°, 22.4°, and 12.7° and one or more of 24.2°, 16.8°, 8.1°. In some embodiments, Mixture II has an XRPD pattern including degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 16.1°, 22.4°, and 12.7° and one of 24.2°, 16.8°, 8.1°. In some embodiments, Mixture II has an XRPD pattern including degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 16.1°, 22.4°, and 12.7° and two of 24.2°, 16.8°, 8.1°. In some embodiments, Mixture II has an XRPD pattern including degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 16.1°, 22.4°, and 12.7° and three of 24.2°, 16.8°, 8.1°. In some embodiments, Mixture II has an XRPD pattern including degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 16.1°, 22.4°, 12.7°, 24.2°, 16.8°, and 8.1°. In some embodiments, Mixture II has an XRPD pattern including any three degree 2-theta reflections (+ / - 0.2 degree 2-theta) selected from the group consisting of 16.1°, 22.4°, 12.7°, 24.2°, 16.8°, 8.1°, 13.9°, 17.5°, 11.1°, 10.7°, 14.7°, and 19.8°.

[0092] In some embodiments, the compound of Formula la is Mixture III having an XRPD pattern including degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 16.7°, 12.6°, and 17.2°. In some embodiments, Mixture III has an XRPD pattern including degree 2-theta reflections (+ / - 0.2 degree 2-theta) at one or more of 16.7°, 12.6°, and 17.2° and 19.6° and 14.1°. In some embodiments, Mixture III has an XRPD pattern including degree 2-theta reflections (+ / - 0.2 degree 2-theta) at one of 16.7°, 12.6°, and 17.2° and 19.6° and 14.1°. In some embodiments, Mixture III has an XRPD pattern including degree 2-theta reflections (+ / - 0.2 degree 2-theta) at two of 16.7°, 12.6°, and 17.2° and 19.6° and 14.1°. In some embodiments, Mixture III has an XRPD pattern including degree 2-theta reflections (+ / - 0.2 degree 2-theta) at 16.7°, 12.6°, 17.2°, 19.6°, and 14.1°. In some embodiments, Mixture III has an XRPD pattern including any three degree 2-theta reflections (+ / - 0.2 degree 2-theta) selected from the group consisting of 16.7°, 12.6°, 17.2°, 19.6°, and 14.1°.

[0093] The compound of Formula I, Formula la, or Formula lb can have any suitable purity. For example, the compound of Formula I, Formula la, or Formula lb can have a purity of at least about 90%, or at least about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or at least about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, or at least about 99.9%. In some embodiments, the compound of Formula I, Formula la, or Formula lb has a purity of at least about 99.1%. In some embodiments, the compound of Formula I, Formula la, or Formula lb has a purity of at least about 99.3%. In some embodiments, the compound of Formula I, Formula la, or Formula lb has a purity of at least about 99.5%. In some embodiments, the compound of Formula I, Formula la, or Formula lb has a purity of at least about 99.7%.

[0094] Impurities present in the compound of Formula I, Formula la, or Formula lb can include unreacted starting materials, undesired byproducts, and other materials. Representative impurities include Impurity A:

[0095] .

[0096] Impurity A can be present in an amount less than about 0.5%, or less than about 0.45%, about 0.40%, about 0.35%, about 0.30%, about 0.25%, about 0.20%, about 0.15%, about 0.10%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, or less than about 0.01%. The amount of impurity A can be measured as % AN (% area normalized) as measured by HPLC, or can be based on weight (w / w). In some embodiments, the compound of Formula I, Formula la, or Formula lb comprises less than about 0.10% of impurity A. In some embodiments, the compound of Formula I, Formula la, or Formula lb comprises less than about 0.05% of impurity A.

[0097] In some embodiments, the compound of Formula I, Formula la, or Formula lb can have a purity of at least about 99.1% and comprise less than about 0.10% of impurity A. In some embodiments, the compound of Formula I, Formula la, or Formula lb can have a purity of at least about 99.1% and comprise less than about 0.05% of impurity A. In some embodiments, the compound of Formula I, Formula la, or Formula lb can have a purity of at least about 99.1% and comprise less than about 0.04% of impurity A. In some embodiments, the compound of Formula I, Formula la, or Formula lb can have a purity of at least about 99.5% and comprise less than about 0.04% of impurity A. In some embodiments, the compound of Formula I, Formula la, or Formula lb can have a purity of at least about 99.5% and comprise less than about 0.04% of impurity A.

[0098] In some embodiments, the compound of Formula I, Formula la, or Formula lb is in a micronized form. In some embodiments, the micronized form has a d 90 less than 50 µm. For example, the micronized form can have a d 90 less than 45 µm, 40 µm, 35 µm, 30 µm, 25 µm, 20 µm, 15 µm, 10 µm, 9 µm, 8 µm, 7 µm, 6 µm, 5 µm, 4 µm, 3 µm, 2 µm, or 1 µm. In some embodiments, the micronized form has a d 90about 0.1 µm to 50 µm, e.g., about 0.1 µm to 45 µm, 0.1 µm to 40 µm, 0.1 µm to 35 µm, 0.1 µm to 30 µm, 0.1 µm to 25 µm, 0.1 µm to 20 µm, 0.1 µm to 15 µm, 0.1 µm to 10 µm, 0.1 µm to 9 µm, 0.1 µm to 8 µm, 0.1 µm to 7 µm, 0.1 µm to 6 µm, 0.1 µm to 5 µm, 0.1 µm to 4 µm, 0.1 µm to 3 µm, 0.1 µm to 2 µm, about 0.5 µm to 50 µm, about 0.5 µm to 45 µm, 0.5 µm to 40 µm, 0.5 µm to 35 µm, 0.5 µm to 30 µm, 0.5 µm to 25 µm, 0.5 µm to 20 µm, 0.5 µm to 15 µm, 0.5 µm to 10 µm, 0.5 µm to 9 µm, 0.5 µm to 8 µm, 0.5 µm to 7 µm, 0.5 µm to 6 µm, 0.5 µm to 5 µm, 0.5 µm to 4 µm, 0.5 µm to 3 µm, 0.5 µm to 2 µm, about 1 µm to 50 µm, about 1 µm to 45 µm, 1 µm to 40 µm, 1 µm to 35 µm, 1 µm to 30 µm, 1 µm to 25 µm, 1 µm to 20 µm, 1 µm to 15 µm, 1 µm to 10 µm, 1 µm to 9 µm, 1 µm to 8 µm, 1 µm to 7 µm, 1 µm to 6 µm, 1 µm to 5 µm, 1 µm to 4 µm, 1 µm to 3 µm, or 1 µm to 2 µm. In some embodiments, the micronized form of d 90 is about 10 µm, e.g., about 5 µm. In some embodiments, the micronized form of d 90 is about 1 µm to 10 µm, e.g., 0.1 µm to about 5 µm. In some embodiments, the micronized form has a d 90 of about 0.1 µm to 5 µm. In some embodiments, the micronized form has a d 90 of about 4 µm to 5 µm.

[0099] In some embodiments, the micronized form has a d 50 of less than 30 µm. For example, the micronized form of d 50 is less than 25 µm, 20 µm, 15 µm, 10 µm, 9 µm, 8 µm, 7 µm, 6 µm, 5 µm, 4 µm, 3 µm, 2 µm, or 1 µm. In some embodiments, the micronized form of d 50about 0.1 pm to 30 pm, e.g., about 0.1 pm to 25 pm, 0.1 pm to 20 pm, 0.1 pm to 15 pm, 0.1 pm to 10 pm, 0.1 pm to 9 pm, 0.1 pm to 8 pm, 0.1 pm to 7 pm, 0.1 pm to 6 pm, 0.1 pm to 5 pm, 0.1 pm to 4 pm, 0.1 pm to 3 pm, 0.1 pm to 2 pm, about 0.1 pm to 1 pm, 0.5 pm to 30 pm, 0.5 pm to 25 pm, 0.5 pm to 20 pm, 0.5 pm to 15 pm, 0.5 pm to 10 pm, 0.5 pm to 9 pm, 0.5 pm to 8 pm, 0.5 pm to 7 pm, 0.5 pm to 6 pm, 0.5 pm to 5 pm, 0.5 pm to 4 pm, 0.5 pm to 3 pm, 0.5 pm to 2 pm, 0.5 pm to 1 pm, 1 pm to 30 pm, 1 pm to 25 pm, 1 pm to 20 pm, 1 pm to 15 pm, 1 pm to 10 pm, 1 pm to 9 pm, 1 pm to 8 pm, 1 pm to 7 pm, 1 pm to 6 pm, 1 pm to 5 pm, 1 pm to 4 pm, 1 pm to 3 pm, or 1 pm to 2 pm. In some embodiments, the micronized form has a d 50 about 1 pm to 10 pm. In some embodiments, the micronized form has a d 50 about 1 pm to 5 pm. In some embodiments, the micronized form has a d 50 about 4 pm, 3 pm, 2 pm, and 1 pm. In some embodiments, the micronized form has a d 50 about 3 pm to 4 pm.

[0100] In some embodiments, the micronized form has a d 10 less than 20 pm. For example, the micronized form has a d 10 less than 15 pm, 10 pm, 9 pm, 8 pm, 7 pm, 6 pm, 5 pm, 4 pm, 3 pm, 2 pm, 1 pm, 0.5 pm, 0.4 pm, 0.3 pm, 0.2 pm, or 0.1 pm. In some embodiments, the micronized form has a d 10about 0.1 pm to 20 pm, e.g., about 1 pm to 20 pm, 1 pm to 15 pm, 1 pm to 10 pm, 1 pm to 9 pm, 1 pm to 8 pm, 1 pm to 7 pm, 1 pm to 6 pm, 1 pm to 5 pm, 1 pm to 4 pm, 1 pm to 3 pm, 1 pm to 2 pm, 0.1 pm to 15 pm, 0.1 pm to 10 pm, 0.1 pm to 9 pm, 0.1 pm to 8 pm, 0.1 pm to 7 pm, 0.1 pm to 6 pm, 0.1 pm to 5 pm, 0.1 pm to 4 pm, 0.1 pm to 3 pm, 0.1 pm to 2 pm, or 0.1 pm to 1 pm. In some embodiments, the micronized form of d 10 about 0.1 pm to 10 pm. In some embodiments, the micronized form of d 10 about 0.1 pm to 5 pm. In some embodiments, the micronized form of d 10 about 0.5 pm to 5 pm. In some embodiments, the micronized form of d 10 about 4 pm, 3 pm, 2 pm, 1 pm, 0.9 pm, 0.8 pm, 0.7 pm, 0.6 pm, 0.5 pm, 0.4 pm, 0.3 pm, 0.2 pm, or 0.1 pm. In some embodiments, the micronized form of d 10 about 1 pm to 3 pm.

[0101] In some embodiments, the compound of Formula I, Formula la, or Formula lb is not micronized (also referred to as non-micronized or unmicronized).

[0102] 2. Solvents and co-solvents

[0103] The pharmaceutical formulations described herein comprise a compound of Formula I, Formula la, or Formula lb in an aqueous vehicle. The water in the aqueous vehicle can be any suitable water, such as DI water, distilled water, or sterile water. In some embodiments, the water is DI water.

[0104] In some embodiments, the aqueous vehicle further comprises a cosolvent. Exemplary cosolvents include, but are not limited to, ethanol, glycerol, propylene glycol, or PEG (polyethylene glycol, e.g., PEG 100), N-methyl-2-pyrrolidone, and dimethyl sulfoxide. In some embodiments, the cosolvent is ethanol, glycerol, propylene glycol, PEG (e.g., PEG 100), or a combination thereof. In some embodiments, the cosolvent is ethanol, glycerol, propylene glycol, N-methyl-2-pyrrolidone, dimethyl sulfoxide, or a combination thereof. In some embodiments, the cosolvent is ethanol, glycerol, propylene glycol, or a combination thereof.

[0105] The compounds of Formula I, Formula la, or Formula lb can exist in the pharmaceutical formulations in any form. For example, the compounds of Formula I, Formula la, or Formula lb can exist as a solution, a suspension, or an emulsion in an aqueous vehicle. In some embodiments, the compounds of Formula I, Formula la, or Formula lb exist as a solution in an aqueous vehicle. In some embodiments, the compounds of Formula I, Formula la, or Formula lb exist as a suspension in an aqueous vehicle. In some embodiments, the compounds of Formula I, Formula la, or Formula lb exist as an emulsion in an aqueous vehicle.

[0106] 3. Surfactants

[0107] The pharmaceutical formulations described herein further comprise a surfactant. Surfactants that can be used to form the pharmaceutical formulations described include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a hydrophilic surfactant or a mixture of two or more hydrophilic surfactants can be employed, a lipophilic surfactant or a mixture of two or more lipophilic surfactants can be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be employed.

[0108] Some useful surfactants that can be used in the pharmaceutical formulations disclosed herein include, but are not limited to, oleic acid available under the trade name Mednique 6322 and Emersol 6321 (from Cognis Corp., Cincinnati, Ohio); cetylpyridinium chloride (from Arrow Chemical, Inc. Westwood, N.J.); soy lecithin available under the trade name Epikuron 200 (from Lucas Meyer Decatur, Ill.); polyoxyethylene (20) sorbitan monolaurate available under the trade name Tween 20 (from ICI Specialty Chemicals, Wilmington, Del.); polyoxyethylene (20) sorbitan monostearate available under the trade name Tween 60 (from ICI); polyoxyethylene (20) sorbitan monooleate available under the trade name Tween 80 (from ICI); polyoxyethylene (10) stearyl ether available under the trade name Brij 76 (from ICI); polyoxyethylene (2) oleyl ether available under the trade name Brij 92 (from ICI); polyoxyethylene-polyoxypropylene- ethylenediamine block copolymer available under the trade name Tetronic 150 R1 (from BASF); polyoxypropylene-polyoxyethylene block copolymer available under the trade names Pluronic L-92, Pluronic L-121 and Pluronic F68 (from BASF); castor oil ethoxylate available under the trade name Alkasurf CO-40 (from Rhone-Poulenc Mississauga Ontario, Canada); and mixtures thereof.

[0109] An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds with HLB values greater than about 10, and the HLB scale is generally not applicable to anionic, cationic, or zwitterionic compounds. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with HLB values equal to or less than about 10. However, the HLB value of a surfactant is only a rough guide, generally used to achieve formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0110] The hydrophilic surfactant can be ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkyl ammonium salts; fusidate salts; fatty acid derivatives of amino acids, oligopeptides and polypeptides; glyceride derivatives of amino acids, oligopeptides and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acylalky! lactylate salts; mono- and diacetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0111] Within the foregoing group, some ionic surfactants include, by way of example, lecithin, lysolecithin, phospholipids, lysophospholipids, and derivatives thereof. carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acylalkyl lactylate salts; mono- and diacetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0112] The ionic surfactant can be lecithin, lysolecithin, phosphatidylcholine, phospholipid stain, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactylate, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides, choline sulfate, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, tetraacetoyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

[0113] The hydrophilic nonionic surfactant can include, but is not limited to, alkyl glucoside; alkyl maltoside; alkylthio glucoside; lauryl polyoxyethylene glycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkyl phenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glyceryl fatty acid esters; polyglyceryl fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic interesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogs thereof; polyoxyethylene- vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic interesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a sugar.

[0114] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate / caprylate glycerides, PEG-8 caprate / caprylate glycerides, polyglyceryl 10 laurate, PEG-30 cholesterol, PEG-25 phytosteryl, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl 10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamer.

[0115] In some embodiments, the pharmaceutical formulations provided herein comprise a non-ionic surfactant. In some embodiments, the surfactant is a polysorbate or a poloxamer. For example, the surfactant is polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), polysorbate 60 (Tween 60), polysorbate 65 (Tween 65), polysorbate 80 (Tween 80), polysorbate 85 (Tween 85), poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, or poloxamer 407. In some embodiments, the surfactant is a polysorbate, e.g., the surfactant is polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), polysorbate 60 (Tween 60), polysorbate 65 (Tween 65), polysorbate 80 (Tween 80), or polysorbate 85 (Tween 85). In some embodiments, the surfactant is polysorbate 80 (Tween 80).

[0116] In some embodiments, the surfactant is a poloxamer. For example, the surfactant is poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, or poloxamer 407. In some embodiments, the surfactant is poloxamer 237.

[0117] By way of example only, suitable lipophilic surfactants include fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylenated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic interesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Within this group, some lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic interesterification products of polyols with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0118] Any desired amount of surfactant can be used in the pharmaceutical formulations described herein. Typically, the surfactant is present in an amount of about 0.01% to about 2.0% weight / volume, relative to the volume of the pharmaceutical formulation. For example, the surfactant is present in an amount of about 0.01% to about 1.5% or about 0.01% to about 1.0% weight / volume, relative to the volume of the pharmaceutical formulation. In some embodiments, the surfactant is present in an amount of about 0.5%, relative to the volume of the pharmaceutical formulation.

[0119] In some examples, the surfactant is present in an amount of about 0.01% to about 1.0% weight / volume relative to the volume of the pharmaceutical formulation. In some examples, the surfactant is present in an amount of about 0.01% to about 0.05% relative to the volume of the pharmaceutical formulation. For example, the surfactant is present in an amount of about 0.02% weight / volume relative to the volume of the pharmaceutical formulation.

[0120] In some embodiments, the surfactant is a poloxamer and is present in an amount of about 0.01% to about 2.0% weight / volume relative to the volume of the pharmaceutical formulation. For example, the surfactant is a poloxamer and is present in an amount of about 0.01% to about 1.5% or about 0.01% to about 1.0% weight / volume relative to the volume of the pharmaceutical formulation. In some embodiments, the surfactant is a poloxamer and is present in an amount of about 0.5% weight / volume relative to the volume of the pharmaceutical formulation.

[0121] In some embodiments, the surfactant is poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, or poloxamer 407 and is present in an amount of about 0.01% to about 2.0% weight / volume relative to the volume of the pharmaceutical formulation. For example, the surfactant is poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, or poloxamer 407 and is present in an amount of about 0.01% to about 1.5% or about 0.01% to about 1.0% weight / volume relative to the volume of the pharmaceutical formulation. In some embodiments, the surfactant is poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, or poloxamer 407 and is present in an amount of about 0.5% weight / volume relative to the volume of the pharmaceutical formulation.

[0122] In some embodiments, the surfactant is poloxamer 237 and is present in an amount of about 0.01% to about 2.0% weight / volume relative to the volume of the pharmaceutical formulation. For example, the surfactant is poloxamer 237 and is present in an amount of about 0.01% to about 1.5% or about 0.01% to about 1.0% weight / volume relative to the volume of the pharmaceutical formulation. In some embodiments, the surfactant is poloxamer 237 and is present in an amount of about 0.5% weight / volume relative to the volume of the pharmaceutical formulation.

[0123] In some examples, the surfactant is a polysorbate and is present in an amount of about 0.01% to about 1.0% weight / volume relative to the volume of the pharmaceutical formulation. For example, the surfactant is a polysorbate and is present in an amount of about 0.01% to about 0.05% relative to the volume of the pharmaceutical formulation. In some embodiments, the surfactant is a polysorbate and is present in an amount of about 0.02% weight / volume relative to the volume of the pharmaceutical formulation.

[0124] In some examples, the surfactant is polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), polysorbate 60 (Tween 60), polysorbate 65 (Tween 65), polysorbate 80 (Tween 80), or polysorbate 85 (Tween 85), and is present in an amount of about 0.01% to about 1.0% weight / volume relative to the volume of the pharmaceutical formulation. For example, the surfactant is polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), polysorbate 60 (Tween 60), polysorbate 65 (Tween 65), polysorbate 80 (Tween 80), or polysorbate 85 (Tween 85), and is present in an amount of about 0.01% to about 0.05% relative to the volume of the pharmaceutical formulation. In some embodiments, the surfactant is polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), polysorbate 60 (Tween 60), polysorbate 65 (Tween 65), polysorbate 80 (Tween 80), or polysorbate 85 (Tween 85), and is present in an amount of about 0.02% weight / volume relative to the volume of the pharmaceutical formulation.

[0125] In some examples, the surfactant is polysorbate 80 (Tween 80), and is present in an amount of about 0.01% to about 1.0% weight / volume relative to the volume of the pharmaceutical formulation. For example, the surfactant is polysorbate 80 (Tween 80), and is present in an amount of about 0.01% to about 0.05% relative to the volume of the pharmaceutical formulation. In some embodiments, the surfactant is polysorbate 80 (Tween 80), and is present in an amount of about 0.02% weight / volume relative to the volume of the pharmaceutical formulation.

[0126] In some embodiments, the pharmaceutical formulations described herein comprise about 10 mg to about 40 mg (e.g., about 15 mg) of a compound of Formula I, Formula la, or Formula lb (e.g., Formula la) per mL of the pharmaceutical formulation and an aqueous vehicle, wherein the aqueous vehicle comprises polysorbate 80 (Tween 80) in an amount of about 0.01% to about 1.0% (e.g., about 0.01% to about 0.05%, e.g., about 0.02%) weight / volume relative to the volume of the pharmaceutical formulation.

[0127] In some embodiments, the pharmaceutical formulations described herein comprise about 10 mg to about 40 mg (e.g., about 15 mg) of a compound of Formula I, Formula la, or Formula lb (e.g., Formula la) per mL of the pharmaceutical formulation and an aqueous vehicle, wherein the aqueous vehicle comprises poloxamer 237 in an amount of about 0.01% to about 1.5% (e.g., or about 0.01% to about 1.0%, e.g., about 0.5%) weight / volume relative to the volume of the pharmaceutical formulation.

[0128] 4. Suspending agents

[0129] In some embodiments, the pharmaceutical formulation described herein further comprises a suspending agent. In some examples, the suspending agent is a polymer, e.g., a cellulose-based polymer.

[0130] In some embodiments, the suspending agent is selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxymethyl cellulose, hydroxypropyl methylcellulose (HPMC), methylcellulose polymers, hydroxyethyl cellulose, sodium carboxymethyl cellulose (Na-CMC), microcrystalline cellulose, carboxymethyl cellulose, and cellulose. In some embodiments, the suspending agent is selected from methylcellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, and povidone (e.g., povidone K12, povidone K17, povidone K25, povidone K30, or povidone K90). In some embodiments, the suspending agent is selected from the group consisting of carboxymethyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose. In some embodiments, the suspending agent is carboxymethyl cellulose. In some embodiments, the suspending agent is hydroxypropyl methylcellulose.

