Formulations for CFTR modulators

Abstract

Disclosed herein are pharmaceutical compositions for the treatment of respiratory diseases and disorders, including rhinosinusitis. In some aspects, the compositions provide selective delivery to the upper airway and facilitate the transport active agents effectively across membranes.

Description

Attorney Docket No. 10029-122WO1 FORMULATIONS FOR CFTR MODULATORS ^ CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application 63 / 561,879, filed March 6, 2024, which is incorporated by reference herein in its entity. BACKGROUND

[0002] Chronic Rhinosinusitis (CRS) has been described in the literature as an “unrecognized epidemic” due to its high prevalence, its substantial impact on patient quality of life and the significant limitations of currently available treatment options. Chronic rhinosinusitis (CRS) is one of the most common chronic medical conditions worldwide, affecting all age groups. Its estimated incidence is 12.3% in the USA, 10.9% in Europe and 13% in China (CDC Data and Statistics (August 5, 2020; J Clin Med.2020 Jul; 9(7): 2285). It also drives an enormous burden of healthcare utilization, including approximately 10 million outpatient visits for CRS every year, of which approximately 70% result in prescription of an antibiotic and 40% fail medical management (Smith et al., 2013). In addition, CRS can also trigger asthma exacerbations which can be associated with serious clinical consequences. Furthermore, it is documented that CRS is also an economic burden for society. It is estimated that in the USA, the direct costs associated with CRS are approximately $10–13 billion per year (Rudmik L. Economics of chronic rhinosinusitis. Curr. Allergy Asthma Rep.2017; 17: 20). Moreover, indirect costs of CRS are due to missed workdays, absenteeism and productivity loss, and are estimated to exceed $20 billion per year in the USA including approximately $5 billion on sinus surgeries (Bhattacharyya N. Ann. Otol. Rhinol. Laryngol.2011; 120: 423–427.

[0003] In medical literature and practice, chronic rhinosinusitis is commonly divided into two subgroups: chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP). Chronic rhinosinusitis patients with and without nasal polyps suffer from chronic inflammation of the lining of the deep nasal passages and sinuses. Patients with chronic rhinosinusitis with nasal polyps also develop non-cancerous polyps on these chronically inflamed surfaces, typically originating in the deep crevices or sinus cavities on both sides of the nose. It is estimated that up to 10 million adults in the United States have chronic rhinosinusitis with nasal polyps ((Bhattacharyya N. Ann. Otol. Rhinol. Laryngol.2011; 120: 423–427). ^^Attorney Docket No. 10029-122WO1

[0004] Both subgroups of chronic rhinosinusitis also share the same four defining diagnostic symptoms: nasal congestion / obstruction; facial pain and pressure; rhinorrhea (runny nose) and postnasal drip; and loss of sense of smell and taste. Additional symptoms include headaches, chronic sleep problems, fatigue, frequent episodes of acute rhinosinusitis and mood disorders. There is evidence suggesting that the harm to a sufferer's quality of life from chronic rhinosinusitis, as measured in multiple domains, such as bodily pain, social functioning and mental health, is comparable to or worse than other serious diseases, including chronic obstructive pulmonary disease, congestive heart failure and angina. As a result, many patients eventually seek surgery for symptom relief.

[0005] Rhinosinusitis is considered chronic when it lasts at least three months. Chronic rhinosinusitis is different from the more common form of rhinosinusitis (called "acute rhinosinusitis" or just "sinusitis"), which is a temporary infection of the sinuses that often occurs following colds. The diagnosis requires objective evidence of mucosal inflammation. More precisely, it is a heterogeneous group of related disorders that share certain clinical and pathologic features. In the past, CRS lacked clear definition and was approached differently by various specialties. Chronic rhinosinusitis is a more persistent problem, which requires a specific treatment approach. It is sometimes overlooked by both patients and health care providers because the symptoms are sometimes low grade and chronic (Chronic rhinosinusitis without nasal polyposis: Management and prognosis – UpToDate).

[0006] HDCF104 is a PDE4 inhibitor (PDE4i) that could be used for treating patients with Cystic Fibrosis and Non-CF chronic rhinosinusitis. Intranasal delivery of HDCF104 is an approach for delivery of PDE4i to the nasal cavity where the benefits include lower risk of systemic side effects, lower dosing due to targeted delivery, circumventing first-pass metabolism, and larger surface area available for drug absorption. However, there are several challenges to delivering therapeutics to the nose such as the rapid mucociliary clearance, the low delivery volume (20-200 uL) due to nasal dripping and run-offs, which subsequently could impact drugs with low solubility, and enzymatic activity in the nose.

[0007] There remains a need for improved compositions and methods for delivering CFTR modulators to relevant tissues. There remains a need for improved compositions and methods for treating sinusitis and other respiratory conditions. There remains a need for improved compositions and methods for delivering therapeutics to the nasal cavity. There remains a need for improved compositions that provide rapid absorption of intranasally administered therapeutics. There remains a need for improved compositions and methods ^^Attorney Docket No. 10029-122WO1 providing delivering therapeutics such as HDCF104 and related compounds to relevant tissues. The compositions and methods disclosed herein address these and other needs. SUMMARY

[0008] Disclosed are compounds and compositions and methods of making and using thereof.

[0009] In one aspect disclosed are pharmaceutical compositions include. a) a compound of Formula (1):[Formula (1)], or a pharmaceutically acceptable salt thereof, wherein R1is alkyl, aryl or heterocyclyl, wherein R1is optionally substituted with one or more, the same or different, R10; R2is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R1is optionally substituted with one or more, the same or different, R10; R3and R4are each, individually and independently, hydrogen, alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R3and R4are optionally substituted with one or more, the same or different, R10; R10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, alkanoyl, benzoyl, carbocyclyl, aryl, or heterocyclyl, wherein R10is optionally substituted with one or more, the same or different, R11; and R11is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl- N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N- ^^Attorney Docket No. 10029-122WO1 dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N- diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl; b) a surfactant; c) cellulose, cellulose derivative, or a combination thereof, and d) water; wherein the composition comprises the compound of Formula 1 in a concentration from 0.05-5 mg / g, from 0.05-2.5 mg / g, from 0.05-1 mg / g, from 0.05-0.5 mg / g, from 0.1-0.5 mg / g, from 0.1-0.25 mg / g, from 0.25-0.5 mg / g, from 0.2-0.4 mg / g, or from 0.25-0.35 mg / g.

[0010] In certain aspects the compositions include polysorbate 80, microcrystalline cellulose, and carboxymethyl cellulose sodium. In further aspects