[0131] Any amount of suspending agent can be used. In some embodiments, the amount of suspending agent is about 0.01% to about 5.0% weight / volume, relative to the volume of the pharmaceutical formulation. For example, the amount of suspending agent is about 0.01% to 4.5%, 0.01% to 4.0%, 0.01% to 3.5%, 0.01% to 3.0%, 0.01% to 2.5%, 0.01% to 2.0%, 0.01% to 1.5%, 0.01% to 1.0%, 0.01% to 0.5%, 0.05% to 5.0%, 0.05% to 4.5%, 0.5% to 4.0%, 0.05% to 3.5%, 0.05% to 3.0%, 0.05% to 2.05%, 0.05% to 2.0%, 0.05% to 1.5%, 0.05% to 1.0%, 0.05% to 0.5% weight / volume, relative to the volume of the pharmaceutical formulation. In some embodiments, the amount of suspending agent is about 0.01% to about 1.0% weight / volume, relative to the volume of the pharmaceutical formulation, e.g., about 0.05% to about 1.5% weight / volume, relative to the volume of the pharmaceutical formulation. In some embodiments, the amount of suspending agent is about 0.1% weight / volume, relative to the volume of the pharmaceutical formulation.

[0132] In some embodiments, the suspending agent is hydroxypropyl cellulose, and is present in an amount of about 0.01% to about 1.0% weight / volume, relative to the volume of the pharmaceutical formulation, e.g., about 0.05% to about 1.5% weight / volume, relative to the volume of the pharmaceutical formulation. In some embodiments, the suspending agent is hydroxypropyl cellulose, and is present in an amount of about 0.1% weight / volume, relative to the volume of the pharmaceutical formulation.

[0133] In some embodiments, the pharmaceutical formulations described herein comprise about 10 mg to about 40 mg (e.g., about 15 mg) of a compound of Formula I, Formula la, or Formula lb (e.g., Formula la) per mL of the pharmaceutical formulation and an aqueous vehicle, wherein the aqueous vehicle comprises: (i) poloxamer 237 in an amount of about 0.01% to about 1.5% (e.g., or about 0.01% to about 1.0%, e.g., about 0.5%) weight / volume relative to the volume of the pharmaceutical formulation; and (ii) hydroxypropyl cellulose in an amount of about 0.01% to about 1.0% (e.g., about 0.05% to about 1.5%, e.g., about 0.1%) relative to the volume of the pharmaceutical formulation.

[0134] In some embodiments, the pharmaceutical formulations described herein comprise about 10 mg to about 40 mg (e.g., about 15 mg) of a compound of Formula I, Formula la, or Formula lb (e.g., Formula la) per mL of the pharmaceutical formulation and an aqueous vehicle, wherein the aqueous vehicle comprises: (i) polysorbate 80 (Tween 80) in an amount of about 0.01% to about 1.0% (e.g., about 0.01% to about 0.05%, e.g., about 0.02%) weight / volume relative to the volume of the pharmaceutical formulation; and (ii) hydroxypropyl cellulose in an amount of about 0.01% to about 1.0% (e.g., about 0.05% to about 1.5%, e.g., about 0.1%) relative to the volume of the pharmaceutical formulation.

[0135] 5. Tonicity agents

[0136] In some embodiments, the pharmaceutical formulations disclosed herein further include a tonicity agent. In some embodiments, the tonicity agent can enhance the overall comfort of the patient. In some embodiments, the tonicity agent is used to adjust the osmolarity of the pharmaceutical composition to about 150 to about 1200 mOsm / Kg. In some embodiments, the tonicity agent is used to adjust the osmolarity of the pharmaceutical composition to about 200 mOsm / Kg to about 800 mOsm / Kg, e.g., about 200 mOsm / Kg to about 600 mOsm / Kg, about 250 mOsm / Kg to about 500 mOsm / Kg, about 250 mOsm / Kg to about 350 mOsm / Kg, about 275 mOsm / Kg to about 325 mOsm / Kg. In some embodiments, the tonicity agent is used to adjust the osmolarity of the pharmaceutical composition to about 300 mOsm / Kg.

[0137] Tonicity agents that can be used in the pharmaceutical formulations disclosed herein include, but are not limited to, sodium chloride, sodium sulfate, dextrose, lactose, sodium phosphate, sorbitol, mannitol, and sucrose, or combinations thereof. In some embodiments, the tonicity agent is sodium chloride or sodium sulfate. In some embodiments, the tonicity agent is sodium chloride. In some embodiments, the tonicity agent is sodium sulfate.

[0138] In some embodiments, the osmotic pressure of the pharmaceutical composition is adjusted to about 150 to about 1200 mOsm / Kg, for example, about 200 mOsm / Kg to about 800 mOsm / Kg, using sodium chloride or sodium sulfate. In some embodiments, the osmotic pressure of the pharmaceutical composition is adjusted to about 300 mOsm / Kg using sodium chloride or sodium sulfate.

[0139] In some embodiments, the osmotic pressure of the pharmaceutical composition is adjusted to about 150 to about 1200 mOsm / Kg, for example, about 200 mOsm / Kg to about 800 mOsm / Kg, using sodium chloride. In some embodiments, the osmotic pressure of the pharmaceutical composition is adjusted to about 300 mOsm / Kg using sodium chloride.

[0140] In some embodiments, the osmotic pressure of the pharmaceutical composition is adjusted to about 150 to about 1200 mOsm / Kg, for example, about 200 mOsm / Kg to about 800 mOsm / Kg, using sodium sulfate. In some embodiments, the osmotic pressure of the pharmaceutical composition is adjusted to about 300 mOsm / Kg using sodium sulfate.

[0141] In some embodiments, the pharmaceutical formulations described herein comprise, per mL of the pharmaceutical formulation, about 10 mg to about 40 mg (e.g., about 15 mg) of a compound of Formula I, Formula la, or Formula lb (e.g., Formula la), and an aqueous-containing vehicle, wherein the aqueous-containing vehicle comprises: (i) poloxamer 237 in an amount of about 0.01% to about 1.5% (e.g., or about 0.01% to about 1.0%, e.g., 0.5%) weight / volume relative to the volume of the pharmaceutical formulation; (ii) hydroxypropyl cellulose in an amount of about 0.01% to about 1.0% (e.g., about 0.05% to about 1.5%, e.g., about 0.1%) relative to the volume of the pharmaceutical formulation; and (iii) sodium chloride in an amount such that the osmotic pressure of the pharmaceutical composition is about 150 mOsm / Kg to about 1200 mOsm / Kg (e.g., about 200 mOsm / Kg to about 800 mOsm / Kg, e.g., 300 mOsm / Kg).

[0142] In some embodiments, the pharmaceutical formulations described herein comprise the compound of Formula I, Formula la, or Formula lb (e.g., Formula la) in an amount of about 10 mg to about 40 mg (e.g., about 15 mg) per mL of the pharmaceutical formulation and an aqueous vehicle, wherein the aqueous vehicle comprises: (i) polysorbate 80 (Tween 80) in an amount of about 0.01% to about 1.0% (e.g., about 0.01% to about 0.05%, e.g., about 0.02%) weight / volume relative to the volume of the pharmaceutical formulation; (ii) hydroxypropylcellulose in an amount of about 0.01% to about 1.0% (e.g., about 0.05% to about 1.5%, e.g., about 0.1%) relative to the volume of the pharmaceutical formulation; and (iii) sodium chloride in an amount such that the osmolarity of the pharmaceutical composition is about 150 mOsm / Kg to about 1200 mOsm / Kg (e.g., about 200 mOsm / Kg to about 800 mOsm / Kg, e.g., 300 mOsm / Kg).

[0143] 6. Buffering agents

[0144] In some embodiments, the pharmaceutical formulations described herein can also comprise a pH adjusting agent (or buffer). Buffers are used to adjust or maintain the pH of the pharmaceutical composition to a desired range for one or more of the following reasons: (1) to provide an environment for better product stability, (2) to provide better comfort to the patient at the time of administration (extreme pH can cause irritation and / or discomfort to the administration site), and (3) to provide a pH range for better antimicrobial preservative activity.

[0145] The pharmaceutical formulations of the present disclosure can be formulated with one or more pharmaceutically acceptable buffers such that the pH of the pharmaceutical composition is between about 3 to about 8, for example, between 3 to about 7, between 3 to about 6.5, between 3 to about 6.0, between 3 to about 5.5, between 3 to about 5, between 4 to about 5. Examples of buffers that can be used include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, phosphoric acid, fumaric acid, citric acid, tartaric acid, maleic acid, succinic acid, ammonia solution, ammonium carbonate, sodium borate, sodium carbonate, trihydroxyethylamine, triethanolamine, and sodium hydroxide.

[0146] In some embodiments, the buffering agent is a citrate buffering agent, which can also serve as a taste-masking or flavoring agent. In some embodiments, the pH of the pharmaceutical composition is about 3 to about 6.5, and the buffering agent is a citrate buffering agent. Any pharmaceutically acceptable citrate buffering agent can be used in the pharmaceutical formulations disclosed herein. In some embodiments, the citrate buffering agent comprises sodium citrate, potassium citrate, citric acid, or a combination thereof. In some examples, the citrate buffering agent comprises sodium citrate. In some embodiments, the citrate buffering agent results from a mixture of sodium citrate and citric acid. In some examples, the citrate buffer comprises potassium citrate. In some embodiments, the citrate buffering agent results from a mixture of potassium citrate and citric acid.

[0147] In some embodiments, the buffering agent is a phosphate buffering agent. In some embodiments, the pH of the pharmaceutical composition is about 6 to about 8, and the buffering agent is a phosphate buffering agent. Any pharmaceutically acceptable phosphate buffering agent can be used in the pharmaceutical formulations disclosed herein. In some embodiments, the phosphate buffering agent comprises sodium phosphate monobasic, potassium phosphate monobasic, sodium phosphate dibasic, potassium phosphate dibasic, phosphoric acid, or a combination thereof.

[0148] 7. Cyclodextrins

[0149] In some embodiments, the pharmaceutical formulations described herein further comprise a cyclodextrin. Cyclodextrins are a chemical family of cyclic compounds typically having 6, 7, or 8 sugar units. In some embodiments, the cyclodextrin comprises 6 sugar units (alpha-cyclodextrin (a-cyclodextrin)). In some embodiments, the cyclodextrin comprises 7 sugar units (beta-cyclodextrin (b-cyclodextrin)). In some embodiments, the cyclodextrin comprises 8 sugar units (gamma-cyclodextrin (g-cyclodextrin)).

[0150]

[0151] In some embodiments, the pharmaceutical formulations described herein comprise a cyclodextrin derivative. Cyclodextrin derivatives are cyclodextrins in which one or more of the -OH groups are modified to -OR groups. Non-limiting examples of cyclodextrin derivatives include, but are not limited to, cyclodextrins in which the -OH groups are modified to -OR, where each R is independently an alkyl, hydroxyalkyl, glucosyl, or maltosyl group, or -(CH2)4SO3 - Na + .

[0152] Non-limiting examples of commercial cyclodextrin derivatives used in the pharmaceutical formulations described herein include, but are not limited to, CAPTISOL® ® , CAVITRON® ® , DEXOLVE-7® ®and KLEPTOSE ® CAPTISOL ® CAPTISOL (referred to herein as Captisol) is a registered trademark of Ligand Corporation. Captisol refers to the sulfobutyl alkyl ether-beta-cyclodextrin (sodium sulfonate salt) sold or licensed by Ligand Pharmaceuticals Corporation. CAVITRON ® CAVITRON (referred to herein as Cavitron) is a registered trademark of Wacker Chemie AG. Cavitron is an excipient that is prepared by replacing the hydroxyl groups on natural cyclodextrins to obtain hydroxypropyl-beta-cyclodextrin (HPBCD), which significantly increases their solubility and makes them more suitable for drug solubilization. DEXOLVE-7 ® DEXOLVE-7 (referred to herein as Dexolve-7) is a registered trademark of CycloLabs Limited. Dexolve-7 is a sulfobutyl alkyl ether-beta-cyclodextrin sodium salt, an excipient for use in pharmaceutical formulations to increase solubility. ® KLEPTOSE (referred to herein as Kleptose) is a registered trademark of Roquette Pharmaceuticals, Inc., Geneva, IL. Kleptose is a brand of hydroxypropyl-beta-cyclodextrin.

[0153] In some embodiments, the cyclodextrin used in the pharmaceutical formulations described herein is a beta-cyclodextrin derivative selected from the group consisting of sulfobutyl alkyl ether-beta-cyclodextrin, beta-cyclodextrin sulfobutyl ether sodium, and hydroxypropyl-beta-cyclodextrin. In some embodiments, the cyclodextrin is sulfobutyl ether-beta-cyclodextrin. In some embodiments, the cyclodextrin is beta-cyclodextrin sulfobutyl ether sodium. In some embodiments, the cyclodextrin is hydroxypropyl-beta-cyclodextrin. In some embodiments, the cyclodextrin has the following formula:

[0154]

[0155] wherein R is -H or CH2CH2CH2CH2SO3 - Na + .

[0156] In some embodiments, the pharmaceutical formulations described herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, a cyclodextrin, and optionally a pH adjusting agent. In some embodiments, the pharmaceutical formulations described herein comprise a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, a cyclodextrin, and optionally a pH adjusting agent.

[0157] In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, a beta-cyclodextrin, and optionally a pH adjusting agent. In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, a beta-cyclodextrin, and optionally a pH adjusting agent.

[0158] In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, a beta-cyclodextrin, and optionally a pH adjusting agent, wherein the beta-cyclodextrin is sulfobutyl alkyl ether-beta-cyclodextrin, sodium sulfobutyl ether beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin. In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and a beta-cyclodextrin, and optionally a pH adjusting agent, wherein the beta-cyclodextrin is sulfobutyl alkyl ether-beta-cyclodextrin, sodium sulfobutyl ether beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin.

[0159] In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and a beta-cyclodextrin, and optionally a pH adjusting agent, wherein the beta-cyclodextrin is sodium sulfobutyl ether beta-cyclodextrin. In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and a beta-cyclodextrin, and optionally a pH adjusting agent, wherein the beta-cyclodextrin is sodium sulfobutyl ether beta-cyclodextrin.

[0160] In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and a beta-cyclodextrin, and optionally a pH adjusting agent, wherein the pH adjusting agent is NaOH and HC1. In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and a beta-cyclodextrin, and optionally a pH adjusting agent, wherein the pH adjusting agent is NaOH and HC1.

[0161] In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, a beta-cyclodextrin, and at least one pH adjusting agent. In some embodiments, the pharmaceutical formulations described herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, a beta-cyclodextrin, and at least two pH adjusting agents. In some embodiments, the pharmaceutical formulations described herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, a beta-cyclodextrin, and the pH adjusting agents HC1 and NaOH.

[0162] In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, beta-cyclodextrin, and at least one pH adjusting agent. In some embodiments, the pharmaceutical formulations described herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, beta-cyclodextrin, and at least two pH adjusting agents. In some embodiments, the pharmaceutical formulations described herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, beta-cyclodextrin, and the pH adjusting agents HC1 and NaOH.

[0163] In some embodiments, the pharmaceutical compositions described herein comprise 90 mg to 175 mg of a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent. In some embodiments, the pharmaceutical compositions described herein comprise 90 mg to 110 mg of a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent. In some embodiments, the pharmaceutical compositions described herein comprise 145 mg to 165 mg of a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent. In some embodiments, the compositions comprise 100 mg of a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent. In some embodiments, the pharmaceutical compositions described herein comprise 150 mg of a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent.

[0164] In some embodiments, the pharmaceutical compositions described herein comprise 90 mg to 175 mg of a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent. In some embodiments, the pharmaceutical compositions described herein comprise 90 mg to 110 mg of a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent. In some embodiments, the pharmaceutical compositions described herein comprise 145 mg to 165 mg of a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent. In some embodiments, the compositions comprise 100 mg of a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent. In some embodiments, the pharmaceutical compositions described herein comprise 150 mg of a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent.

[0165] In some embodiments, the pharmaceutical compositions described herein comprise 90 mg to 175 mg of a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the pH adjusting agent is NaOH and HC1. In some embodiments, the pharmaceutical compositions described herein comprise 90 mg to 110 mg of a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the pH adjusting agent is NaOH and HC1. In some embodiments, the pharmaceutical compositions described herein comprise 145 mg to 165 mg of a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the pH adjusting agent is NaOH and HC1. In some embodiments, the pharmaceutical compositions comprise 100 mg of a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the pH adjusting agent is NaOH and HC1. In some embodiments, the pharmaceutical compositions described herein comprise 150 mg of a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the pH adjusting agent is NaOH and HC1.

[0166] In some embodiments, the pharmaceutical compositions described herein comprise 90 mg to 175 mg of a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the pH adjusting agent is NaOH and HC1. In some embodiments, the pharmaceutical compositions described herein comprise 90 mg to 110 mg of a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the pH adjusting agent is NaOH and HC1. In some embodiments, the pharmaceutical compositions described herein comprise 145 mg to 165 mg of a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the pH adjusting agent is NaOH and HC1. In some embodiments, the pharmaceutical compositions comprise 100 mg of a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the pH adjusting agent is NaOH and HC1. In some embodiments, the pharmaceutical compositions described herein comprise 150 mg of a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the pH adjusting agent is NaOH and HC1.

[0167] In some embodiments of the pharmaceutical formulations described herein, the cyclodextrin is present in an amount of about 5% to 30% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of about 10% to 25% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of about 14% to 21% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of about 15% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of about 20% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of 15% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of 20% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of about 5% to 15% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of 8% to 12% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of 10% w / v relative to the volume of the pharmaceutical composition.

[0168] In some embodiments of the pharmaceutical formulations described herein, the cyclodextrin is present in an amount of about 5% to 30% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of about 10% to 25% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of about 14% to 21% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of about 15% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of about 20% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of 15% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of 20% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of about 5% to 15% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of 8% to 12% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the cyclodextrin is present in an amount of 10% w / v relative to the volume of the pharmaceutical composition.

[0169] In some embodiments of the pharmaceutical formulations provided herein, the compound of Formula I, Formula la, or Formula lb is present in an amount of about 1.0 mg / mL to 10.0 mg / mL. In some embodiments, the compound of Formula I, Formula la, or Formula lb is present in an amount of about 4.0 mg / mL to 8.0 mg / mL. In some embodiments, the compound of Formula I, Formula la, or Formula lb is present in an amount of about 5.0 mg / mL to 7.0 mg / mL. In some embodiments, the compound of Formula I, Formula la, or Formula lb is present in an amount of about 5.0 mg / mL. In some embodiments, the compound of Formula I, Formula la, or Formula lb is present in an amount of about 6.7 mg / mL. In some embodiments, the compound of Formula I, Formula la, or Formula lb is present in an amount of 5.0 mg / mL. In some embodiments, the compound of Formula I, Formula la, or Formula lb is present in an amount of 6.7 mg / mL.

[0170] In some embodiments of the pharmaceutical formulations provided herein, the compound of Formula la is present in an amount of about 1.0 mg / mL to 10.0 mg / mL. In some embodiments, the compound of Formula la is present in an amount of about 4.0 mg / mL to 8.0 mg / mL. In some embodiments, the compound of Formula la is present in an amount of about 5.0 mg / mL to 7.0 mg / mL. In some embodiments, the compound of Formula la is present in an amount of about 5.0 mg / mL. In some embodiments, the compound of Formula la is present in an amount of about 6.7 mg / mL. In some embodiments, the compound of Formula la is present in an amount of 5.0 mg / mL. In some embodiments, the compound of Formula la is present in an amount of 6.7 mg / mL.

[0171] In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, is present in an amount of about 4.0 to 8.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 5% to 30% w / v. In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, is present in an amount of about 4.0 to 8.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 10% to 25% w / v. In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, is present in an amount of about 4.0 to 8.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 14% to 21% w / v.

[0172] In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, is present in an amount of about 4.0 to 8.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 5% to 15% w / v. In some embodiments, the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, is present in an amount of about 4.0 to 8.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 8% to 12% w / v. In some embodiments, the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, is present in an amount of about 5.0 to 7.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 5% to 15% w / v. In some embodiments, the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, is present in an amount of about 5.0 to 7.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 8% to 12% w / v. In some embodiments, the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, is present in an amount of about 6.0 to 7.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 10% w / v.

[0173] In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula la, or a pharmaceutically acceptable salt thereof, is present in an amount of about 4.0 to 8.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 5% to 15% w / v. In some embodiments, the compound of Formula la, or a pharmaceutically acceptable salt thereof, is present in an amount of about 4.0 to 8.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 8% to 12% w / v. In some embodiments, the compound of Formula la, or a pharmaceutically acceptable salt thereof, is present in an amount of about 5.0 to 7.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 5% to 15% w / v. In some embodiments, the compound of Formula la, or a pharmaceutically acceptable salt thereof, is present in an amount of about 5.0 to 7.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 8% to 12% w / v. In some embodiments, the compound of Formula la, or a pharmaceutically acceptable salt thereof, is present in an amount of about 6.0 to 7.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 10% w / v.

[0174] In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula la, or a pharmaceutically acceptable salt thereof, is present in an amount of about 4.0 to 8.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 5% to 30% w / v. In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula la, or a pharmaceutically acceptable salt thereof, is present in an amount of about 4.0 to 8.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 10% to 25% w / v. In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula la, or a pharmaceutically acceptable salt thereof, is present in an amount of about 4.0 to 8.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 14% to 21% w / v.

[0175] In some embodiments, the pharmaceutical compositions provided herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula I, Formula la, or Formula lb is present in an amount of about 5.0 to 7.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 5% to 30% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula I, Formula la, or Formula lb is present in an amount of about 5.0 to 7.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 10% to 25% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula I, Formula la, or Formula lb is present in an amount of about 5.0 to 7.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 14% to 21% w / v relative to the volume of the pharmaceutical composition.

[0176] In some embodiments, the pharmaceutical compositions provided herein comprise a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula la, or a pharmaceutically acceptable salt thereof, is present in an amount of about 5.0 to 7.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 5% to 30% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula la, or a pharmaceutically acceptable salt thereof, is present in an amount of about 5.0 to 7.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 10% to 25% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula la, or a pharmaceutically acceptable salt thereof, is present in an amount of about 5.0 to 7.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 14% to 21% w / v relative to the volume of the pharmaceutical composition.

[0177] In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, is present in an amount of about 5.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 15% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, is present in an amount of about 6.7 mg / mL, and the beta-cyclodextrin is present in an amount of about 20% w / v relative to the volume of the pharmaceutical composition.

[0178] In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula la, or a pharmaceutically acceptable salt thereof, is present in an amount of about 5.0 mg / mL, and the beta-cyclodextrin is present in an amount of about 15% w / v relative to the volume of the pharmaceutical composition. In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of Formula la, or a pharmaceutically acceptable salt thereof, water, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula la, or a pharmaceutically acceptable salt thereof, is present in an amount of about 6.7 mg / mL, and the beta-cyclodextrin is present in an amount of about 20% w / v relative to the volume of the pharmaceutical composition.

[0179] In some embodiments, the pharmaceutical formulations for inhalation disclosed herein are obtained by reconstitution of a solid or powdered formulation. In some examples, the pharmaceutical formulations for inhalation disclosed herein are obtained by reconstitution of a lyophilized formulation, for example a lyophilized formulation disclosed by WO2019 / 014247.

[0180] Lyophilized formulations

[0181] In some embodiments, the pharmaceutical formulations for inhalation disclosed herein are obtained by reconstitution of a lyophilized or dehydrated composition comprising a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, and a cyclodextrin. In some embodiments, the pharmaceutical formulations for inhalation disclosed herein are obtained by reconstitution of a lyophilized composition comprising a compound of Formula la, or a pharmaceutically acceptable salt thereof, and a cyclodextrin. The lyophilized composition can be in any suitable solid form, such as a powder.

[0182] The compound of Formula I, Formula la, or Formula lb can be present in the lyophilized composition in an amount of 1% to 10% w / w, for example, 1% to 5%, or 2% to 4%, or 3% to 4%, or 3 to 3.5% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of 1% to 10% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of 1% to 5% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of 2% to 4% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of 3% to 3.5% w / w.

[0183] In some embodiments, the lyophilized composition comprises the compound of Formula la, or a pharmaceutically acceptable salt thereof, in an amount of 1% to 10% w / w, for example, 1% to 5%, 2% to 4%, 3% to 4%, or 3% to 3.5% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la, or a pharmaceutically acceptable salt thereof, in an amount of 1% to 10% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la, or a pharmaceutically acceptable salt thereof, in an amount of 1% to 5% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la, or a pharmaceutically acceptable salt thereof, in an amount of 2% to 4% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la, or a pharmaceutically acceptable salt thereof, in an amount of 3% to 3.5% w / w.

[0184] In some embodiments, the lyophilized formulation comprises the compound of Formula I, Formula la, or Formula lb in an amount of about 1% to 10% w / w relative to the weight of the pharmaceutical formulation, for example, about 1 to 5% w / w, about 2% to 4% w / w, about 3% to 4% w / w, or about 3% to 3.5% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of about 1% to 10% w / w relative to the weight of the pharmaceutical formulation. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of about 1% to 5% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of about 2% to 4% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of about 3% to 3.5% w / w.

[0185] In some embodiments, the lyophilized formulation comprises the compound of Formula la in an amount of about 1% to 10% w / w relative to the weight of the pharmaceutical formulation, for example, about 1 to 5% w / w, about 2% to 4% w / w, about 3% to 4% w / w, or about 3% to 3.5% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of about 1% to 10% w / w relative to the weight of the pharmaceutical formulation. In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of about 1% to 5% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of about 2% to 4% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of about 3% to 3.5% w / w.

[0186] In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, in an amount of about 1% w / w, 1.5% w / w, 2% w / w, 2.1% w / w, 2.2% w / w, 2.3% w / w, 2.4% w / w, 2.5% w / w, 2.6% w / w, 2.7% w / w, 2.8% w / w, 3.9% w / w, 3% w / w, 3.1% w / w, 3.2% w / w, 3.3% w / w, 3.4% w / w, 3.5% w / w, 3.6% w / w, 3.7% w / w, 3.8% w / w, 3.9% w / w, 4% w / w, 4.5% w / w, 5% w / w, 6% w / w, 7% w / w, 8% w / w, 9% w / w, or about 10% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb, in an amount of about 3.2% w / w.

[0187] In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of about 1% w / w, 1.5% w / w, 2% w / w, 2.1% w / w, 2.2% w / w, 2.3% w / w, 2.4% w / w, 2.5% w / w, 2.6% w / w, 2.7% w / w, 2.8% w / w, 3.9% w / w, 3% w / w, 3.1% w / w, 3.2% w / w, 3.3% w / w, 3.4% w / w, 3.5% w / w, 3.6% w / w, 3.7% w / w, 3.8% w / w, 3.9% w / w, 4% w / w, 4.5% w / w, 5% w / w, 6% w / w, 7% w / w, 8% w / w, 9% w / w, or about 10% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of about 3.2% w / w.

[0188] In some embodiments, the cyclodextrin is present in the lyophilized composition in an amount of about 90% to 99% w / w, for example, about 95% to 99% w / w, about 96% to 98% w / w, or about 96.5% to 97% w / w. In some embodiments, the lyophilized composition comprises cyclodextrin in an amount of about 90% to 99% w / w. In some embodiments, the lyophilized composition comprises cyclodextrin in an amount of about 95% to 99% w / w. In some embodiments, the lyophilized composition comprises cyclodextrin in an amount of about 96% to 98% w / w. In some embodiments, the lyophilized composition comprises cyclodextrin in an amount of about 96.5% to 97% w / w.

[0189] In some embodiments, the lyophilized composition comprises cyclodextrin in an amount of about 90% w / w, about 91% w / w, about 92% w / w, about 93% w / w, about 94% w / w, about 95% w / w, about 95.1% w / w, about 95.2% w / w, about 95.3% w / w, about 95.4% w / w, about 95.5% w / w, about 95.6% w / w, about 95.7% w / w, about 95.8% w / w, about 95.9% w / w, about 96% w / w, about 96.1% w / w, about 96.2% w / w, about 96.3% w / w, about 96.4% w / w, about 96.5% w / w, about 96.6% w / w, about 96.7% w / w, about 96.8% w / w, about 96.9% w / w, about 97% w / w, about 97.1% w / w, about 97.2% w / w, about 97.3% w / w, about 97.4% w / w, about 97.5% w / w, about 97.6% w / w, about 97.7% w / w, about 97.8% w / w, about 97.9% w / w, about 98% w / w, or about 99% w / w. In some embodiments, the lyophilized composition comprises cyclodextrin in an amount of about 96.8% w / w. In some embodiments, the lyophilized composition comprises sodium sulfobutyl ether beta-cyclodextrin in an amount of about 96.8% w / w.

[0190] In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of about 3.2% w / w, and cyclodextrin in an amount of about 96.8% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of about 3.2% w / w, and sodium sulfobutyl ether beta-cyclodextrin in an amount of about 96.8% w / w.

[0191] In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of about 3.2% w / w and the cyclodextrin in an amount of about 96.8% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of about 3.2% w / w and the sodium sulfobutyl ether beta-cyclodextrin in an amount of about 96.8% w / w.

[0192] In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of 1% to 10% w / w, for example 1% to 5%, or 2% to 4%, or 3% to 4%, or 3% to 3.5%, and the cyclodextrin in an amount of 90% to 99% w / w, for example 95% to 99%, or 96% to 98%, or 96.5% to 97% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of 1% to 10% w / w, and the cyclodextrin in an amount of 90% to 99% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of 1% to 5% w / w, and the cyclodextrin in an amount of 95% to 99% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of about 2% to 4% w / w, and the cyclodextrin in an amount of 96% to 98% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of 3% to 3.5% w / w, and the cyclodextrin in an amount of 96.5% to 97% w / w.

[0193] In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of 1% to 10% w / w, for example 1% to 5%, or 2% to 4%, or 3% to 4%, or 3% to 3.5%, and the cyclodextrin in an amount of 90% to 99% w / w, for example 95% to 99%, or 96% to 98%, or 96.5% to 97% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of 1% to 10% w / w, and the cyclodextrin in an amount of 90% to 99% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of 1% to 5% w / w, and the cyclodextrin in an amount of 95% to 99% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of about 2% to 4% w / w, and the cyclodextrin in an amount of 96% to 98% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of 3% to 3.5% w / w, and the cyclodextrin in an amount of 96.5% to 97% w / w.

[0194] In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of about 3.2% w / w and the cyclodextrin in an amount of about 96.8% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of 3.2% w / w and the cyclodextrin in an amount of 96.8% w / w. In some embodiments, the lyophilized composition consists essentially of the compound of Formula I, Formula la, or Formula lb in an amount of about 3.2% w / w and the cyclodextrin in an amount of about 96.8% w / w. In some embodiments, the lyophilized composition consists essentially of the compound of Formula I, Formula la, or Formula lb in an amount of 3.2% w / w and the cyclodextrin in an amount of 96.8% w / w.

[0195] In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of about 3.2% w / w and the cyclodextrin in an amount of about 96.8% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of 3.2% w / w and the cyclodextrin in an amount of 96.8% w / w. In some embodiments, the lyophilized composition consists essentially of the compound of Formula la in an amount of about 3.2% w / w and the cyclodextrin in an amount of about 96.8% w / w. In some embodiments, the lyophilized composition consists essentially of the compound of Formula la in an amount of 3.2% w / w and the cyclodextrin in an amount of 96.8% w / w.

[0196] In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of about 3.2% w / w and the sodium sulfobutyl ether beta-cyclodextrin in an amount of about 96.8% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb in an amount of 3.2% w / w and the sodium sulfobutyl ether beta-cyclodextrin in an amount of 96.8% w / w. In some embodiments, the lyophilized composition consists essentially of the compound of Formula I, Formula la, or Formula lb in an amount of about 3.2% w / w and the sodium sulfobutyl ether beta-cyclodextrin in an amount of about 96.8% w / w. In some embodiments, the lyophilized composition consists essentially of the compound of Formula I, Formula la, or Formula lb in an amount of 3.2% w / w and the sodium sulfobutyl ether beta-cyclodextrin in an amount of 96.8% w / w.

[0197] In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of about 3.2% w / w and sodium sulfobutyl ether beta-cyclodextrin in an amount of about 96.8% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of 3.2% w / w and sodium sulfobutyl ether beta-cyclodextrin in an amount of 96.8% w / w. In some embodiments, the lyophilized composition consists essentially of the compound of Formula la in an amount of about 3.2% w / w and sodium sulfobutyl ether beta-cyclodextrin in an amount of about 96.8% w / w. In some embodiments, the lyophilized composition consists essentially of the compound of Formula la in an amount of 3.2% w / w and sodium sulfobutyl ether beta-cyclodextrin in an amount of 96.8% w / w.

[0198] The cyclodextrin of the lyophilized composition can include any suitable cyclodextrin as described above. For example, the cyclodextrin can be a beta-cyclodextrin, such as a sulfobutyl alkyl ether-beta-cyclodextrin, sodium sulfobutyl ether beta-cyclodextrin, or a hydroxypropyl-beta-cyclodextrin. In some embodiments, the lyophilized composition comprises a beta-cyclodextrin. In some embodiments, the lyophilized composition comprises a sulfobutyl alkyl ether-beta-cyclodextrin, sodium sulfobutyl ether beta-cyclodextrin, or a hydroxypropyl-beta-cyclodextrin. In some embodiments, the lyophilized composition comprises sodium sulfobutyl ether beta-cyclodextrin.

[0199] In some embodiments, the lyophilized composition comprises a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, and a beta- cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula I, Formula la, or Formula lb is present in an amount of 3% ± 1% w / w and the beta-cyclodextrin is present in an amount of 97% ± 1% w / w. In some embodiments, the lyophilized composition comprises a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, and a beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula I, Formula la, or Formula lb is present in an amount of about 3% ± 0.5% w / w and the beta-cyclodextrin is present in an amount of about 97% ± 0.5% w / w. In some embodiments, the lyophilized composition comprises a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, and a beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula I, Formula la, or Formula lb is present in an amount of about 3.2% w / w and the beta-cyclodextrin is present in an amount of about 96.8% w / w.

[0200] In some embodiments, the lyophilized composition comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula I is present in an amount of about 3% ± 1% w / w and the beta-cyclodextrin is present in an amount of 97% ± 1% w / w. In some embodiments, the lyophilized composition comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula I is present in an amount of about 3% ± 0.5% w / w and the beta-cyclodextrin is present in an amount of about 97% ± 0.5% w / w. In some embodiments, the lyophilized composition comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, and beta-cyclodextrin, and optionally a pH adjusting agent, wherein the compound of Formula I is present in an amount of about 3.2% w / w and the beta-cyclodextrin is present in an amount of about 96.8% w / w.

[0201] In some embodiments, the lyophilized composition comprises a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, in an amount of 5% to 10% w / w. In some embodiments, the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, is present in an amount of 5% to 7% w / w. In some embodiments, the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, is present in an amount of 6% to 7% w / w. In some embodiments, the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, is present in an amount of 6.0% to 6.5% w / w. In some embodiments, the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, is present in an amount of about 6.3% w / w.

[0202] In some embodiments, the lyophilized composition comprises a compound of Formula la, or a pharmaceutically acceptable salt thereof, in an amount of 5% to 10% w / w. In some embodiments, the lyophilized composition comprises a compound of Formula la, or a pharmaceutically acceptable salt thereof, in an amount of 5% to 7% w / w. In some embodiments, the lyophilized composition comprises a compound of Formula la, or a pharmaceutically acceptable salt thereof, in an amount of 6% to 7% w / w. In some embodiments, the lyophilized composition comprises a compound of Formula la, or a pharmaceutically acceptable salt thereof, in an amount of 6.0% to 6.5% w / w. In some embodiments, the lyophilized composition comprises a compound of Formula la, or a pharmaceutically acceptable salt thereof, in an amount of about 6.3% w / w.

[0203] In some embodiments, the lyophilized composition comprises the compound of Formula Ia in an amount of 5% to 10% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula Ia in an amount of 5% to 7% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula Ia in an amount of 6% to 7% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I in an amount of 6.0% to 6.5% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I in an amount of about 6.3% w / w.

[0204] In some embodiments, the lyophilized composition comprises the compound of Formula Ia in an amount of 5% to 10% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula Ia in an amount of 5% to 7% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula Ia in an amount of 6% to 7% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I in an amount of 6.0% to 6.5% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I in an amount of about 6.3% w / w.

[0205] In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, in an amount of about 5% to 7% w / w and the cyclodextrin in an amount of about 93% to 95% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, in an amount of about 5% to 7% w / w and the sodium sulfobutyl ether beta-cyclodextrin in an amount of about 93% to 95% w / w.

[0206] In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, in an amount of about 5% to 7% w / w and the cyclodextrin in an amount of about 93% to 95% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula Ia, or Formula Ib, or a pharmaceutically acceptable salt thereof, in an amount of about 5% to 7% w / w and the sodium sulfobutyl ether beta-cyclodextrin in an amount of about 93% to 95% w / w.

[0207] In some embodiments, the lyophilized composition comprises the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, in an amount of about 5% to 7% w / w and the cyclodextrin in an amount of about 93% to 95% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula Ia, or a pharmaceutically acceptable salt thereof, in an amount of about 5% to 7% w / w and the sodium sulfobutyl ether beta-cyclodextrin in an amount of about 93% to 95% w / w.

[0208] In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of about 5% to 7% w / w and the cyclodextrin in an amount of about 93% to 95% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of about 5% to 7% w / w and sodium sulfobutyl ether beta-cyclodextrin in an amount of about 93% to 95% w / w.

[0209] In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, in an amount of about 6.3% w / w and the cyclodextrin in an amount of about 93.7% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, in an amount of about 6.3% w / w and sodium sulfobutyl ether beta-cyclodextrin in an amount of about 93.7% w / w.

[0210] In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb, in an amount of about 6.3% w / w and the cyclodextrin in an amount of about 93.7% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula I, Formula la, or Formula lb, in an amount of about 6.3% w / w and sodium sulfobutyl ether beta-cyclodextrin in an amount of about 93.7% w / w.

[0211] In some embodiments, the lyophilized composition comprises the compound of Formula la, or a pharmaceutically acceptable salt thereof, in an amount of about 6.3% w / w and the cyclodextrin in an amount of about 93.7% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la, or a pharmaceutically acceptable salt thereof, in an amount of about 6.3% w / w and sodium sulfobutyl ether beta-cyclodextrin in an amount of about 93.7% w / w.

[0212] In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of about 6.3% w / w and the cyclodextrin in an amount of about 93.7% w / w. In some embodiments, the lyophilized composition comprises the compound of Formula la in an amount of about 6.3% w / w and sodium sulfobutyl ether beta-cyclodextrin in an amount of about 93.7% w / w.

[0213] The lyophilized composition can comprise the compound of Formula I, Formula la, or Formula lb, in various forms. For example, the compound of Formula I, Formula la, or Formula lb, can be amorphous or crystalline, or mixtures thereof. In some embodiments, the lyophilized composition comprises an amorphous compound of Formula I, Formula la, or Formula lb.

[0214] Reconstituted lyophilized formulations for inhalation

[0215] In some embodiments, the present disclosure provides pharmaceutical compositions, wherein the pharmaceutical compositions are obtained by reconstitution of a lyophilized formulation as described above.

[0216] In some embodiments, the present disclosure provides pharmaceutical compositions for administration by inhalation, wherein the pharmaceutical compositions are obtained by reconstitution of a lyophilized formulation as described above.

[0217] The reconstituted compositions for administration by inhalation comprise the lyophilized compositions described above and water. In some embodiments, the present disclosure provides pharmaceutical compositions for administration by inhalation comprising (I) a compound of Formula I, Formula la, or Formula I, or a pharmaceutically acceptable salt thereof, in an amount of 0.1% w / v to 10% w / v relative to the volume of the pharmaceutical composition, (ii) a cyclodextrin in an amount of 10% to 50% w / v relative to the volume of the pharmaceutical composition; and (iii) water. In some embodiments, the present disclosure provides pharmaceutical compositions for administration by inhalation comprising (I) a compound of Formula la, or a pharmaceutically acceptable salt thereof, in an amount of 0.1% w / v to 10% w / v relative to the volume of the pharmaceutical composition, (ii) a cyclodextrin in an amount of 10% to 50% w / v relative to the volume of the pharmaceutical composition; and (iii) water.

[0218] The cyclodextrin of the reconstituted lyophilized compositions for inhalation can include any suitable cyclodextrin as described above. For example, the cyclodextrin can be a beta-cyclodextrin, such as sulfobutyl alkyl ether-beta-cyclodextrin, sodium sulfobutyl ether beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin. In some embodiments, the reconstituted lyophilized compositions for inhalation comprise a beta-cyclodextrin. In some embodiments, the reconstituted lyophilized compositions for inhalation comprise sulfobutyl alkyl ether-beta-cyclodextrin, sodium sulfobutyl ether beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin. In some embodiments, the reconstituted lyophilized compositions for inhalation comprise sodium sulfobutyl ether beta-cyclodextrin.

[0219] The water in the reconstituted lyophilized compositions for inhalation can be any suitable type of water. In some embodiments, the water in the reconstituted lyophilized compositions for inhalation is DI water, distilled water, or sterile water.

[0220] The reconstituted lyophilized composition for inhalation comprises any suitable amount of the compound of Formula I, Formula la, or Formula lb, for example, 0.1% to 10% w / v. In some embodiments, the compound of Formula I, Formula la, or Formula lb is present in an amount of about 0.1% to 5% w / v, about 0.1% to 4% w / v, about 0.1% to 3% w / v, about 0.1% to 2% w / v, about 0.1% to 1% w / v, about 0.2% to 0.8% w / v, about 0.3% to 0.7% w / v, or about 0.4% to 0.6% w / v. In some embodiments, the amount of the compound of Formula I, Formula la, or Formula lb in the reconstituted lyophilized composition for inhalation 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, or about 1% w / v. In some embodiments, the amount of the compound of Formula I, Formula la, or Formula lb in the reconstituted lyophilized composition for inhalation is about 0.1% to 10% w / v. In some embodiments, the amount of the compound of Formula I, Formula la, or Formula lb in the reconstituted lyophilized composition for inhalation is about 0.1% to 1% w / v. In some embodiments, the amount of the compound of Formula I, Formula la, or Formula lb in the reconstituted lyophilized composition for inhalation is about 0.5% w / v.

[0221] The reconstituted lyophilized composition for inhalation comprises any suitable amount of the compound of Formula la, for example, 0.1% to 10% w / v. In some embodiments, the compound of Formula la is present in an amount of about 0.1% to 5% w / v, about 0.1% to 4% w / v, about 0.1% to 3% w / v, about 0.1% to 2% w / v, about 0.1% to 1% w / v, about 0.2% to 0.8% w / v, about 0.3% to 0.7% w / v, or about 0.4% to 0.6% w / v. In some embodiments, the amount of the compound of Formula la in the reconstituted lyophilized composition for inhalation 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, or about 1% w / v. In some embodiments, the amount of the compound of Formula la in the reconstituted lyophilized composition for inhalation is about 0.1% to 10% w / v. In some embodiments, the amount of the compound of Formula la in the reconstituted lyophilized composition for inhalation is about 0.1% to 1% w / v. In some embodiments, the amount of the compound of Formula la in the reconstituted lyophilized composition for inhalation is about 0.5% w / v.

[0222] A reconstituted lyophilized composition for inhalation comprises any suitable amount of a compound of Formula I, Formula la, or Formula lb, for example, about 0.1 mg / mL to 100 mg / mL. In some embodiments, a compound of Formula I, Formula la, or Formula lb can be present in a reconstituted lyophilized composition for inhalation in an amount of 0.1 mg / mL to 100 mg / mL, for example, in an amount of 0.1 mg / mL to 50 mg / mL, 0.5 mg / mL to 10 mg / mL, 1 mg / mL to 10 mg / mL, 2 mg / mL to 8 mg / mL, 3 mg / mL to 7 mg / mL, 4 mg / mL to 6 mg / mL, or 4.5 mg / mL to 5.5 mg / mL. In some embodiments, the amount of a compound of Formula I, Formula la, or Formula lb in a reconstituted lyophilized composition for inhalation is about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 4.6 mg / mL, about 4.7 mg / mL, about 4.8 mg / mL, about 4.9 mg / mL, about 5 mg / mL, about 5.1 mg / mL, about 5.2 mg / mL, about 5.3 mg / mL, about 5.4 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, or about 25 mg / mL. In some embodiments, the amount of a compound of Formula I, Formula la, or Formula lb in a reconstituted lyophilized composition for inhalation is about 1 mg / mL to 10 mg / mL. In some embodiments, the amount of a compound of Formula I, Formula la, or Formula lb in a reconstituted lyophilized composition for inhalation is about 4 mg / mL to 6 mg / mL. In some embodiments, the amount of a compound of Formula I, Formula la, or Formula lb in a reconstituted lyophilized composition for inhalation is about 5 mg / mL.

[0223] A reconstituted lyophilized composition for inhalation comprises any suitable amount of a compound of Formula la, for example, about 0.1 mg / mL to 100 mg / mL. In some embodiments, a compound of Formula la can be present in a reconstituted lyophilized composition for inhalation in an amount of 0.1 mg / mL to 100 mg / mL, for example, in an amount of 0.1 mg / mL to 50 mg / mL, 0.5 mg / mL to 10 mg / mL, 1 mg / mL to 10 mg / mL, 2 mg / mL to 8 mg / mL, 3 mg / mL to 7 mg / mL, 4 mg / mL to 6 mg / mL, or 4.5 mg / mL to 5.5 mg / mL. In some embodiments, the amount of a compound of Formula la in a reconstituted lyophilized composition for inhalation is about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 4.6 mg / mL, about 4.7 mg / mL, about 4.8 mg / mL, about 4.9 mg / mL, about 5 mg / mL, about 5.1 mg / mL, about 5.2 mg / mL, about 5.3 mg / mL, about 5.4 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, or about 25 mg / mL. In some embodiments, the amount of a compound of Formula la in a reconstituted lyophilized composition for inhalation is about 1 mg / mL to 10 mg / mL. In some embodiments, the amount of a compound of Formula la in a reconstituted lyophilized composition for inhalation is about 4 mg / mL to 6 mg / mL. In some embodiments, the amount of a compound of Formula la in a reconstituted lyophilized composition for inhalation is about 5 mg / mL.

[0224] The reconstituted lyophilized composition for inhalation also includes any suitable amount of a cyclodextrin, such as about 5% to 50% w / v relative to the volume of the pharmaceutical formulation. In some embodiments, the cyclodextrin is present in an amount of about 5% to 25% w / v or about 10% to 20% w / v. In some embodiments, the cyclodextrin is present in an amount of about 5% w / v, about 6% w / v, about 7% w / v, about 8% w / v, about 9% w / v, about 10% w / v, about 11% w / v, about 12% w / v, about 13% w / v, about 14% w / v, about 15% w / v, about 16% w / v, about 17% w / v, about 18% w / v, about 19% w / v, about 20% w / v, about 25% w / v, about 30% w / v, about 35% w / v, about 40% w / v, about 45% w / v, or about 50% w / v. In some embodiments, the cyclodextrin is present in an amount of about 5% to 50% w / v. In some embodiments, the cyclodextrin is present in an amount of about 10% to 20% w / v. In some embodiments, the cyclodextrin is present in an amount of about 15% w / v. In some embodiments, the cyclodextrin is present in an amount of about 15% w / v of sodium sulfobutyl ether beta-cyclodextrin.

[0225] In some embodiments, the reconstituted lyophilized composition includes cyclodextrin in an amount of about 5% to 10% w / v. In some embodiments, the cyclodextrin is present in an amount of about 6% to 8% w / v. In some embodiments, the cyclodextrin is present in an amount of about 7% to 8% w / v. In some embodiments, the cyclodextrin is present in an amount of about 7.5% w / v of sodium sulfobutyl ether beta-cyclodextrin.

[0226] In some embodiments, the reconstituted lyophilized composition for inhalation comprises any suitable combination of a compound of Formula I, Formula la, or Formula lb, a cyclodextrin, and water in amounts as described above. For example, the reconstituted lyophilized composition for inhalation comprises (i) a compound of Formula I, Formula la, or Formula lb in an amount of about 0.1% to 5% w / v, about 0.1% to 4% w / v, about 0.1% to 3% w / v, about 0.1% to 2% w / v, about 0.1% to 1% w / v, about 0.2% to 0.8% w / v, about 0.3% to 0.7% w / v, or about 0.4% to 0.6% w / v relative to the volume of the pharmaceutical formulation, (ii) a cyclodextrin in an amount of about 5% to 50% w / v, about 5% to 25% w / v, about 10% to 20% w / v relative to the volume of the pharmaceutical formulation, and (iii) water. In some embodiments, the reconstituted lyophilized composition for inhalation comprises (i) a compound of Formula I, Formula la, or Formula lb in an amount of 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, or about 1% w / v, (ii) a cyclodextrin in an amount of about 6% w / v, about 7% w / v, about 8% w / v, about 9% w / v, about 10% w / v, about 11% w / v, about 12% w / v, about 13% w / v, about 14% w / v, about 15% w / v, about 16% w / v, about 17% w / v, about 18% w / v, about 19% w / v, about 20% w / v, about 25% w / v, about 30% w / v, about 35% w / v, about 40% w / v, about 45% w / v, or about 50% w / v, and (iii) water. In some embodiments, the reconstituted lyophilized composition for inhalation comprises (i) a compound of Formula I, Formula la, or Formula lb in an amount of 0.1% to 10% w / v, (ii) a cyclodextrin in an amount of 5% to 50% w / v, and (iii) water. In some embodiments, the reconstituted lyophilized composition for inhalation comprises (i) a compound of Formula I, Formula la, or Formula lb in an amount of 0.1% to 1% w / v, (ii) a cyclodextrin in an amount of 10% to 20% w / v, and (iii) water. In some embodiments, the reconstituted lyophilized composition for inhalation comprises (i) a compound of Formula I, Formula la, or Formula lb in an amount of about 0.5% w / v, (ii) a cyclodextrin in an amount of about 15% w / v, and (iii) water. In some embodiments, the reconstituted lyophilized composition for inhalation comprises (i) a compound of Formula I, Formula la, or Formula lb in an amount of about 0.5% w / v, (ii) a beta-cyclodextrin sulfobutyl ether sodium in an amount of about 15% w / v, and (iii) water.

[0227] In some embodiments, the reconstituted lyophilized composition comprises (i) a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, in an amount of 0.1% to 1% w / v, (ii) a cyclodextrin in an amount of 5% to 10% w / v, and (iii) water. In some embodiments, the reconstituted lyophilized composition comprises (i) a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, in an amount of about 0.5% w / v, (ii) a cyclodextrin in an amount of about 6% to 8% w / v, and (iii) water. In some embodiments, the reconstituted lyophilized composition for inhalation comprises (i) a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, in an amount of about 0.5% w / v, (ii) sodium sulfobutyl ether beta-cyclodextrin in an amount of about 7% to 8% w / v, and (iii) water. In some embodiments, the reconstituted lyophilized composition for inhalation comprises (i) a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof, in an amount of about 0.5% w / v, (ii) sodium sulfobutyl ether beta-cyclodextrin in an amount of about 7.5% w / v, and (iii) water.

[0228] In some embodiments, the reconstituted lyophilized composition for inhalation comprises (i) a compound of Formula la, or a pharmaceutically acceptable salt thereof, in an amount of about 0.5% w / v, (ii) sodium sulfobutyl ether beta-cyclodextrin in an amount of about 7.5% w / v, and (iii) water. In some embodiments, the reconstituted lyophilized composition for inhalation comprises (i) a compound of Formula la, in an amount of about 0.5% w / v, (ii) sodium sulfobutyl ether beta-cyclodextrin in an amount of about 7.5% w / v, and (iii) water.

[0229] In some embodiments, the reconstituted lyophilized composition for inhalation comprises any suitable combination of a compound of Formula la, a cyclodextrin, and water in amounts as described above. For example, the reconstituted lyophilized composition for inhalation comprises (i) a compound of Formula la or Formula lb in an amount of about 0.1% to 5% w / v, about 0.1% to 4% w / v, about 0.1% to 3% w / v, about 0.1% to 2% w / v, about 0.1% to 1% w / v, about 0.2% to 0.8% w / v, about 0.3% to 0.7% w / v, or about 0.4% to 0.6% w / v, (ii) a cyclodextrin in an amount of about 5% to 50% w / v, or about 5% to 25% w / v, or about 10% to 20% w / v, and (iii) water. In some embodiments, the reconstituted lyophilized composition for inhalation comprises (i) a compound of Formula I, Formula la, or Formula lb in an amount of about 0.1% w / v, or 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, or about 1% w / v, (ii) a cyclodextrin in an amount of about 6% w / v, about 7% w / v, about 8% w / v, about 9% w / v, about 10% w / v, about 11% w / v, about 12% w / v, about 13% w / v, about 14% w / v, about 15% w / v, about 16% w / v, about 17% w / v, about 18% w / v, about 19% w / v, about 20% w / v, about 25% w / v, about 30% w / v, about 35% w / v, about 40% w / v, about 45% w / v, or about 50% w / v, and (iii) water. In some embodiments, the reconstituted lyophilized composition for inhalation comprises (i) a compound of Formula I, Formula la, or Formula lb in an amount of 0.1% to 10% w / v, (ii) a cyclodextrin in an amount of 5% to 50% w / v, and (iii) water. In some embodiments, the reconstituted lyophilized composition for inhalation comprises (i) a compound of Formula I, Formula la, or Formula lb in an amount of 0.1% to 1% w / v, (ii) a cyclodextrin in an amount of 10% to 20% w / v, and (iii) water. In some embodiments, the reconstituted lyophilized composition for inhalation comprises (i) a compound of Formula I in an amount of about 0.5% w / v, (ii) a cyclodextrin in an amount of about 15% w / v, and (iii) water. In some embodiments, the reconstituted lyophilized composition for inhalation comprises (i) a compound of Formula I, Formula la, or Formula lb in an amount of about 0.5% w / v, (ii) a cyclodextrin in an amount of about 15% w / v, and (iii) water.

[0230] In some embodiments, the reconstituted lyophilized composition for inhalation comprises 0.1% to 10% w / v of the compound of Formula I, Formula la, or Formula lb relative to the volume of the drug formulation, cyclodextrin in an amount of 10% to 20% w / v relative to the volume of the drug formulation. In some embodiments, the reconstituted lyophilized composition for inhalation comprises about 0.5% w / v of the compound of Formula I, Formula la, or Formula lb relative to the volume of the drug formulation, cyclodextrin in an amount of about 15% w / v relative to the volume of the drug formulation, and water. In some embodiments, the reconstituted lyophilized composition for inhalation consists essentially of about 0.5% w / v of the compound of Formula I, Formula la, or Formula lb relative to the volume of the drug formulation, cyclodextrin in an amount of about 15% w / v relative to the volume of the drug formulation, and water.

[0231] In some embodiments, the reconstituted lyophilized composition for inhalation comprises 0.1% to 10% w / v of the compound of Formula la relative to the volume of the drug formulation, cyclodextrin in an amount of 10% to 20% w / v relative to the volume of the drug formulation. In some embodiments, the reconstituted lyophilized composition for inhalation comprises about 0.5% w / v of the compound of Formula la relative to the volume of the drug formulation, cyclodextrin in an amount of about 15% w / v relative to the volume of the drug formulation, and water. In some embodiments, the reconstituted lyophilized composition for inhalation consists essentially of about 0.5% w / v of the compound of Formula la relative to the volume of the drug formulation, cyclodextrin in an amount of about 15% w / v relative to the volume of the drug formulation, and water.

[0232] In some embodiments, the reconstituted lyophilized composition for inhalation comprises 0.1% to 10% w / v of the compound of Formula I, Formula la, or Formula lb relative to the volume of the drug formulation, β-cyclodextrin sulfobutyl ether sodium in an amount of 10% to 20% w / v relative to the volume of the drug formulation. In some embodiments, the reconstituted lyophilized composition for inhalation comprises about 0.5% w / v of the compound of Formula I, Formula la, or Formula lb relative to the volume of the drug formulation, β-cyclodextrin sulfobutyl ether sodium in an amount of about 15% w / v relative to the volume of the drug formulation, and water. In some embodiments, the reconstituted lyophilized composition for inhalation consists essentially of about 0.5% w / v of the compound of Formula I, Formula la, or Formula lb relative to the volume of the drug formulation, β-cyclodextrin sulfobutyl ether sodium in an amount of about 15% w / v relative to the volume of the drug formulation, and water.

[0233] In some embodiments, the reconstituted lyophilized composition for inhalation comprises 0.1% to 10% w / v of the compound of Formula la relative to the volume of the pharmaceutical formulation, beta-cyclodextrin sulfobutyl ether sodium in an amount of 10% to 20% w / v relative to the volume of the pharmaceutical formulation. In some embodiments, the reconstituted lyophilized composition for inhalation comprises about 0.5% w / v of the compound of Formula la relative to the volume of the pharmaceutical formulation, beta-cyclodextrin sulfobutyl ether sodium in an amount of about 15% w / v relative to the volume of the pharmaceutical formulation, and water. In some embodiments, the reconstituted lyophilized composition for inhalation consists essentially of about 0.5% w / v of the compound of Formula la relative to the volume of the pharmaceutical formulation, beta-cyclodextrin sulfobutyl ether sodium in an amount of about 15% w / v relative to the volume of the pharmaceutical formulation, and water.

[0234] The reconstituted lyophilized composition for inhalation can be contained in any suitable container, such as a sealed vial or a nebulizer. In some embodiments, the present application provides a sealed vial comprising the reconstituted lyophilized composition for inhalation. In some embodiments, the present application provides a nebulizer comprising the reconstituted lyophilized composition for inhalation. In some embodiments, the present application provides a nebulizer comprising an injectable composition consisting essentially of about 0.5% w / v of the compound of Formula I, Formula la, or Formula lb relative to the volume of the pharmaceutical formulation, cyclodextrin in an amount of about 15% w / v relative to the volume of the pharmaceutical formulation, and water.

[0235] 8. Antimicrobial agents or preservatives

[0236] The pharmaceutical formulations disclosed herein can additionally comprise an antimicrobial agent or preservative, which can help improve the stability of the pharmaceutical formulation. Examples of antimicrobial agents or preservatives include, but are not limited to, aminobenzoate (e.g., parabens), a quaternary ammonium compound (e.g., benzalkonium chloride (BKC), benzethonium chloride, bronopol), an aryl acid (e.g., benzoic acid), an aryl alcohol (e.g., benzyl alcohol), a biguanide (e.g., chlorhexidine), chloromethylphenol, chloroxylenol, a formaldehyde donor (e.g., imidurea, bromonitropal), an alkyl acid (e.g., propionic acid and sorbic acid), a phenolic compound (e.g., m-cresol), a phenylmercury salt (e.g., acetate, borate, and nitrate), and a phenoxyethanol, thiomersal.

[0237] In some embodiments, the antimicrobial agent or preservative is methylparaben, propylparaben, chlorobutanol, benzalkonium chloride, cetylpyridinium chloride, thymol, ascorbic acid, sodium bisulfite, sodium metabisulfite, sodium sulfite, sodium bisulfate, EDTA, or a combination thereof. In some embodiments, the antimicrobial agent or preservative is methylparaben, propylparaben, chlorobutanol, benzalkonium chloride, sodium sulfate, or a combination thereof.

[0238] 9. Taste-masking / flavoring agents

[0239] The pharmaceutical formulations disclosed herein can further include a taste masking or flavoring agent. A variety of pharmaceutically compatible flavoring agents can be utilized. Such flavoring agents include natural and artificial flavoring agents selected from synthetic flavor oils and flavoring aromatics and / or oils, oleoresins and extracts derived from plants, leaves, flowers, fruits, etc. and combinations thereof. Examples of flavoring agents that can be used include, but are not limited to, citric acid, sodium citrate, ascorbic acid, menthol, or sodium saccharin.

[0240] IV. KITS

[0241] The present disclosure also provides for the use of a kit comprising a pharmaceutical formulation disclosed herein. In some embodiments, the kit further comprises a label and / or instructions for using the pharmaceutical formulation.

[0242] In some embodiments, the kits provided herein comprise a pharmaceutical formulation disclosed herein and a syringe. In some embodiments, the kit further comprises a label and / or instructions for using the pharmaceutical formulation.

[0243] In some embodiments, the kits provided herein comprise (i) a lyophilized pharmaceutical formulation disclosed herein, (ii) water (e.g., water for injection) for reconstituting the lyophilized pharmaceutical formulation, and (iii) a syringe. In some embodiments, the kits provided herein comprise (i) a first vial comprising a lyophilized pharmaceutical formulation disclosed herein, (ii) a second vial comprising water (e.g., water for injection) for reconstituting the lyophilized pharmaceutical formulation, and (iii) a syringe. In some embodiments, the kit further comprises a vial adapter for the first vial and the second vial. In some embodiments, the kit further comprises a label and / or instructions for using the pharmaceutical formulation.

[0244] In some embodiments, the kits provided herein comprise (i) a first vial comprising a lyophilized pharmaceutical formulation having 35 mg to 45 mg of the compound of Formula la, (ii) a second vial comprising 5 mL to 15 mL of water (e.g., water for injection) for reconstituting the lyophilized pharmaceutical formulation, and (iii) a syringe. In some embodiments, the kit further comprises a vial adapter for the first vial and the second vial. In some embodiments, the kit further comprises a label and / or instructions for using the pharmaceutical formulation.

[0245] In some embodiments, the kits provided herein include (i) a first vial comprising a lyophilized pharmaceutical formulation having 40 mg of a compound of Formula la, (ii) a second vial comprising 10 mL of water (e.g., water for injection) for reconstituting the lyophilized pharmaceutical formulation, and (iii) a syringe. In some embodiments, the kit further includes a vial adapter for the first vial and the second vial. In some embodiments, the kit further includes a label and / or instructions for using the pharmaceutical formulation.

[0246] In some embodiments, the kits provided herein include (i) a lyophilized pharmaceutical formulation disclosed herein and (ii) a syringe comprising water (e.g., water for injection) for reconstituting the lyophilized pharmaceutical formulation. In some embodiments, the kits provided herein include (i) a vial comprising a lyophilized pharmaceutical formulation disclosed herein and (ii) a syringe comprising water (e.g., water for injection) for reconstituting the lyophilized pharmaceutical formulation. In some embodiments, the kit further includes a vial adapter. In some embodiments, the kit further includes a label and / or instructions for using the pharmaceutical formulation.

[0247] In some embodiments, the kits include multiple sets, wherein each set includes (i) a lyophilized pharmaceutical formulation disclosed herein and (ii) a syringe comprising water (e.g., water for injection) for reconstituting the lyophilized pharmaceutical formulation. In some embodiments, the number of sets in the kit is equal to the number of treatment days (i.e., one set is used per treatment day). In some embodiments, the kit further includes a label and / or instructions for using the pharmaceutical formulation.

[0248] In some embodiments, the kits include multiple sets, wherein each set includes (i) a vial comprising a lyophilized pharmaceutical formulation disclosed herein and (ii) a syringe comprising water (e.g., water for injection) for reconstituting the lyophilized pharmaceutical formulation. In some embodiments, each set further includes a vial adapter. In some embodiments, the number of sets in the kit is equal to the number of treatment days (i.e., one set is used per treatment day). In some embodiments, the kit further includes a label and / or instructions for using the pharmaceutical formulation.

[0249] In some embodiments, the kits include five sets, wherein each set includes (i) a vial comprising a lyophilized pharmaceutical formulation disclosed herein and (ii) a syringe comprising water (e.g., water for injection) for reconstituting the lyophilized pharmaceutical formulation. In some embodiments, each set further includes a vial adapter. In some embodiments, the five sets are for five treatment days (one set per day). In some embodiments, the kit further includes a label and / or instructions for using the pharmaceutical formulation.

[0250] In some embodiments, the kit comprises five sets, each set including (i) a vial containing a lyophilized pharmaceutical preparation of formula Ia having 30 mg to 40 mg and (ii) a syringe containing 5 mL to 10 mL of water for injection for reconstituted the lyophilized pharmaceutical preparation. In some embodiments, each set further includes a vial adapter. In some embodiments, the five sets are used for five treatment days (one set per day). In some embodiments, the kit further includes a label and / or instructions for using the pharmaceutical preparation.

[0251] In some embodiments, the kit comprises five sets, each set including (i) a vial containing a lyophilized pharmaceutical preparation of a compound of formula Ia having 38 mg and (ii) a syringe containing 7.8 mL of water for injection for reconstituted the lyophilized pharmaceutical preparation. In some embodiments, each set further includes a vial adapter. In some embodiments, the five sets are used for five treatment days (one set per day). In some embodiments, the kit further includes a label and / or instructions for using the pharmaceutical preparation.

[0252] In some embodiments, the kit further includes a sprayer. Any suitable sprayer can be used. In some embodiments, the sprayer is a glass sprayer. In some embodiments, the sprayer is a handheld bulb sprayer. In some embodiments, the sprayer is a jet sprayer or a vibrating mesh sprayer. In some embodiments, the sprayer is a jet sprayer (e.g., VixOne). ™ AeroEclipse ® Pari LC ® Plus). In some examples, the sprayer is a vibrating mesh sprayer (e.g., eFlow). ® (rapid). In some embodiments, the nebulizer is an ultrasonic nebulizer. In some embodiments, the nebulizer is an adaptive aerosol delivery nebulizer. In some embodiments, the nebulizer is a metered-dose inhaler (e.g., a metered-dose liquid inhaler).

[0253] V. METHODS OF USE

[0254] This disclosure also provides a method for treating or preventing viral infection in a subject (e.g., a person) in need of such treatment, the method comprising administering the pharmaceutical preparation described herein to the subject, wherein administration is by inhalation.

[0255] In some embodiments, this disclosure provides a method for treating a viral infection in a subject (e.g., a person) in need, the method comprising administering the pharmaceutical preparation described herein to the subject in need, wherein administration is by inhalation.

[0256] In some embodiments, the present disclosure provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a pharmaceutical formulation disclosed herein and at least one additional active therapeutic agent by inhalation.

[0257] In some embodiments, the present disclosure provides a method of treating a viral infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a pharmaceutical formulation disclosed herein and at least one additional active therapeutic agent by inhalation.

[0258] In one embodiment, the present disclosure provides a method of inhibiting a viral polymerase in a cell, the methods comprising contacting a cell infected with a virus with a pharmaceutical formulation disclosed herein, thereby inhibiting the viral polymerase.

[0259] In one embodiment, the present disclosure provides a method of inhibiting a viral polymerase in a cell, the methods comprising contacting a cell infected with a virus with a pharmaceutical formulation disclosed herein and at least one additional active therapeutic agent, thereby inhibiting the viral polymerase.

[0260] Also provided herein is the use of a pharmaceutical formulation disclosed herein for the treatment or prevention of a viral infection in a subject in need thereof. For example, provided herein is the use of a pharmaceutical formulation disclosed herein for the treatment of a viral infection in a subject in need thereof.

[0261] In some embodiments, the viral infection is a Paramyxoviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method for treating a Paramyxoviridae infection in a human in need thereof, the method comprising administering to the human a pharmaceutical formulation disclosed herein, wherein the administration is by inhalation. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles, mumps, and parainfluenza viruses.

[0262] In some embodiments, the viral infection is a Pneumoviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating a Pneumoviridae virus infection in a human in need thereof, the method comprising administering to the human a pharmaceutical formulation provided herein, wherein the administration is by inhalation. Pneumoviridae viruses include, but are not limited to, respiratory syncytial virus and human metapneumovirus. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection. metapneumovirus ) infection.

[0263] In some embodiments, the present disclosure provides a pharmaceutical formulation disclosed herein for use in treating a Pneumoviridae virus infection in a human in need thereof. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0264] In some embodiments, this disclosure provides a method for treating RSV infection in a person in need, the method comprising administering to the person a pharmaceutical preparation provided herein, wherein administration is by inhalation. In some embodiments, the person has a chronic respiratory syncytial virus infection. In some embodiments, the person is acutely infected with RSV.

[0265] In some embodiments, a method for inhibiting RSV replication is provided, wherein the method includes administering the pharmaceutical preparation disclosed herein to a person in need thereof, wherein the administration is by inhalation.

[0266] In some embodiments, this disclosure provides a method for reducing viral load associated with RSV infection, wherein the method includes administering a pharmaceutical preparation disclosed herein to a person infected with RSV, wherein the administration is by inhalation.

[0267] In some implementation schemes, viral infection is classified as a piconeriviridae family ( picornaviridae Viral infections. Therefore, in some embodiments, this disclosure provides a method for treating a person in need of a picoriviridae virus infection, the method comprising administering a pharmaceutical preparation of this disclosure to the person, wherein the administration is by inhalation. Picoriviridae viruses are heterogeneous enteroviruses that cause a wide range of infections, including herpetic pharyngitis, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), nonparalytic poliomyelitis-like syndrome, epidemic pleuropneumonia (an acute, febrile, infectious disease that typically occurs during epidemics), hand-foot-mouth disease, pancreatitis in children and adults, and severe myocarditis. In some embodiments, the picoriviridae virus infection is a human rhinovirus infection.

[0268] In some embodiments, this disclosure provides pharmaceutical preparations for treating microRNAviridae virus infections in individuals in need. In some embodiments, the microRNAviridae virus infection is a human rhinovirus infection.

[0269] In some embodiments, the viral infection is a Flaviviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating a Flaviviridae virus infection in a human in need thereof, the method comprising administering to the human a pharmaceutical composition described herein, wherein administration is by inhalation. Representative Flaviviridae viruses include, but are not limited to, dengue, yellow fever, West Nile virus, Zika virus, Japanese encephalitis virus, and hepatitis C virus (HCV). In some embodiments, the Flaviviridae virus infection is a dengue virus infection. In some embodiments, the Flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus virus infection. In some embodiments, the Flaviviridae virus infection is a Japanese encephalitis virus infection. In some embodiments, the Flaviviridae virus infection is a hepatitis C virus infection.

[0270] In some embodiments, the present disclosure provides use of a pharmaceutical preparation disclosed herein for treating a Flaviviridae virus infection in a human in need thereof. In some embodiments, the Flaviviridae virus infection is a dengue virus infection. In some embodiments, the Flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus virus infection. In some embodiments, the Flaviviridae virus infection is a hepatitis C virus infection.

[0271] In some embodiments, the viral infection is a Filoviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating a Filoviridae virus infection in a human in need thereof, the method comprising administering to the human a pharmaceutical preparation disclosed herein, wherein administration is by inhalation. Representative Filoviridae viruses include, but are not limited to, Ebola virus (variant Zaire, Bundibugio, Sudan, Tai Forest, or Reston) and Marburg virus. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0272] In some embodiments, the present disclosure provides a pharmaceutical preparation for treating a Filoviridae virus infection in a human in need thereof. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0273] In some embodiments, the viral infection is a coronavirus infection. Accordingly, in some embodiments, provided herein are methods of treating a human in need thereof for a coronavirus viral infection, wherein the method comprises administering to the human a pharmaceutical preparation provided herein, wherein administration is by inhalation. In some embodiments, the coronavirus infection is a Severe Acute Respiratory Syndrome (SARS) infection, a Middle East Respiratory Syndrome (MERS) infection, a SARS-CoV-2 infection, other human coronaviruses (229E, NL63, OC43, HKU1, or WIV1) infection, a zoonotic coronavirus (PEDV or HKU CoV isolates, such as HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a Severe Acute Respiratory Syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East Respiratory Syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection. The pharmaceutical preparations provided herein can be used to treat all SARS-CoV-2 infections (COVID-19), for example, to treat mild, moderate, or severe SARS-CoV-2 infections. In some embodiments, the pharmaceutical preparations for inhalation provided herein are used to treat severe SARS-CoV-2 infections. In some embodiments, the pharmaceutical preparations for inhalation provided herein are used to treat moderate SARS-CoV-2 infections. In some embodiments, the pharmaceutical preparations for inhalation provided herein are used to treat mild SARS-CoV-2 infections. In some embodiments, the pharmaceutical preparations for inhalation provided herein are used to treat early SARS-CoV-2 infections when the virus is primarily replicating in the upper respiratory tract of the subject.

[0274] In some embodiments, the pharmaceutical preparations for inhalation provided herein are used to treat a zoonotic coronavirus infection, in some embodiments, the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

[0275] In some embodiments, the viral infection is caused by a variant of SARS-CoV-2, for example by the B.1.1.7 variant (UK variant), the B.1.351 variant (South African variant), the P.1 variant (Brazilian variant), the B.1.1.7 and E484K variant, the B.1.1.207 variant, the B.1.1.317 variant, the B.1.1.318 variant, the B.1.429 variant, the B.1.525 variant, or the P.3 variant. In some embodiments, the viral infection is caused by the B.1.1.7 variant of SARS-CoV-2. In some embodiments, the viral infection is caused by the B.1.351 variant of SARS-CoV-2. In some embodiments, the viral infection is caused by the P.1 variant of SARS-CoV-2.

[0276] In some embodiments, the present disclosure provides a pharmaceutical formulation for use in treating a coronavirus viral infection in a human in need thereof. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, other human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, a zoonotic coronavirus (PEDV or HKU CoV isolates, such as HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection.

[0277] In some embodiments, the viral infection is an arenavirus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating an arenavirus infection in a human in need thereof, the method comprising administering to the human a pharmaceutical formulation disclosed herein, wherein administration is by inhalation. In some embodiments, the arenavirus infection is a Lassa virus infection or a Junin virus infection.

[0278] In some embodiments, the present disclosure provides a pharmaceutical formulation for use in treating an arenavirus infection in a human in need thereof. In some embodiments, the arenavirus infection is a Lassa virus infection or a Junin virus infection.

[0279] In some embodiments, the viral infection is a orthomyxovirus infection, for example an influenza virus infection. In some embodiments, the viral infection is an influenza virus A, influenza virus B, or influenza virus C infection.

[0280] In some embodiments, the human receives at least one additional dose of the compound of Formula I, Formula la, or Formula lb via intravenous administration. In some embodiments, the human receives at least one additional dose of the compound of Formula la via intravenous administration.

[0281] In some embodiments, the methods of treating or preventing a viral infection provided herein further comprise administering to the human at least one dose of the compound of Formula I, Formula la, or Formula lb via intravenous administration. In some embodiments, the methods of treating or preventing a viral infection provided herein further comprise administering to the human at least one dose of the compound of Formula la via intravenous administration. The at least one additional dose can be provided prior to, during, or after inhalation administration of the pharmaceutical formulation disclosed herein.

[0282] The pharmaceutical formulations for inhalation provided herein can also be used to treat and or prevent viral infections in humans with impaired kidney function. In some examples, the pharmaceutical formulations provided herein are used to treat and or prevent viral infections in humans with an estimated glomerular filtration rate (eGFR) of less than 90 (e.g., eGFR of 60 to 89, 45 to 59, 30 to 44, 15 to 29, or less than 15). In some examples, the pharmaceutical formulations provided herein are used to treat and or prevent viral infections in humans with an eGFR of less than 30 (e.g., eGFR of 15 to 29). In some examples, the pharmaceutical formulations provided herein are used to treat and or prevent viral infections in humans with an eGFR of less than 15.

[0283] As described more fully herein, the pharmaceutical formulations described herein can be administered to an individual (e.g., a human) infected with a viral infection with one or more additional therapeutic agents. The additional therapeutic agent(s) can be administered to the infected individual simultaneously with, prior to, or after administration of the pharmaceutical formulations of the present disclosure.

[0284] VI. COMBINATION THERAPIES

[0285] The compounds described herein can also be used in combination with one or more additional therapeutic agents. Accordingly, also provided herein are methods of treating a viral infection in a subject in need thereof, wherein the methods comprise administering to the subject the disclosed pharmaceutical formulations and a therapeutically effective amount of one or more additional therapeutic agents.

[0286] In some embodiments, the additional therapeutic agent is an antiviral agent. Any suitable antiviral agent can be used in the methods described herein. In some embodiments, the antiviral agent is selected from the group consisting of 5-substituted 2'-deoxyuridine analogs, nucleoside analogs, pyrophosphate analogs, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, entry inhibitors, acyclic guanosine analogs, acyclic nucleoside phosphonate analogs, HCV NS5A / NS5B inhibitors, influenza virus inhibitors, interferons, immunostimulants, oligonucleotides, antimitotic inhibitors, and combinations thereof.

[0287] In some embodiments, the additional therapeutic agent is a 5-substituted 2'-deoxyuridine analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of iododeoxyuridine, trifluorouridine, bromovinyldeoxyuridine (BVDU), and combinations thereof.

[0288] In some embodiments, the additional therapeutic agent is a nucleoside analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of vidarabine, entecavir (ETV), telbivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), and combinations thereof. In some embodiments, the additional therapeutic agent is favipiravir, ribavirin, galidesivir, beta-D-N4-hydroxycytidine, or combinations thereof.

[0289] In some embodiments, the additional therapeutic agent is a pyrophosphate analog. For example, in some embodiments, the additional therapeutic agent is foscarnet or phosphonoacetic acid. In some embodiments, the additional therapeutic agent is foscarnet.

[0290] In some embodiments, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof.

[0291] In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is selected from the group consisting of nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, and combinations thereof.

[0292] In some embodiments, the additional therapeutic agent is a protease inhibitor. In some embodiments, the protease inhibitor is an HIV protease inhibitor. For example, in some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, and combinations thereof. In some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, and combinations thereof. In some embodiments, the protease inhibitor is an HCV NS3 / 4A protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, glecaprevir, ribavirin, danoprevir, fidaxomir, veldorevir, sovaprevir, deldeprefir, narlaprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, glecaprevir, and combinations thereof.

[0293] In some embodiments, the additional therapeutic agent is an integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, dolutegravir, elvitegravir, abacavir, lamivudine, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, raltegravir, dolutegravir, cabotegravir, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, dolutegravir, and cabotegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir.

[0294] In some embodiments, the additional therapeutic agent is an entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of docosanol, enfuvirtide, maraviroc, ibalizumab, fostemsavir, leronlimab, ibalizumab, fostemsavir, leronlimab, palivizumab, intravenous respiratory syncytial virus immunoglobulin [RSV-IGIV], varicella zoster immunoglobulin [VariZIG], varicella zoster immunoglobulin [VZIG], and combinations thereof.

[0295] In some embodiments, the additional therapeutic agent is an acyclic guanosine analogue. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valganciclovir), valganciclovir, penciclovir, famciclovir, and combinations thereof.

[0296] In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analogue. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, emtricitabine, efavirenz, lifamavir, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof.

[0297] In some embodiments, the additional therapeutic agent is an HCV NS5A / NS5B inhibitor. In some embodiments, the additional therapeutic agent is an NS3 / 4A protease inhibitor. In some embodiments, the additional therapeutic agent is an NS5A protease inhibitor. In some embodiments, the additional therapeutic agent is an NS5B polymerase inhibitor of the nucleoside / nucleotide type. In some embodiments, the additional therapeutic agent is an NS5B polymerase inhibitor of the non-nucleoside type. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof.

[0298] In some embodiments, the additional therapeutic agent is an influenza virus inhibitor. In some embodiments, the additional therapeutic agent is a matrix 2 inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of: amantadine, memantine, and combinations thereof. In some embodiments, the additional therapeutic agent is a neuraminidase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of: zanamivir, oseltamivir, peramivir, laninamivir octanoate, and combinations thereof. In some embodiments, the additional therapeutic agent is a polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of: ribavirin, favipiravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of: amantadine, memantine, ribavirin, umifenovir, baloxavir marboxil, oseltamivir, peramivir, inosine monophosphate dehydrogenase, laninamivir octanoate, zanamivir, favipiravir, ribavirin, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of: amantadine, memantine, zanamivir, oseltamivir, peramivir, laninamivir octanoate, ribavirin, favipiravir, and combinations thereof.

[0299] In some embodiments, the additional therapeutic agent is an interferon. In some embodiments, the additional therapeutic agent is selected from the group consisting of: interferon alfacon 1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfacon 1, pegylated interferon alfa 1b, pegylated interferon alfa 2a (PegIFN alpha-2a) and PegIFN alpha-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of: interferon alfacon 1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfa 2a (PegIFN alpha-2a) and PegIFN alpha-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of: interferon alfacon 1, pegylated interferon alfa 2a (PegIFN alpha-2a), PegIFN alpha-2b, and ribavirin. In some embodiments, the additional therapeutic agent is pegylated interferon alpha-2a, pegylated interferon alpha-2b, or a combination thereof.

[0300] In some embodiments, the additional therapeutic agent is an immunomodulator. In some embodiments, the additional therapeutic agent is an oligonucleotide. In some embodiments, the additional therapeutic agent is an antimitotic inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of: formivirsen, pudafloxane, imiquimod, resiquimod, and combinations thereof.

[0301] In some embodiments, the additional therapeutic agent is selected from the group consisting of: becilamaf, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FV100, and letermovir, and combinations thereof.

[0302] In some embodiments, the additional therapeutic agent is an agent for treating RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112, or pritelivir. For example, in some embodiments, the antiviral agent is ALS-8112 or pritelivir.

[0303] In some embodiments, the additional therapeutic agent is an agent for treating picornavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of: hydantoin, guanidine hydrochloride, l-butylsulfϊne sulfoximine, Py-11, and combinations thereof. In some embodiments, the additional therapeutic agent is a picornavirus polymerase inhibitor. In some embodiments, the additional therapeutic agent is rupintrivir.

[0304] In some embodiments, the additional therapeutic agent is an agent for treating malaria. In some embodiments, the additional therapeutic agent is chloroquine.

[0305] In some embodiments, the additional therapeutic agent is selected from the group consisting of: hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, proguanil, tafenoquine, pyronaridine, artesunate, dihydroartemisinin, piperaquine, artesunate, amodiaquine, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferroquine, artemisinin, ganaplacide, DSM-265, sipankalim, artemotil, and combinations thereof.

[0306] In some embodiments, the additional therapeutic agent is an agent for treating coronavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of: IFX-1, FM-201, CYNK-001, DPP4-Fc, celgosivir, nafamostat, LB-2, AM-1, antiviral pore protein, and combinations thereof.

[0307] In some embodiments, the additional therapeutic agent is an agent for treating Ebola virus. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of: ribavirin, ZMab, motavizumab, RSV-IGIV (RespiGam ®), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola convalescent plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5- (hydroxymethyl)pyrrolidine-3,4-diol), favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N- bis[3-(dimethylamino)propyl]-3,9-dimethylquinolo[8,7-h]quinolin-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN filo, brovidoxil, an Ebola vaccine based on Vaxart adenoviral vector 5, Ad26-ZEBOV, FiloVax vaccine, GOVX-E301, GOVX-E302, Ebola virus entry inhibitors (NPC1 inhibitors), rVSV-EBOV, and combinations thereof. In some embodiments, the additional therapeutic agent is ZMapp, mAB114, REGEN-EB3, and combinations thereof.

[0308] In some embodiments, the additional therapeutic agent is an agent for treating HCV. In some embodiments, the additional therapeutic agent is an HCV polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of sofosbuvir, GS-6620, PSI-938, ribavirin, tegobuvir, radalbuvir, MK-0608, and combinations thereof. In some embodiments, the additional therapeutic agent is an HCV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of, such as GS-9256, veldolpavir, voxilaprevir, and combinations thereof.

[0309] In some embodiments, the additional therapeutic agent is an NS5A inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ledipasvir, velpatasvir, and combinations thereof.

[0310] In some embodiments, the additional therapeutic agent is an anti-HBV agent. For example, in some embodiments, the additional therapeutic agent is tenofovir disoproxil fumarate and emtricitabine or a combination thereof. Examples of additional anti-HBV agents include, but are not limited to, a-hydroxytopotecan, amdoxovir, andrographolide, b-hydroxycytosine nucleoside, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporin A, gentiopicroside (gentiopicrin), HH-003, hepraplatide, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (molixan, BAM-205), oligonucleotide, mivitript, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, carotene, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster 0014--01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007, sofosbuvir, ledipasvir, UB-551, and ZH-2N, as well as the compounds disclosed in US20150210682 (Roche), US 2016 / 0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche), and US2015031687A (Roche). In some embodiments, the additional therapeutic agent is an HBV polymerase inhibitor. Examples of HBV DNA polymerase inhibitors include, but are not limited to, adefovir (HEPSERA ®), emtricitabine (EMTRIVA ® ), tenofovir disoproxil fumarate (VIREAD ® ), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir bis-pivaloyloxymethyl ester, tenofovir bis- pivaloyloxymethyl fumarate, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, bestrafϊvir, entecavir (BARACLUDE ® ), entecavir maleate, telbivudine (TYZEKA ® ), filoximevir, pradefovir, clevudine, ribavirin, lamivudine (EPIVIR-HBV ® ), phosphazide, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, aspartic acid tenofovir disoproxil, orotic acid tenofovir disoproxil, and HS-10234. In some embodiments, the additional therapeutic agent is an HBV capsid inhibitor.

[0311] In some embodiments, the additional therapeutic agent is an agent for treating HIV. In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, entry inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, acyclic nucleoside phosphonate analogs, and combinations thereof.

[0312] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutics, antibody-drug conjugates, gene modifying agents, gene editing agents (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), and cell therapies (such as chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapies).

[0313] In some embodiments, the additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and “antibody-like” therapeutic proteins, and combinations thereof.

[0314] In some examples, the additional therapeutic agent is an HIV combination drug. Examples of HIV combination drugs include, but are not limited to, ATRIPLA ® (EVITEVRA®; efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY ® (bictegravir, emtricitabine, and tenofovir alafenamide); COMPLERA ® (EVIPLERA ® ; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD ® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA ® (tenofovir disoproxil fumarate and emtricitabine; TDF + FTC); DESCOVY ® (tenofovir alafenamide and emtricitabine); ODEFSEY ® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA ® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA ® (darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat); SYMFI ™ (efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDU ™ (lamivudine and tenofovir disoproxil fumarate); tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR ® (zidovudine and lamivudine; AZT + 3TC); EPZICOM ® (LIVEXA ® ; abacavir sulfate and lamivudine; ABC + 3TC); KALETRA ® (ALUVIA ® ; lopinavir and ritonavir); TRIUMEQ® (Drutvir, Abacavir, and Lamivudine); TRIZIVIR ® (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Atazanavir and cobistat; Atazanavir sulfate and cobistat; Atazanavir sulfate and ritonavir; Dermiravir and cobistat; Dulutegravir and rilpivirine; Dulutegravir and rilpivirine hydrochloride; Dulutegravir, abacavir sulfate, and lamivudine; Lamivudine, nevirapine, and zidovudine; Rytegvir and lamivudine; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Dapivirine + levonorgestrel, Dulutegravir + lamivudine; Durutvir + Emtricitabine + Tenofovir Alamenosamine, Alfavirine + Emtricitabine + Tenofovir Disoproxil Fumarate, Lamivudine + Abacavir + Zidovudine, Lamivudine + Abacavir, Lamivudine + Tenofovir Disoproxil Fumarate, Lamivudine + Zidovudine + Nevirapine, Lopinavir + Ritonavir, Lopinavir + Ritonavir + Abacavir + Lamivudine, Lopinavir + Ritonavir + Zidovudine + Lamivudine, Tenofovir + Lamivudine, Tenofovir Disoproxil Fumarate + Emtricitabine + Rilpivirine Hydrochloride, Lopinavir, Ritonavir, Zidovudine, and Lamivudine.

[0315] In some implementations, the adjunctive treatment is an HIV protease inhibitor. For example, in some implementations, the adjunctive treatment is selected from the group consisting of: saquinavir, ritonavir, indinavir, nelfinavir, ampravir, lopinavir, atazanavir, fossavir, drenellavir, telanavir, cobistat, ASC-09, AEBL-2, MK-8718, GS-9500, GS-1156, and combinations thereof. For example, in some implementations, the adjunctive treatment is selected from the group consisting of: saquinavir, ritonavir, indinavir, nelfinavir, ampravir, lopinavir, atazanavir, fossavir, drenellavir, telanavir, and cobistat. In some examples, the adjunctive therapy is selected from the group consisting of: ampranavir, atazanavir, becanavir, deruravir, fossavir, fossavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, telanavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, TMC-310911, and combinations thereof.

[0316] In some embodiments, the additional therapeutic agent is an HIV integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, elvitegravir, dolutegravir, abacavir, lamivudine, bictegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir. In some examples, the additional therapeutic agent is selected from the group consisting of bictegravir, elvitegravir, curcumin, a derivative of curcumin, chlorogenic acid, a derivative of chlorogenic acid, 3,5-dicaffeoylquinic acid, a derivative of 3,5-dicaffeoylquinic acid, aurogygones tricarboxylic acid, a derivative of aurogygones tricarboxylic acid, caffeic acid phenethyl ester, a derivative of caffeic acid phenethyl ester, a tyrosine kinase inhibitor, a derivative of a tyrosine kinase inhibitor, quercetin, a derivative of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, BMS-986197, cabotegravir (long-acting injectable), diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, cabotegravir, and combinations thereof.

[0317] In some embodiments, the additional therapeutic agent is an HIV entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of enfuvirtide, maraviroc, and combinations thereof. Additional examples of HIV entry inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adatansvir (RAP-101), nelfavirsen (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu). Examples of CXCR4 inhibitors include protegrin, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0318] In some embodiments, the additional therapeutic agent is an HIV nucleoside reverse transcriptase inhibitor. In some embodiments, the additional therapeutic agent is an HIV non-nucleoside reverse transcriptase inhibitor. In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analog. In some embodiments, the additional therapeutic agent is an HIV capsid inhibitor.

[0319] In some embodiments, the additional therapeutic agent is an HIV nucleoside or nucleotide reverse transcriptase inhibitor. For example, the additional therapeutic agent is selected from the group consisting of adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX ® and VIDEX EC ® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, alitaskin, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, eduvirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, islatravir, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rofavirine-ethavirine amide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and combinations thereof.

[0320] In some examples, the additional therapeutic agent is an HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitor. For example, the additional agent is selected from the group consisting of dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, eduvirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, efavirenz rilp (VM-1500), and combinations thereof.

[0321] In some embodiments, the additional therapeutic agent is selected from ATRIPLA ® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA ® (EVIPLERA ® ; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD ® (etravirine, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (Fumaric acid tenofovir disoproxil and emtricitabine; TDF + FTC); DESCOVY ® (Tenofovir alafenamide and emtricitabine); ODEFSEY ® (Tenofovir alafenamide, emtricitabine and rilpivirine); GENVOYA ® (Tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ ® (Dolutegravir, abacavir and lamivudine); dolutegravir, abacavir sulfate and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA ® (KALETRA ® ; lopinavir and ritonavir); COMBIVIR ® (Zidovudine and lamivudine; AZT + 3TC); EPZICOM ® (LIVEXA ® ; abacavir sulfate and lamivudine; ABC + 3TC); TRIZIVIR ® (Abacavir sulfate, zidovudine and lamivudine; ABC + AZT + 3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; platinil; fosamprenavir; fosamprenavir calcium efavirenz; Etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (Receptor Alcohol); lamivudine and fumaric acid tenofovir disoproxil; efavirenz, lamivudine and fumaric acid tenofovir disoproxil; phosphazide; lamivudine, nevirapine and zidovudine; abacavir; and abacavir sulfate.

[0322] In some embodiments, the additional therapeutic agent is selected from the group consisting of: colistin, valrubicin, ibudilast, betahistine, epirubicin, epoprosetnol, vapiprost, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, plazidox, bictegravir, nelfinavir, tegobuvi, nelfinavir, praziquantel, pitavastatin, perampanel, dexzopiclone, and zopiclone.

[0323] In some embodiments, the additional therapeutic agent is an inhibitor of Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene ID: 695). For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of: (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, acalabrutinib, danvatrivine, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of: tirabrutinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of: tirabrutinib, ibrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is tyrosine kinase inhibitor A9 (A9).

[0324] In some embodiments, the additional therapeutic agent is a KRAS inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620 (G12C), SML-8-73-1 (G12C), Compound 3144 (G12D), Kobe0065 / 2602 (Ras GTP), RT11, MRTX-849 (G12C), and K-Ras (G12D) selective inhibitory peptides, including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d (Ac-RRRRCPLYISYDPVCRRRR-NH2), and combinations thereof.

[0325] In some embodiments, the additional therapeutic agent is a proteasome inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ixazomib, carfilzomib, marizomib, bortezomib, and combinations thereof. In some embodiments, the additional therapeutic agent is carfilzomib.

[0326] In some embodiments, the additional therapeutic agent is a vaccine. For example, in some embodiments, the additional therapeutic agent is a DNA vaccine, an RNA vaccine, a live attenuated vaccine, a therapeutic vaccine, a prophylactic vaccine, a protein-based vaccine, or a combination thereof. In some embodiments, the additional therapeutic agent is mRNA-1273. In some embodiments, the additional therapeutic agent is INO-4800 or INO-4700. In some embodiments, the additional therapeutic agent is a live attenuated RSV vaccine MEDI-559, an anti-RSV human monoclonal antibody REGN2222, palivizumab, respiratory syncytial virus immune globulin, respiratory syncytial virus immune globulin intravenous [RSV-IGIV], and combinations thereof. In some embodiments, the additional therapeutic agent is an HBV vaccine, such as pediarix, engerix-B, and recombivax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, such as zostavax and varivax. In some embodiments, the additional therapeutic agent is an HPV vaccine, such as cervarix, gardasil9, and gardasil. In some embodiments, the additional therapeutic agent is an influenza virus vaccine. For example, (i) an influenza A monovalent vaccine (e.g., influenza A [H5N1] virus monovalent vaccine and influenza A [H1N1] 2009 virus monovalent vaccine), (ii) an influenza A and B trivalent vaccine (e.g., Afluria, Agriflu, Fluad, Fluarix, Flublok, Flucelvax, FluLaval, Fluvirin, and Fluzone), and (iii) an influenza A and B quadrivalent vaccine (FluMist, Fluarix, Fluzone, and FluLaval). In some embodiments, the additional therapeutic agent is a human adenovirus vaccine (e.g., Adenovirus types 4 and 7 vaccine, live, oral). In some embodiments, the additional therapeutic agent is a rotavirus vaccine (e.g., Rotarix for rotavirus serotypes G1, G3, G4, or G9 and RotaTeq for rotavirus serotypes G1, G2, G3, or G4). In some embodiments, the additional therapeutic agent is a hepatitis A virus vaccine (e.g., Havrix and Vaqta). In some embodiments, the additional therapeutic agent is a poliovirus vaccine (e.g., Kinrix, Quadracel, and Ipol). In some embodiments, the additional therapeutic agent is a yellow fever virus vaccine (e.g., YF-Vax). In some embodiments, the additional therapeutic agent is a Japanese encephalitis virus vaccine (e.g., Ixiaro and JE-Vax). In some embodiments, the additional therapeutic agent is a measles vaccine (e.g., M-M-R II and ProQuad). In some embodiments, the additional therapeutic agent is a mumps vaccine (e.g., M-M-R II and ProQuad).In some embodiments, the additional therapeutic agent is a rubella vaccine (e.g., M-M-R II and ProQuad). In some embodiments, the additional therapeutic agent is a varicella vaccine (e.g., ProQuad). In some embodiments, the additional therapeutic agent is a rabies vaccine (e.g., Imovax and RabAvert). In some embodiments, the additional therapeutic agent is a smallpox virus (variola) vaccine (ACAM2000). In some embodiments, the additional therapeutic agent is a hepatitis E virus (HEV) vaccine (e.g., HEV239). In some embodiments, the additional therapeutic agent is a 2019-nCov vaccine.

[0327] In some embodiments, the additional therapeutic agent is an antibody, e.g., a monoclonal antibody. For example, the additional therapeutic agent is an anti-2019-nCov antibody selected from the group consisting of: a Regeneron antibody, a Wuxi antibody, a Vir Biotechnology antibody, an antibody targeting SARS-CoV-2 spike protein, an antibody that can neutralize SARS-CoV-2 (SARS-CoV-2 neutralizing antibody), and combinations thereof. In some embodiments, the additional therapeutic agent is the anti-SARS CoV antibody CR-3022. In some embodiments, the additional therapeutic agent is an aPD-1 antibody.

[0328] In some embodiments, the additional therapeutic agent is a recombinant cytokine gene-derived protein injection.

[0329] In some embodiments, the additional therapeutic agent is a polymerase inhibitor. In some embodiments, the additional therapeutic agent is a DNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is cidofovir. In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of: ribavirin, favipiravir, lamivudine, pimodivir, and combinations thereof.

[0330] In some embodiments, the additional therapeutic agent is selected from the group consisting of: lopinavir, ritonavir, interferon alpha-2b, ritonavir, arbidol, hydroxychloroquine, delaviradine, and combivir, arbidol hydrochloride, oseltamivir, litonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinations thereof.

[0331] In some embodiments, the additional therapeutic agent is selected from the group consisting of 6'-fluorinated mangrove analogs, acyclovir fleximer analogs, disulfiram, thiopurine analogs, ASC09F, GC376, GC813, phenylisoserine derivatives, neuraminidase inhibitor analogs, pyrithioxate derivatives, pannarini and 5-hydroxychromone derivatives, SSYA10-001, griffithsin, HR2P-M1, HR2P-M2, P21S10, dihydrotanshinone E-64-C and E-64-D, OC43-HR2P, MERS-5HB, 229E-HR1P, 229E-HR2P, resveratrol, 1-thiophene-4-azaspiro[4.5]decane-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferon, cyclosporine A, ala- porevir, imatinib mesylate, dasatinib, semetinib, trametinib, rapamycin, serabtinib, chlopro- mazine, triflupromazine, fluphenazine, thioridazine, promethazine, cyclophilin inhibitors, K11777, camostat, k22, teicoplanin derivatives, benzoheterocyclic amine derivatives N30, mycophenolic acid, silvestrol, and combinations thereof.

[0332] In some embodiments, the additional therapeutic agent is an antibody. In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, for example an antibody that binds to SARS or MERS. In some embodiments, the additional therapeutic agent is a 2019-nCoV viral antibody.

[0333] The compositions of the present application are also used in combination with other active ingredients. For the treatment of 2019-nCoV viral infection, preferably, the other active therapeutic agent has activity against coronavirus infection, e.g., activity against 2019-nCoV viral infection. The compounds and compositions of the present application are also intended for use in the general care of patients with 2019-nCoV viral infection, including parenteral fluids (including dextrose saline and Ringer’s lactate) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylactics, fever and pain medications, antiemetics (such as metoclopramide) and / or antidiarrheal agents, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immunomodulatory drugs (e.g., interferons), other small molecule or biologic antiviral agents targeting 2019-nCoV (such as, but not limited to, lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, neutralizing antibodies, etc.), vaccines, pain medications, and medications for other common diseases in the patient population, such as anti-malarial agents (including artemether and artemether-lumefantrine combination therapy), typhoid fever vaccines (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or Shigella disease vaccines. In some embodiments, the additional therapeutic agent is dihydroartemisinin / piperaquine. In some embodiments, the additional therapeutic agent is EIDD-2801 (MH-4482, molnupiravir).

[0334] In some examples, the additional therapeutic agent is an immunomodulatory agent. Examples of immune-based therapies include toll-like receptor modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death ligand 1 (Pd-L1) modulators; IL-15 modulators; DermaVir; interleukin-7; hydroxychloroquine (Plaquenil); Proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxyurea; mycophenolic acid mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; the polymer polyethylenimine (PEI); gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, NKTR-262, NKTR-214, Noviluma, peginterferon alfa-2a, peginterferon alfa-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103. In some embodiments, the additional therapeutic agent refers to fingolimod, leflunomide, or a combination thereof. In some embodiments, the additional therapeutic agent is thalidomide.

[0335] In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, for example, tocilizumab, sarilumab, or a combination thereof.

[0336] In some embodiments, the additional therapeutic agent is an anti-TNF inhibitor. For example, the additional therapeutic agent is adalimumab, etanercept, golimumab, infliximab, or a combination thereof.

[0337] In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example, the additional therapeutic agent is baricitinib, filgotinib, baricinib, or a combination thereof.

[0338] In some embodiments, the additional therapeutic agent is an inflammation inhibitor, for example, pirfenidone.

[0339] In some embodiments, the additional therapeutic agent is an antibiotic for secondary bacterial pneumonia. For example, the additional therapeutic agent is a macrolide antibiotic (e.g., azithromycin, clarithromycin, and mycoplasma pneumoniae (MP) (e.g., clarithromycin, doxycycline, and azithromycin). mycoplasma pneumoniaefluoroquinolones (e.g., ciprofloxacin and levofloxacin), tetracyclines (e.g., doxycycline and tetracycline), or combinations thereof.

[0340] In some embodiments, the compounds disclosed herein are used in combination with standard of care for pneumonia (see, e.g., Pediatric Community Pneumonia Guidelines, CID 2011:53 (October 1)). Treatment of pneumonia generally involves curing the infection and preventing complications. The specific treatment will depend on several factors, including the type and severity of the pneumonia, the age and overall health of the individual. Options include: (i) antibiotics, (ii) cough medicine, and (iii) fever / pain relievers (e.g., aspirin, ibuprofen (Advil, Motrin IB, etc.), and acetaminophen (Tylenol, etc.). In some embodiments, the additional therapeutic agent is a bromhexine cough suppressant.

[0341] In some embodiments, the compounds disclosed herein are used in combination with immunoglobulin from convalescing COVID-19 patients. In some embodiments, the compounds disclosed herein are used in combination with plasma transfusion. In some embodiments, the compounds disclosed herein are used in combination with stem cells.

[0342] In some examples, the additional therapeutic agent is a TLR agonist. Examples of TLR agonists include, but are not limited to, visamminode (GS-9620), GS-986, IR-103, resiquimod, tilsotolimod, rintatlimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratolimod. RO-7020531.

[0343] In some examples, the additional therapeutic agent is selected from the group consisting of bortezomib, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, serindole, clevidipine, atorvastatin, cinoxolone, clofazimine, fosaprepitant, and combinations thereof.

[0344] In some examples, the additional therapeutic agent is a calicheamicin, suramin, triazirine, dipyridamole, bevacizumab, mepolizumab, GD31 (Rhizobium), an NLRP inflammasome inhibitor, or an alpha-ketamine. In some embodiments, the additional therapeutic agent is recombinant human angiotensin-converting enzyme 2 (rhACE2). In some embodiments, the additional therapeutic agent is viral macrophage inflammatory protein (vMIP).

[0345] In some embodiments, the additional therapeutic agent is an antiviral pore protein therapeutic. For example, the additional therapeutic agent is BIT-314 or BIT-225. In some embodiments, the additional therapeutic agent is a coronavirus E protein inhibitor. For example, the additional therapeutic agent is BIT-009. Additional examples of additional therapeutic agents include those described in WO-2004112687, WO-2006135978, WO-2018145148, and WO-2009018609.

[0346] Any of the compounds of the present application can also be combined with one or more additional active therapeutic agents in a single dosage form for simultaneous or sequential administration to a patient. Combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more administrations.

[0347] Co-administration of a compound of the present application with one or more other active therapeutic agents generally refers to the administration of a compound of the present application and one or more other active therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of both the compound of the present application and the one or more other active therapeutic agents are present in the patient's body.

[0348] Co-administration includes administration of a unit dose of a compound of the present application prior to or following administration of a unit dose of one or more other active therapeutic agents, for example, within seconds, minutes, or hours of administration of the one or more other active therapeutic agents. For example, a unit dose of a compound of the present application can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed within seconds or minutes by administration of a unit dose of a compound of the present application. In some cases, it can be desirable to administer a unit dose of a compound of the present application first, followed by administration of a unit dose of one or more other active therapeutic agents several hours (e.g., 1 hour to 12 hours) later. In other cases, it can be desirable to administer a unit dose of one or more other active therapeutic agents first, followed by administration of a unit dose of a compound of the present application several hours (e.g., 1 hour to 12 hours) later.

[0349] Combination therapy can provide "synergy" and "potentiation" such that the effect of the active ingredients when used together is greater than the sum of the effects of the compounds when given alone. A synergistic effect can be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation, a synergistic effect can occur where the compounds are administered or delivered sequentially. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic anti-viral effect means that the anti-viral effect is greater than the predicted additive effect of the compounds in the combination.

[0350] 1. Combination therapies for the treatment of Pneumoviridae

[0351] The pharmaceutical formulations provided herein are also used in combination with other active therapeutic agents. For the treatment of Pneumoviridae virus infections, preferably, the other active therapeutic agent has activity against Pneumoviridae virus infections, in particular, respiratory syncytial virus infection and / or metapneumovirus infection. Non-limiting examples of these other active therapeutic agents with activity against RSV are ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam ® ), MEDI-557, A-60444 (also known as RSV604), MDT-637, BMS-433771, ALN-RSV0, ALX-0171, and mixtures thereof. Other non-limiting examples of other active therapeutic agents with activity against respiratory syncytial virus infection include inhibitors of respiratory syncytial virus protein F, such as AK-0529; RV-521, ALX-0171, JNJ-53718678, BTA-585, and presatovir; RNA polymerase inhibitors, such as lumicitabine and ALS-8112; anti-RSV G protein antibodies, such as anti-G protein mAbs; viral replication inhibitors, such as nitazoxanide.

[0352] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of RSV, including but not limited to MVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI deltaM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccine.

[0353] Non-limiting examples of other active therapeutic agents with activity against metapneumovirus infection include sialidase modulators such as DAS-181; RNA polymerase inhibitors such as ALS-8112; and antibodies for treating metapneumovirus infection such as EV-046113.

[0354] In some embodiments, the other active therapeutic agent can be a vaccine for treating or preventing metapneumovirus infection, including but not limited to mRNA-1653 and rHMPV-Pa vaccine.

[0355] 2. Combination therapies for the treatment of Picornaviridae

[0356] The pharmaceutical formulations provided herein are also used in combination with other active therapeutic agents. For the treatment of Picornaviridae virus infection, preferably the other active therapeutic agent has activity against Picornaviridae virus infection, in particular enterovirus infection. Non-limiting examples of these other active therapeutic agents are capsid binding inhibitors such as pleconaril, BTA-798 (vapendavir) and other compounds disclosed by Wu et al. (US 7,078,403) and Watson (US 7,166,604); fusion sialidase proteins such as DAS-181; capsid protein VP1 inhibitors such as VVX-003 and AZN-001; viral protease inhibitors such as CW-33; phosphatidylinositol 4 kinase beta inhibitors such as GSK-480 and GSK-533; anti-EV71 antibodies.

[0357] In some embodiments, the other active therapeutic agent can be a vaccine for treating or preventing Picornaviridae virus infection, including but not limited to EV71 vaccine, TAK-021 and EV-D68 adenoviral vector-based vaccine.

[0358] 3. Combination therapies for respiratory infections

[0359] Many infections with viruses of the Metapneumoviridae and Picornaviridae families are respiratory tract infections. Accordingly, additional active therapeutic agents for treating respiratory symptoms and sequelae of infection can be used in combination with the pharmaceutical formulations provided herein. The additional therapeutic agents are preferably administered orally or by direct inhalation. For example, other preferred additional therapeutic agents for use in combination with the compounds provided herein for the treatment of viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids.

[0360] glucocorticoids

[0361] Glucocorticoids, first introduced as a therapy for asthma in 1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the most effective and consistently effective therapy for this disease, but their mechanism of action is not fully understood (Morris, J. Allergy Clin. Immunol., 75 (1 Pt) 1-13, 1985). Unfortunately, oral glucocorticoid therapy is associated with serious adverse side effects such as truncal obesity, hypertension, glaucoma, glucose intolerance, accelerated cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents (Goodman and Gilman, 10th Edition, 2001). A solution to the systemic side effects is to deliver the steroid drug directly to the site of inflammation. Inhaled corticosteroids (ICS) have been developed to reduce the serious side effects of oral steroids. Non-limiting examples of corticosteroids that can be used in combination with the compounds provided herein are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol etabonate, loteprednol etabonate ophthalmic solution, hydrocortisone, prednisolone, flurandrenolide, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone dipropionate, methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluocinonide-21 -butyrate, flumethasone, flumethasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone, AZD-7594, ciclesonide; or a pharmaceutically acceptable salt thereof.

[0362] anti-inflammatory agents

[0363] Other anti-inflammatory agents that act through anti-inflammatory cascades can also be used as additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections. The use of "anti-inflammatory signal transduction modulators" (referred to herein as AISTMs), such as phosphodiesterase inhibitors (e.g., specific for PDE-4, PDE-5, or PDE-7), transcription factor inhibitors (e.g., block NFκB through IKK inhibition), or kinase inhibitors (e.g., block P38 MAP, JNK, PI3K, EGFR, or Syk) is a logical approach to cutting off inflammation, as these small molecules target a limited number of common intracellular pathways - those signal transduction pathways that are key points of intervention for anti-inflammatory therapy (see review by P.J. Barnes, 2006). These non-limiting additional therapeutic agents include: 5-(2,4-difluoro-phenoxy)-l-isobutyl-lH-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRY-797); 3-cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-benzamide (PDE-4 inhibitor Roflumilast); 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5-dichloro-4-pyridinyl)-4-difluoromethoxy-8-[(methylsulfonyl)amino]-l-dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-dichloro-pyridin-4-yl)-2-[l-(4-fluorobenzyl)-5-hydroxy-lH-indol-3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD 12-281); 8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-l-oxo-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591); 4-[5-(4-fluorophenyl)-2-(4-methanesulfinyl-phenyl)-lH-imidazol-4-yl]-pyridine (P38 inhibitor SB-203850); 4-[4-(4-fluorophenyl)-l-(3-phenylpropyl)-5-pyridin-4-yl-lH-imidazol-2-yl]-but-3-yn-1-ol (P38 inhibitor RWJ-67657); 4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-cyclohexanecarboxylic acid 2-diethylamino-ethyl ester (2-diethyl-ethyl ester prodrug of Cilomilast, PDE-4 inhibitor); (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (gefitinib, EGFR inhibitor); and 4-(4-methyl-piperazin-l-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib, EGFR inhibitor).

[0364] beta2-adrenergic receptor agonist bronchodilators

[0365] Combinations of inhaled β2-adrenergic receptor agonists and bronchodilators such as formoterol, salbutamol, or salmeterol with the compounds provided herein are also suitable, but not limiting, combinations for the treatment of respiratory viral infections.

[0366] Inhaled β2-adrenergic receptor agonists and bronchodilators such as formoterol or salmeterol, in combination with ICS, are also used to treat bronchoconstriction and inflammation (symmbicort, respectively). ® and Advair ® Combinations of these ICS and β2-adrenergic receptor agonists, as well as combinations of the compounds presented herein, are also suitable, but not limiting, combinations for the treatment of respiratory viral infections.

[0367] Other examples of β2-adrenergic receptor agonists are bedoradine, vilanterol, indacaterol, olodaterol, tuloterrol, formoterol, abidilol, salbutamol, afortrol, levosalbutamol, fenoterol, and TD-5471.

[0368] anticholinergic agents

[0369] Anticholinergic agents have potential use in the treatment or prevention of bronchoconstriction and can therefore be used as adjunctive therapy in combination with the compounds presented herein for the treatment of viral respiratory infections. These anticholinergic agents include, but are not limited to, muscarinic receptor antagonists (particularly the M3 subtype), which have been shown to be effective in controlling cholinergic tension in humans for COPD (Witek, 1999); 1-{4-hydroxy-1-[3,3,3-tris-(4-fluorophenyl)propionyl]pyrrolidine-2-carbonyl}-pyrrolidine-2-carboxylic acid (1-methylpiperidin-4-ylmethyl)-amide; 3-[3-(2-diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azine - Bicyclo[3.2.1]octane (ipratropium-N,N-diethylglycine ester); 1-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (sofenadine); 2-hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (revatropide); 2-{1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidine-3-yl}-2,2-diphenyl-acetamide (dafinacin); 4-azacycloheptane-1-yl-2,2-diphenyl-butamide (Buzepide); 7-[3-(2-diethylamino-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-aza - Tricyclic [3.3.1.02,4]nonane (oxytropine-N,N-diethylglycine ester); 7-[2-(2-diethylamino-acetoxy)-2,2-di-thiophene-2-yl-acetoxy]-9,9-dimethyl-3-oxa-9-aza - Tricyclic [3.3.1.02,4]nonane (tiotropium-N,N-diethylglycine ester); dimethylaminoacetic acid 2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester (tolterodine-N,N-dimethylglycine ester); 3-[4,4-bis-(4-fluorophenyl)-2-oxo-imidazolidine-1-yl]-1-methyl-1-(2-oxo-2-pyridin-2-yl-ethyl)pyrrolidine ; 1-[1-(3-fluorobenzyl)-piperidin-4-yl]-4,4-bis-(4-fluorophenyl)-imidazolidine-2-one; 1-cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2]oct-3-yl)-1-phenyl-prop-2-yn-1-ol; 3-[2-(2-diethylamino-acetoxy)-2,2-dithiophene-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-aza - Bicyclo[2.2.2]octane (aldeionium bromide-N,N-diethylglycine ester); or (2-diethylamino-acetoxy)-dithiophene-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester; refenapyridine, glyphosate bromide, wudeionium bromide, tiotropium bromide, adeionium bromide, benzylquinoline bromide.

[0370] mucolytic agents

[0371] The pharmaceutical formulations described herein can also be combined with mucolytics to treat symptoms of infections and respiratory tract infections. A non-limiting example of a mucolytic is ambroxol. Similarly, the pharmaceutical formulations can be combined with expectorants to treat symptoms of infections and respiratory tract infections. A non-limiting example of an expectorant is guaifenesin.

[0372] Nebulized hypertonic saline is used to improve immediate and long-term clearance of small airways in patients with lung disease (Kuzik, J. Pediatrics 2007, 266). Thus, the compounds provided herein can also be combined with nebulized hypertonic saline, particularly when the viral infection is complicated by bronchiolitis. The combination of the pharmaceutical formulations provided herein with hypertonic saline can also include any of the additional agents discussed above. In one embodiment, about 3% nebulized hypertonic saline is used.

[0373] 4. Combination therapies for the treatment of Flaviviridae viral infections

[0374] The compounds and compositions provided herein are also used in combination with other active therapeutic agents. For the treatment of Flaviviridae viral infections, preferably the other active therapeutic agent has activity against Flaviviridae viral infections.

[0375] For the treatment of dengue viral infections, non-limiting examples of other active therapeutic agents are host cytokine modulators such as GBV-006; fenretinide ABX-220, BRM-211; alpha-glucosidase 1 inhibitors such as siseguvac; platelet-activating factor receptor (PAFR) antagonists such as modipafant; cadherin-5 / factor la modulators such as FX-06; NS4B inhibitors such as JNJ-8359; viral RNA splicing modulators such as ABX-202; NS5 polymerase inhibitors; NS3 protease inhibitors; and TLR modulators.

[0376] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of dengue, including but not limited to TetraVax-DV, Dengvaxia ® , DPIV-001, TAK-003, live attenuated dengue vaccine, tetravalent dengue vaccine, tetravalent DNA vaccine, rDEN2delta30-7169; and DENV-1 PIV.

[0377] 5. Combination therapies for the treatment of Filoviridae viral infections

[0378] The pharmaceutical formulations provided herein are also used in combination with other active therapeutic agents. For the treatment of Filoviridae viral infections, preferably the other active therapeutic agent has activity against Filoviridae viral infections, particularly Marburgvirus, Ebolavirus, and Queuvirus infections. Non-limiting examples of these other active therapeutic agents are: ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam ®), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola convalescent plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5- (hydroxymethyl)pyrrolidine-3,4-diol), TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9- dimethylquinolo[8,7-h]quinolin-1,7-diamine), rNAPc2, OS-2966, brincidofovir, remdesivir; RNA polymerase inhibitors such as Galidesivir, favipiravir (also known as T-705 or Avigan), JK-05; host cytokine modulators such as GMV-006; Cadherin-5 / Factor la modulators such as FX-06; and antibodies for treating Ebola such as REGN-3470-3471-3479 and ZMapp.

[0379] Other non-limiting active therapeutic agents with anti-Ebola activity include alpha-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonists, HLA class II antigen modulators, host cytokine modulators, interferon alpha ligands, neutral alpha glucosidase AB inhibitors, Niemann-Pick Cl protein inhibitors, nucleoprotein inhibitors, polymerase cofactor VP35 inhibitors, serine protease inhibitors, tissue factor inhibitors, TLR-3 agonists, viral envelope glycoprotein inhibitors, and Ebola virus entry inhibitors (NPC1 inhibitors).

[0380] In some embodiments, other active therapeutic agents can be vaccines for treating or preventing Ebola, including but not limited to VRC-EBOADC076-00-VP, an adenovirus-based Ebola vaccine, rVSV-EBOV, rVSVN4CT1-EBOVGP, MVA-BN Filo + Ad26-ZEBOV regimen, INO-4212, VRC-EBODNA023-00-VP, VRC-EBOADC069-00-VP, GamEvac-combi vaccine, SRC VB vector, HPIV3 / EboGP vaccine, MVA-EBOZ, Ebola recombinant glycoprotein vaccine, Vaxart adenovirus vector 5-based Ebola vaccine, FiloVax vaccine, GOVX-E301, and GOVX-E302.

[0381] The pharmaceutical formulations provided herein can also be used in combination with aminophosphoramidate morpholino oligomers (PMOs), which are synthetic antisense oligonucleotide analogs designed to interfere with the translation process by forming base-paired duplexes with specific RNA sequences. Examples of PMOs include, but are not limited to, AVI-7287, AVI-7288, AVI-7537, AVI-7539, AVI-6002, and AVI-6003.

[0382] The pharmaceutical formulations provided herein are also intended for use with the general care provided for patients infected with a virus of the family Orthomyxoviridae, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylactics, fever and pain medications, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), pain medications, and medications for other common ailments in the patient population, such as anti-malarial agents (including artemether and artemether-lumefantrine combination therapy), typhoid fever vaccines (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or Shigella disease vaccines.

[0383] VII. METHODS OF MAKING PHARMACEUTICAL FORMULATIONS

[0384] Also provided herein are methods of making the pharmaceutical formulations described herein. Methods of making the pharmaceutical formulations described herein generally include combining a compound of Formula I, Formula la, or Formula lb with an aqueous vehicle. In some embodiments, the method further includes preparing an aqueous formulation by mixing appropriate amounts of the desired excipients in water (e.g., in DI water, distilled water, or sterile water). The excipients include one or more agents selected from a co-solvent, a surfactant, a cyclodextrin, a suspending agent, a buffer / pH adjuster, a tonicity adjuster, an antimicrobial / antiseptic, and / or a taste-masking / flavoring agent as described in detail herein. The excipients can be mixed in any suitable order. In some embodiments, the excipients are mixed simultaneously. In some embodiments, the excipients are mixed sequentially.

[0385] In some embodiments, the method of making the pharmaceutical formulations disclosed herein further includes milling to micronize the compound of Formula I, Formula la, or Formula lb. The milling can be performed before (dry milling) or after (wet milling) adding the compound of Formula I, Formula la, or Formula lb to the aqueous vehicle.

[0386] In some embodiments, the methods of preparing the pharmaceutical formulations disclosed herein comprise (i) preparing a pre-milled formulation by combining a compound of Formula I, Formula la, or Formula lb with an aqueous vehicle and (ii) milling the pre-milled formulation to reduce the particle size of the compound of Formula I, Formula la, or Formula lb to form a milled suspension. In some embodiments, these methods further comprise diluting the milled suspension to achieve the target concentration of the pharmaceutical formulation.

[0387] VIII. EXAMPLES

[0388] Example 1: General procedure for the preparation of solution formulations

[0389] A bulk solution of the intended formulation vehicle is prepared prior to combining the vehicle with the compound of Formula I, Formula la, or Formula lb. The vehicle is prepared by dissolving the appropriate excipients (e.g., co-solvents, surfactants, solubilizing polymers such as cyclodextrins, buffers / pH adjusters, tonicity adjusters, antimicrobials / preservatives, and / or taste-masking / flavoring agents) in DI water to form a solution. The appropriate form of the compound of Formula I, Formula la, or Formula lb (e.g., the free form of the compound of Formula I, Formula la, or Formula lb in a co-solvent, a salt, a co-crystal, or a solution of the compound of Formula I, Formula la, or Formula lb) is then dissolved in the vehicle to form a solution of the target concentration of the final formulation.

[0390] Example 2: General procedure for the preparation of suspension formulations

[0391] A bulk solution of the intended formulation vehicle is prepared prior to combining the compound of Formula I, Formula la, or Formula lb with the vehicle. Typically, the vehicle is prepared by dissolving the appropriate excipients (e.g., co-solvents, surfactants, cyclodextrins, suspending agents, buffers / pH adjusters, tonicity adjusters, antimicrobials / preservatives, and / or taste-masking / flavoring agents) in DI water to form an excipient solution at the desired concentration. The pre-milled formulation intermediate of the concentrated compound of Formula I, Formula la, or Formula lb is then prepared by combining the solid compound of Formula I, Formula la, or Formula lb with the vehicle to form a crude slurry. The slurry is wet milled to reduce the particle size of the compound of Formula I, Formula la, or Formula lb to the target size and form a suspension. The concentration of the compound of Formula I, Formula la, or Formula lb in the suspension is measured, and the suspension is diluted with the vehicle to achieve the target concentration of the final formulation.

[0392] Example 3: Preparation of exemplary aqueous vehicles of the disclosure

[0393] 0.1% w / v HPMC 、 0.5% w / v Poloxamer 237 and 0.9% w / vAqueous solution of sodium chloride: Add a stir bar and 330 mL of DI water to a 1000 mL culture medium bottle and heat to approximately 90°C. Stir the water until a vortex forms, and add 1.00 g of HPMC to the vortex. Stir the mixture for 15 min. Then remove the mixture from the heat and add 670 mL of cold DI water to the bottle. Add 8.75 g of sodium chloride and 5.00 g of poloxamer 237. Continue stirring as the solution cools to ambient temperature.

[0394] 0.1% HPMC of PBS Solution: Add a stir bar and 330 mL of DI water to a 1000 mL culture medium bottle and heat to approximately 90°C. Stir the water until a vortex forms, and slowly add 1.00 g of HPMC to the vortex. Stir the mixture for 15 min. Remove the mixture from the heat and add 670 mL of cold DI water to the bottle. Then add 8.75 g of sodium chloride, 0.850 g of sodium dihydrogen phosphate monohydrate, and 5.05 g of disodium hydrogen phosphate heptahydrate, and continue stirring as the solution cools to ambient temperature.

[0395] 0.5% w / v Polosham 237 and 0.9% w / v Aqueous solution of sodium chloride. Add a stir bar, 5.00 g poloxamer 237, 8.75 g NaCl, and 1000 mL DI water to a 1000 mL culture medium bottle. Stir the mixture until a solution is formed.

[0396] Example 4: Preparation of exemplary pharmaceutical formulations of the disclosure

[0397] contain 0.1% w / v HPMC , 0.5% w / v Polosham 237 and 0.9% Sodium chloride in water 15mg / mL The form la Compound: An aqueous solvent containing excipients HPMC, poloxamer 237, and sodium chloride was prepared as described in Example 3 above. Then, 4.00 mL of the solvent, 98.83 mg of the compound of formula Ia, and 12 g of 0.5 mm zirconia grinding beads were added to a 7 mL soft tissue homogenization vial. The vial was capped, briefly vortexed, and then placed in a Bertin Instruments Precellys container. ®Evolution blender. The blend was mixed by wet milling for 15 x 30 second cycles with 120 seconds rest time between cycles. The blender speed was 7,200 rpm and the cooling setting was set to high. After milling, the milled suspension was separated from the beads by withdrawing the suspension from the vial using a syringe with a 1.5" 25G needle. The recovered volume of the concentrated suspension was 2.97 mL and the concentration was 25.8 mg / mL. The suspension was diluted with 2.14 mL of vehicle to achieve the target concentration of 15 mg / mL. The measured osmolality of the final formulation was 285 mOsm / kg, the pH was 6.89, and the volume average diameter particle size was 3.65 pm.

[0398] containing 0.1% w / v HPMC , 0.5% w / v poloxamer 237 and 0.9% sodium chloride in water 100mg / mL of the formula la Compound: A suspension vehicle containing excipients HPMC, poloxamer 237, and sodium chloride was prepared as described above in Example 3. A pre-mill formulation intermediate was then prepared by mixing 150 mL of vehicle with 25.0 g of the solid compound of Formula la. The Netzsch DeltaVita (R) 15-300 mill was used to reduce the particle size of the compound of Formula la in the pre-mill formulation intermediate by wet milling. The mill was configured with a 200 mL reservoir, a 50z continuous milling chamber containing 150 g of 0.5 pm zirconium oxide beads, a 300 pm screen, and an Ultracool ™ UC4 process chiller. The chiller was set to 30 °F, the pump was set to 100 rpm, and the agitator was set to 3000 rpm. The pump was primed with 100 mL of vehicle and the first 80 mL of flow after priming was sent to waste. The mill was then set to recirculate while continuing to feed, 150 mL of the pre-mill formulation intermediate was added, followed by a 25 mL vehicle rinse. The formulation was recirculated through the mill for 1 hour, then the flow was directed to a collection bottle. After 100 mL of the concentrated suspension formulation was collected in the bottle, the vehicle jacket was fed into the mill. The collection was stopped when the recovered volume reached 250 mL. The particle size of the compound of Formula la in the final formulation was < 5 pm by polarized light microscopy, with a measured concentration of 99.9 mg / mL.

[0399] Example 5: Suspension stability of pharmaceutical formulations of the compound of Formula la

[0400] Formulations of the following compounds of Formula la were prepared according to the methods described above.

[0401]

[0402] The sedimentation of each formulation was evaluated by visual inspection. The results of these experiments were... Figure 1 As shown in the image. Figure 1 As observed, after standing for four hours, the formulations in vials 3, 4 and 5 showed reduced sedimentation compared to the other formulations evaluated.

[0403] Example 6: Effect of particle size .

[0404] Formulations of compounds of formula Ia were prepared and evaluated by visual inspection and microscopic analysis.

[0405]

[0406] The results of these experiments are Figure 2 to Figure 6 As shown in the image. Figure 2 As shown, samples from pre-ground suspensions settled more readily than the ground formulations (bottles 2 and 3; particle size <5µM) (bottles 1 and 3 in each figure). After 24 hours of settling, complete sedimentation was observed in the pre-ground samples, but only partial sedimentation was observed in the ground samples (right figure).

[0407] In addition, such as Figure 3 to Figure 6 As seen, the preparation after grinding ( Figure 4 to Figure 6 Compared to pre-ground formulations, milled formulations show... Figure 3 The formation showed enhanced aggregation. Among the three milled formulations, the formulation containing 150 mM NaCl and 0.5% poloxamer 237 (…) Figure 6 The largest cluster is shown.

[0408] Example 7. Stability study of exemplary solution formulations (pre-lyophilized) of the disclosure

[0409] Pre-lyophilization solution formulations of Formula la (6.7 mg / mL) were prepared at a range of SBECD (sulfobutyl ether beta-cyclodextrin sodium, also known as sodium sulfobutyl ether beta-cyclodextrin) concentrations and held at ambient and refrigerated conditions in the presence and absence of crystalline Formula la seed crystals. Samples for freeze-thaw cycling were also prepared and tested. For each condition, physical stability was measured as %LS (label strength) and compared to the %LS at T=0. The results of these experiments are presented in Table 1 below. As seen, the 20% and 10% SBECD formulations were physically stable in the presence and absence of seeding when held at room temperature and 2°C to 8°C for 48 hours. The 20% and 10% SBECD formulations were also physically stable under freeze / thaw cycling (three cycles were performed). The 7.5% SBECD formulation was physically stable in the presence and absence of seeding when held at room temperature and 2°C to 8°C for 24 hours. The 7.5% SBECD formulation was also stable under freeze / thaw cycling (three cycles were performed). Precipitation was observed under certain conditions at 5% SBECD.

[0410] Table 1. Stability data for exemplary formulations

[0411]

[0412] 24h time point

[0413] Seeded with approximately 10% solids of crystalline Formula la

[0414] Example 8. Stability study of exemplary solution formulations (pre-lyophilized) under stress conditions up to pH 3.8

[0415] Pre-lyophilization solutions of Formula la (6.7 mg / mL) and SBECD (10% w / v SBECD) were set up with pH values of 3.8 and 4.0 and analyzed for physical stability. For each condition, physical stability was measured as %LS and compared to the %LS at T=0. The results of these studies are presented in Tables 2 to 4 below. As seen, the pre-lyophilization solutions were physically stable for 72 hours at pH=3.8 and stable for 3 freeze-thaw cycles in the presence and absence of seeding when held at room temperature and 2°C to 8°C.

[0416] Table 2. Stability data for exemplary formulations at pH 4.0 and 3.8 .

[0417]

[0418] Table 3. Stability data for exemplary formulations at pH 4.0 and 3.8 (in the presence of inoculation) .

[0419]

[0420] Inoculate with approximately 7.5% (20 μί, 200 mg / mL) of crystalline Form Ia suspension.

[0421] Table 4. Stability data for exemplary formulations at pH 4.0 and 3.8 (3 freeze-thaw cycles)

[0422]

[0423] Inoculate with approximately 7.5% (20 μί, 200 mg / mL) of crystalline Form Ia suspension.

[0424] Example 9. Chemical stability of exemplary solution formulations (pre-lyophilized) at pH 1.8, 2.0, 3.5, 3.8, and 4.0 Study

[0425] Pre-lyophilized formulations of Form Ia (6.67 mg / mL) and 10% w / w SBECD with variable pH were set up and analyzed for chemical stability. For each condition, samples were graded under ambient and refrigerated conditions. Samples were analyzed for % assay / degradation, appearance, reconstitution time, pH, and compared to T=0. Data from these studies are presented in Tables 5 and 6 below. The structures of the key impurities / metabolites are shown below. The results of these experiments indicate that the formulation is chemically stable.

[0426]

[0427]

[0428] Table 5. Chemical stability of exemplary pre-lyophilized solution formulations at pH 2.0 and 1.8 (degradation identity expressed as difference from T=0) Table 6. Chemical stability of exemplary pre-lyophilized solution formulations at pH 4.0, 3.8, and 3.5 (degradation identity expressed as difference from T=0)

[0429]

[0430] Example 10. Stability testing of exemplary lyophilized formulations Table 7. Four-week stability data for exemplary lyophilized formulations at 80 °C

[0431]

[0432] Table 8. Accelerated chemical stability of exemplary lyophilized formulations at 40 °C. 75% RH .

[0433] The following lyophilized drug products of Form Ia were prepared and placed in a temperature and humidity controlled room for predetermined time intervals and removed for testing. The drug product vials were tested using analytical methods determined to be indicative of stability, such as liquid chromatography, to monitor product purity. The results of these stability experiments are summarized in Tables 7-9.

[0434]

[0435] Table 9. Chemical stability of exemplary lyophilized formulations at 60 °C and -20 °C

[0436]

[0437] Example 11. Stability testing of exemplary reconstituted lyophilized formulations

[0438]

[0439] Table 10. Stability of reconstituted solutions at different pH

[0440]

[0441] Example 12. Stability comparison of exemplary reconstituted lyophilized formulations

[0442] The simulated reconstituted solutions were prepared and diluted into physiological saline (0.9% NaCl), simulating dilutions into 50 mL and 500 mL IV bags. The target pH and upper limit of pH specification were analyzed over time under ambient and refrigerated conditions. As seen in the data presented in Table 10 below, all pH solutions were physically stable for up to 24 h once diluted into physiological saline and held under ambient and refrigerated conditions.

[0443] The following lyophilized formulations were prepared

[0444]

[0445] Table 11. Stability data for exemplary reconstituted formulations

[0446] Table 12. Stability data for exemplary reconstituted formulations

[0447]

[0448] The lyophilized cake was reconstituted with SWFI (sterile water for injection) and subsequently diluted into physiological saline (0.9% NaCl), simulating dilutions into 50 mL and 500 mL IV bags. A head-to-head comparison of the physical stability of the 10% SBECD formulation and the 20% SBECD formulation was performed. These results are summarized in Tables 11 and 12 below. As seen, the 10% SBECD was physically stable for up to 48 hours under ambient and refrigerated conditions once diluted into physiological saline (no inoculation present).

[0449] Example 13. Use testing of reconstituted solutions

[0450]

[0451] The following lyophilized formulations were prepared

[0452]

[0453] ​​Inoculate with 10% of crystalline Form Ia (suspension)

[0454] Note: Test solutions were prepared by adding 19 mL of SWFI to the lyophilized cake; then diluted 25-fold or 2.5-fold to achieve the target concentration.

[0455] Table 13. Use stability data for exemplary formulations

[0456] Example 14. Pharmacokinetic profile of exemplary formulations :

[0457]

[0458] Lyophilized cakes were reconstituted and diluted into IV bags for a final Form Ia concentration of 2.0 mg / mL and 0.3 mg / mL. IV bags and IV tubing were sampled over time and tested for assay / degradation. The data for these studies are listed in Table 13 below. As seen, the tested formulations were stable when held at room temperature for up to 24 hours and at 2°C to 8°C for 48 hours. Similarly, the formulation was stable when placed in tubing for up to 6 hours (12 times longer than the assumed 30 min infusion time).

[0459] Figure 7

[0460]

[0461] Results are expressed as % w / w.

[0462] A = "Compound A"; C = "Compound C"; F = "Compound F"; G = "Compound G"

[0463] Table 14. PK data for exemplary formulations

[0464] PK studies were performed in cynomolgus monkeys (10 mg / Kg IV dose of Form Ia) with the following exemplary lyophilized formulations. Each formulation was prepared by adding 19 mL of sterile water for injection to the lyophilized cake and then stirring to ensure a uniform reconstituted solution. The reconstituted solution was then sterile filtered prior to IV administration over a 30 minute period. Each formulation was administered to n=3 male cynomolgus monkeys at a concentration of 5 mg / mL and a dose volume of 2 mL / kg for a total dose of 10 mg / kg. For each formulation, plasma samples were collected at the following time intervals: pre-dose, 0.25 hours, 0.48 hours (prior to the end of the infusion), 0.58 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours post-dose (based on the start of the infusion). For each formulation, samples for PBMC analysis were collected at the intervals of 4 hours and 24 hours post-dose (based on the start of the infusion).

[0465]

[0466] The results of these experiments are listed in Table 14 below and shown in the table below. Example 15. SARS-CoV-2 antiviral screening As shown in the figure, the two exemplary formulations exhibit similar concentration-time curves.

[0467] Example 16. Determination of compound of Formula la and its metabolites in AGM PBMCs, nasal mucosa, respiratory tract, liver, and kidney tissues following inhaled administration

[0468]

[0469] Plasma .

[0470] Inoculate each well of a white, opaque 96-well plate (Corning, catalog number 3916) with 1.2 × 10⁻⁶ ppm of phenol red-free DMEM medium supplemented with 2% FBS. 4 A549-hACE2 cells were infected. The next day, a 2-fold serial dilution of the compound was prepared in DMSO. The compound was further diluted 100-fold in 2% FBS medium. The cell culture medium was removed and incubated with 50 µL of the diluted compound solution and 50 µL of SARS-CoV2 nanovirus (MOI 0.025). 48 h post-infection, 50 µL of nanoluciferase substrate (Promega, catalog number N1150) was added to each well. Synergy was used. ™ The Neo2 multimode microplate reader (BioTek) measured luciferase signals. Relative luciferase signals were calculated by normalizing the luciferase signals of the compound treatment group to the luciferase signals of the DMSO treatment group (expressed as a percentage). The relative luciferase signals (Y-axis) were plotted against the log10 values ​​of the compound concentrations (X-axis) in GraphPad Prism 8 software. EC was calculated using a nonlinear regression model (four parameters). 50 (The concentration of compounds that reduce luciferase signal by 50%).

[0471] Using this determination, the EC50 of compounds of formula Ia was... 50 The value is calculated to be 110 nM.

[0472] Figure 8 Figure 9 .

[0473] Single-dose pharmacokinetic studies with the compound of Formula la (RDV, remdesivir or GS-5734) were conducted in male and female African Green Monkeys (AGM). Remdesivir IV formulation (lyophilized powder containing 105 mg of the compound of Formula la (3.23% w / w) and 3146 mg of sulfobutyl ether-beta-cyclodextrin sodium salt (SBECD, sodium sulfobutyl ether beta-cyclodextrin; 96.77% w / w) reconstituted with 19 mL of water for injection to obtain a solution of 5 mg / mL of the compound of Formula la and 150 mg / mL of SBECD at pH 3.6 (range 3.0 to 4.0)) was nebulized using a compressed air nebulizer. The nebulized compound of Formula la was administered to AGM via inhalation through a head-hood device for 30 minutes (Group 1; n=4) and 90 minutes (Group 2; n=4). The exposure times resulted in a mean presented dose of 0.672 mg / kg and 2.14 mg / kg, respectively. The mean deposited dose was calculated to be 0.168 mg / kg and 0.536 mg / kg, respectively. Plasma, peripheral blood mononuclear cells (PBMC), trachea, bronchi, lung lobe, liver, kidney, nasal mucosa, and nasopharyngeal mucosa samples were collected in this study.

[0474] Table 15. Mean plasma concentrations of compound of Formula la and its metabolites (mean ± SD, n = 4) following deposition dose of 0.168 mg / kg of compound of Formula la inhaled by African green monkeys The concentrations of the compound of Formula la and its two metabolites, A (adenosine nucleoside analog) and B (intermediate metabolite), as shown below, were determined in plasma by LC / MS / MS. The mean plasma concentrations of the compound of Formula la and its metabolites in male and female AGM following head-hood inhalation administration of deposited doses of 0.168 mg / kg and 0.536 mg / kg of the compound of Formula la are reported in Tables 15 and 16, respectively. The plasma pharmacokinetic parameters are summarized in Table 17. The mean plasma concentration-time profiles of the compound of Formula la and its metabolites at the 0.168 mg / kg and 0.536 mg / kg dose levels are plotted in Figures 1 and 2, respectively. Table 16. Mean plasma concentrations of compound of Formula la and its metabolites (mean ± SD, n = 4) following deposition dose of 0.536 mg / kg of compound of Formula la inhaled by African green monkeys and Table 17. Mean PK parameters of compound of Formula la and its metabolites (mean ± SD, n = 4) following deposition dose of 0.168 mg / kg or 0.536 mg / kg of compound of Formula la inhaled by African green monkeys

[0475]

[0476] PBMCs Table 18. PBMC concentrations of A, B, C, D, and E (mean ± SD, n = 4) following deposition dose of 0.168 mg / kg of compound of Formula la inhaled by African green monkeys

[0477]

[0478] BLQ: Below the lower limit of quantification. For Formula la: 0.001 µm; for B: 0.019 µM; for A: 0.001 µM.

[0479] Table 19. PBMC concentrations of A, B, C, D, and E (mean ± SD, n = 4) following deposition dose of 0.536 mg / kg of compound of Formula la inhaled by African green monkeys Nasal and nasopharyngeal mucosa

[0480] ​

[0481] BLQ: Below limit of quantitation. 0.001 µM for Formula la; 0.019 µM for B; 0.001 µM for A

[0482] Figure 11 Table 20. Nasal and nasopharyngeal mucosa concentrations of compound of Formula la and its metabolites (mean ± SD, n = 4) 24 hours following deposition dose of 0.168 mg / kg of compound of Formula la inhaled by African green monkeys

[0483]

[0484] Following inhalation administration of the compound of Formula la at calculated deposited doses of 0.168 mg / kg or 0.536 mg / kg, plasma levels of the compound of Formula la increased during inhalation exposure and then rapidly cleared from systemic circulation following cessation of dosing with elimination half-lives of 0.273 h or 0.342 h, respectively. Metabolite A slowly appeared in plasma and persisted over the 24 hour time course with mean estimated terminal elimination half-lives of 7.58 h or 7.10 h, respectively, following dosing at 0.168 mg / kg or 0.536 mg / kg, respectively.

[0485] ​ Concentrations of the compound of Formula la and metabolites A, B, C, D, and E, shown below, were determined in PBMC and tissues by LC / MS / MS. Mean PBMC concentrations of B, A, C, D, and E in AGM following hood inhalation of 0.168 mg / kg and 0.536 mg / kg of the compound of Formula la are reported in Tables 18 and 19, respectively.

[0486] , , , and

[0487] ​ ​

[0488]

[0489] ​ ​

[0490]

[0491] Mean PBMC concentration-time profiles of triphosphate E for the compound of Formula la at dose levels of 0.168 mg / kg and 0.536 mg / kg are plotted in ​ .

[0492] ​Qualitative analysis was performed by measuring the LC-MS / MS peak area of triphosphate E and endogenous ATP in the nasal and nasopharyngeal mucosa. Mucosa contains a heterogeneous cell population and is difficult to characterize; no cell counts were performed. Very small amounts of tissue weight were present in the scrapings and could not be measured.

[0493] For the nasal and nasopharyngeal mucosa, the average peak area ratio of triphosphate E / ATP was determined after 0.168 mg / kg and 0.536 mg / kg doses of RDV to assess the distribution and activation of RDV in the upper respiratory tract. The data are reported in Tables 20 and 21, respectively, and ​

[0494] ​ LC-MS / MS peak area of triphosphate E in nasopharyngeal mucosa (mean ± SD, n = 4)

[0495]

[0496] Table 21. Nasal mucosa and lung concentrations of compound of Formula la 24 hours after deposition of 0.536 mg / kg of compound of Formula la inhaled by African green monkeys LC-MS / MS peak area of triphosphate E in nasopharyngeal mucosa (mean ± SD, n = 4)

[0497]

[0498] Other selected tissues Concentrations of the compound of Formula la, A, B, C, D, and E in AGM lung, trachea, bronchi, liver, and kidney were measured using the LC-MS / MS method. The liver and kidney were harvested after euthanasia, and evidence of increased instability of the phosphorylated metabolites was observed, where different amounts of dephosphorylation appeared to have occurred upon isolation and snap-freezing of the liver and kidney samples. To assess the integrity of the tissue samples, the levels of native nucleotides (AMP, ADP, and ATP) were also determined in each tissue. The average concentrations of the compound of Formula la, A, B, C, D, and E in respiratory tissues at 24 hours post-dose at 0.168 mg / kg and 0.536 mg / kg dose levels of RDV are reported in Tables 22 and 23, respectively. The average concentrations of C, D, and E in respiratory tissues at 24 hours post-dose at 0.168 mg / kg and 0.536 mg / kg dose levels of RDV are plotted in Figure 12 and Figure 13

[0499] Table 22. Compound of Formula la, A, B, C, D, and E respiratory tissue concentrations 24 hours after deposition of 0.168 mg / kg of compound of Formula la inhaled by African green monkeys Compound, A, B, C, D, and E respiratory tissue concentrations (mean ± SD, n = 4)

[0500]

[0501] Table 23. Compound of Formula la, A, B, C, D, and E respiratory tissue concentrations 24 hours after deposition of 0.536 mg / kg of compound of Formula la inhaled by African green monkeys Compound, A, B, C, D, and E respiratory tissue concentrations (mean ± SD, n = 4)

[0502]

[0503] ​​For liver and kidney tissues, the average concentrations of total metabolites including the compound of Formula la, A, B, C, D, and E in these tissues at the 0.168 mg / kg and 0.536 mg / kg dose levels of RDV are reported in Tables 24 and 25, respectively, and are shown as Figure 14

[0504] Table 24. Compound of Formula la, A, B, C, D, and E respiratory tissue concentrations 24 hours after deposition of 0.168 mg / kg of compound of Formula la inhaled by African green monkeys Compound and total nucleotide metabolite liver and kidney concentrations (mean ± SD, n = 4)

[0505]

[0506] Table 25. Compound of Formula la and total nucleotide metabolite liver and kidney concentrations 24 hours after deposition of 0.536 mg / kg of RDV inhaled by African green monkeys Compound and total nucleotide metabolite liver and kidney concentrations (mean ± SD, n = 4)

[0507]

[0508] Inhalation of the compound of Formula la was distributed to all parts of the respiratory tract as well as other tissues collected 24 hours after dosing. Efficient formation of triphosphate E was observed in the upper trachea, lower trachea, main stem bronchus, and lower bronchus, and lower lung lobe, with concentrations of 0.069 nmol / g tissue, 0.266 nmol / g tissue, 0.762 nmol / g tissue, 0.562 nmol / g tissue, and 0.518 nmol / g tissue, respectively, at the 0.168 mg / kg dose, and 0.208 nmol / g tissue, 0.266 nmol / g tissue, 1.99 nmol / g tissue, 1.61 nmol / g tissue, and 1.58 nmol / g tissue, respectively, at the 0.536 mg / kg dose. Compound A, C, D, and E were also observed in the liver and kidney, with total nucleoside (compound of Formula la, compound A, compound B, compound C, compound D, and compound E) concentrations of 0.446 and 0.445 nmol / g tissue at the 0.168 mg / kg dose, and 0.695 and 1.23 nmol / g tissue at the 0.536 mg / kg dose. Triphosphate E was also measured in the nasal and nasopharyngeal mucosa following inhalation of the compound of Formula la, demonstrating distribution of RDV and its activation to the pharmacologically active metabolite in the upper respiratory tract.

[0509] Example 17. Intravenous administration of compound of Formula la

[0510] ​Pharmacokinetic studies following IV administration of the compound of Formula la were conducted in African Green Monkeys (AGM). The same formulation of Formula la used in Example 15 above (a lyophilized powder containing 105 mg of the compound of Formula la (3.23% w / w) and 3146 mg of sulfobutyl ether-beta-cyclodextrin sodium salt (SBECD, sodium sulfobutyl ether beta-cyclodextrin; 96.77% w / w), reconstituted with 19 mL of water for injection, to obtain a solution of 5 mg / mL of the compound of Formula la and 150 mg / mL of SBECD at pH 3.6 (range 3.0 to 4.0)) was used in these studies. The results of these studies are shown in Table 26 below.

[0511] Table 26. IV administration of compound of Formula la

[0512]

[0513] Example 18. In vitro intracellular triphosphate formation assay of PBMCs (peripheral blood mononuclear cells) .

[0514] In vitro intracellular triphosphate formation was measured for a compound of Formula I, Formula la, or Formula lb using the following protocol. Freshly isolated PBMCs were derived from healthy donors and allowed to suspend in culture medium (RPMI 1164 with L-glutamine) to a concentration of 5 million cells / mL prior to the start of the experiment. A 10 mL aliquot of PBMCs was transferred to a 50 mL conical tube with the cap loosened and compound was added to a final concentration of 2 µM. A 1 mL aliquot of each sample was then transferred to a well of a 24 well plate. The PBMC-compound mixture was incubated at 37°C / 5% CO2 for 2 hours with gentle agitation. Following incubation, the PBMCs were spun at 5000 RPM for 3 min and the supernatant was aspirated without disturbing the cell pellet. For samples that received immediate analysis, the samples were resuspended in pre-chilled 1x Tris buffered saline and transferred to a 1.5 mL conical tube containing 0.5 mL of nyosil M25. The sample / oil aliquot was then spun at 13,000 RPM for 1 min. Following centrifugation, all of the culture medium was aspirated from the tube without disturbing the oil layer. Water was added over the oil layer and the spin / aspiration process was repeated followed by an additional water wash. Following the second wash step, all of the oil and water were removed and the cell pellet was snap frozen on dry ice and stored at -80°C until further processing. Samples that did not receive immediate analysis were washed 2x with serum-free media, resuspended in 1 mL of media and incubated at 37c / 5% CO2 until they were processed according to the aforementioned protocol. Each PBMC sample was treated with 500 µL of dry ice cold extraction buffer (70% methanol containing 0.5 µM chloro-adenosine triphosphate as an internal standard). The above solution was vortexed for 5 minutes and then centrifuged at 20,000 x g for 10 minutes. The supernatant was transferred to a fresh tube and stored at -80°C until analysis. gCentrifuge for 20 minutes. Transfer the supernatant to a clean 1.5 mL Eppendorf vial and load it onto a centrifuge evaporator. Once dry, reconstitute the sample with 80 µL of mobile phase A at 20,000 × 10⁻⁶. g Centrifuge for 20 minutes and transfer the supernatant to an HPLC vial for analysis. Inject 10 µL aliquots into a Sciex 6500 LC / MS / MS system. Construct a standard calibration curve for PBMCs based on the pmol of the compound in each sample. Then divide the value from each sample by the total number of cells in the sample to obtain pmol per million cells. The micromolar concentration is then derived using an intracellular volume of 0.2 pL per cell.

[0515] Example 19. Animal pharmacokinetic assay

[0516] Animal pharmacokinetic studies of compounds of formula I, Ia, or Ib were conducted using the following protocol. Live animals weighing 3 kg to 6 kg were used for the study. The test article was administered to male cynomolgus monkeys via inhalation. Plasma samples were collected at 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 4 h, 8 h, and 24 h after administration, and PBMC samples were collected at 2 h and 24 h after administration.

[0517] Blood samples (approximately 1 mL) were collected into pre-cooled collection tubes containing K2EDTA and centrifuged at 4°C to separate isoplasma. For PBMC collection, approximately 8 mL of blood sample was collected at room temperature into CPT vacuum blood collection tubes containing heparin sodium for separation. At each terminal collection, the animal was anesthetized and the lungs were harvested while the animal was still alive. The collected lungs were rapidly frozen in liquid nitrogen immediately after retrieval.

[0518] Protein precipitation was performed on plasma samples from pharmacokinetic studies using acetonitrile containing 75% 5-iodotuberculin as an internal standard. Analytes in plasma samples were separated over 7 min at a flow rate of 250 µL / min using a mobile phase containing 0.2% formic acid and a linear gradient of 2% to 100% acetonitrile on a 4 µm 150 × 2 mm Synergi Max-RP column (Phenomenex, Torrance, CA). An eight-point standard curve prepared in blank plasma covered concentrations from 5.1 nM to 5000 nM and showed linearity exceeding R² of 0.99. Quality control samples prepared separately in plasma at 120 nM and 3000 nM were analyzed at the beginning and end of each sample group to ensure accuracy and precision within 20%.

[0519] Each PBMC sample was treated with 500 pL extraction buffer containing 67 mM ethylenediaminetetraacetic acid (EDTA) in 70% methanol with 0.5 pM chloro-adenosine triphosphate as an internal standard. The extraction buffer was chilled on dry ice. The above solution was vortexed for 5 minutes and then centrifuged at 20,000 x g for 20 minutes. The supernatant was transferred to a clean 1.5 mL Eppendorf vial and loaded onto a centrifugal evaporator. Once dry, the sample was reconstituted with 80 pL of 1 mM ammonium phosphate buffer (pH = 7) and centrifuged at 20,000 x g for 20 minutes and the supernatant was transferred to an HPLC injection vial for analysis. A 10 pL aliquot was injected into an API5000 LC / MS / MS system. To calculate intracellular metabolite concentrations, the total number of cells in each sample was determined using a total DNA counting method (Benech et al., Peripheral Blood Mononuclear Cell Counting Using a DNA-detection-based Method. July 1, 2004; Vol. 330 No. 1: pp. 172-174). A standard calibration curve for PBMCs was constructed based on the pmol of compound per sample. The values from each sample were then divided by the total number of cells in the sample to give pmol per million cells. Intracellular volume of 0.2 pL per cell was then used to derive micromolar concentrations. g g centrifuged at 20,000 x g for 20 minutes and the supernatant was transferred to an HPLC injection vial for analysis. A 10 pL aliquot was injected into an API5000 LC / MS / MS system. To calculate intracellular metabolite concentrations, the total number of cells in each sample was determined using a total DNA counting method (Benech et al., Peripheral Blood Mononuclear Cell Counting Using a DNA-detection-based Method. July 1, 2004; Vol. 330 No. 1: pp. 172-174). A standard calibration curve for PBMCs was constructed based on the pmol of compound per sample. The values from each sample were then divided by the total number of cells in the sample to give pmol per million cells. Intracellular volume of 0.2 pL per cell was then used to derive micromolar concentrations.

[0520] Lung samples were prepared by cutting into smaller pieces and dispensing into pre- weighed 15 mL conical tubes, which were kept on dry ice. Ice-cold extraction buffer (0.1% KOH and 67 mM ethylenediaminetetraacetic acid in 70% methanol with 0.5 pM chloro-adenosine triphosphate as an internal standard, about 2 mL) was added to about 0.5 g of lung sample each. The mixture was homogenized rapidly using an Omni-Tip TH ™ (Omni International) with a disposable hard tissue homogenizer probe. Homogenate aliquots were filtered by using a 0.2 pm 96-well polypropylene filter plate (Varian Captiva ™ ) (Varian). The filtrate was evaporated to dryness and reconstituted with an equal volume of 1 mM ammonium phosphate buffer (pH = 7) prior to LC-MS / MS analysis.

[0521] ​Nucleotide triphosphate quantitation used ion-pairing nucleotide detection LC-MS / MS method. Separation of analytes was performed by a 2.5 pm 2.0 x 50 mm Luna C18 column (Phenomenex, Torrance, CA) using an ion-pairing buffer containing 3 mM ammonium phosphate (pH 5) and 10 mM dimethylhexylamine (DMH) and a 10% to 50% acetonitrile multistage linear gradient to separate analytes in 11 min at a flow rate of 160 pL / min. Seven-point standard curves prepared in blank matrix covered concentrations from 24.0 nM to 17,500 nM and showed a linearity over R 2 values of 0.99.

[0522] Example 20: Comparative study of representative cyclodextrin solution and HPMC suspension formulations of compound of Formula la Figures 15 to 24 .

[0523] Example formulations were prepared as described above and a PK study in AGM monkeys was performed using the following study design:

[0524]

[0525] Results from these experiments are presented in Table 27. PK profiles of Formulation 1 and Formulation 3 and in Tables 27-36 below.

[0526] Table 28. PBMC triphosphate (Compound E; TP) levels of Formulation 1 and Formulation 3 .

[0527]

[0528] Table 29: Respiratory tissue levels of Compound C, D, and E for Formulation 1 and Formulation 3 .

[0529]

[0530] Table 30. Total nucleotide levels in liver and kidney over 24 hours using Formulation 1 and Formulation 3 .

[0531]

[0532] MP = Compound C; DP = Compound D; TP = Compound E.

[0533] Table 31. Mucosal sample: Compound E / ATP ratio for Formulation 1 and Formulation 3 .

[0534]

[0535] Table 32. Plasma PK of Formulation 1 and Formulation 2 .

[0536]

[0537] Table 33. PBMC metabolite levels of Formulation 1 and Formulation 2 .

[0538]

[0539] Table 35. Total nucleotide levels in liver and kidney 24 hours after inhaled administration of Formulation 1 and Formulation 2 .

[0540]

[0541] Table 34. Respiratory tissue metabolite levels for Formulation 1 and Formulation 2.

[0542]

[0543] MP = Compound C; DP = Compound D; TP = Compound E.

[0544] Table 36. Mucosal sample: GS-443902 / ATP ratio for Formulation 1 and Formulation 2 .

[0545]

[0546] Example 21. Nebulizer performance data for exemplary formulations .

[0547]

[0548] As seen in the Figures, equivalent plasma PK profiles and triphosphate levels in tissue and PBMCs were seen between Formulation 1 and 3 in AGM.

[0549] In addition, while Formulation 2, which utilized a suspension, cleared more slowly, the plasma exposure was similar to the solution formulation (Formulation 1). Generally, tissue and PBMC levels were similar between Formulation 1 and Formulation 2. At a significantly shorter duration of exposure (10 minutes vs. 90 minutes), the suspension Formulation 2 achieved a similar PK profile to the solution Formulation 1.

[0550] ​ .

[0551] Aqueous solution containing 5 mg / mL of Formula la, 15% w / v SBECD was nebulized with a PARI Vios ® PRO aerosol delivery system (PARI LC ® Sprint jet nebulizer in combination with a PARI Vios ® PRO compressor; referred to herein as LC ® Sprint) at an 8 mL charge until the end of nebulization. No significant change in % peak area of Formula la or its identified impurities was observed in the residual drug solution in the collected aerosol or nebulizer reservoir.

[0552] All publications, patents, and patent documents cited herein are incorporated by reference herein as if each were individually incorporated by reference.

[0553] The application has been described with reference to various particular and preferred embodiments and techniques. However, a person of ordinary skill in the art will understand that many modifications can be made while remaining within the spirit and scope of the application.

Claims

1. Use of a pharmaceutical formulation in the manufacture of a medicament for treating a viral infection in a human in need thereof, wherein the pharmaceutical formulation comprises: i. a compound of Formula I, Formula la, or Formula lb, or a pharmaceutically acceptable salt thereof: ， ， ， ii. water; and iii. a cyclodextrin selected from sulfobutyl alkyl ether-β-cyclodextrin or sodium β-cyclodextrin sulfobutyl ether; wherein the pharmaceutical formulation is administered to the human via inhalation.

2. The use of claim 1, wherein the use comprises administering at least one additional therapeutic agent to the human.

3. The use of claim 1 or 2, wherein the viral infection is a coronavirus infection.

4. The use of claim 1 or 2, wherein the viral infection is a SARS-CoV-2 infection.

5. The use of claim 1 or 2, wherein the viral infection is a SARS virus infection.

6. The use of claim 1 or 2, wherein the viral infection is a MERS virus infection.

7. The use of claim 1 or 2, wherein the viral infection is a Pneumoviridae virus infection.

8. The use of claim 1 or 2, wherein the viral infection is a respiratory syncytial virus infection.

9. The use of claim 1 or 2, wherein the viral infection is a human metapneumovirus infection.

10. The use of claim 1 or 2, wherein the viral infection is a Picornaviridae virus infection.

11. The use of claim 1 or 2, wherein the viral infection is a human rhinovirus infection.

12. The use of claim 1 or 2, wherein the viral infection is a Flaviviridae virus infection.

13. The use of claim 1 or 2, wherein the viral infection is a Dengue virus infection, a Yellow fever virus infection, a West Nile virus infection, a Tick-borne encephalitis, a Kyasanur virus infection, a Japanese encephalitis, a St. Louis encephalitis, a Murray Valley encephalitis, an Omsk hemorrhagic fever, a Zika virus infection, or a HCV infection.

14. The use of claim 1 or 2, wherein the viral infection is a Filoviridae virus infection.

15. The use of claim 1 or 2, wherein the viral infection is an Ebola virus infection or a Marburg virus infection.

16. The use of claim 1 or 2, wherein the viral infection is a Orthomyxoviridae virus infection.

17. The use of claim 1 or 2, wherein the viral infection is an influenza virus infection.

18. The use of claim 1 or 2, wherein the viral infection is a Paramyxoviridae virus infection.

19. The use of claim 1 or 2, wherein the viral infection is a human parainfluenza virus, a Nipah virus, a Hendra virus, a measles, or a mumps infection.

20. The use of claim 1 or 2, wherein the pharmaceutical formulation comprises: i. a compound of Formula la, or a pharmaceutically acceptable salt thereof: ， ii. water; and iii. a cyclodextrin selected from sulfobutyl alkyl ether-β-cyclodextrin or sodium β-cyclodextrin sulfobutyl ether.

Images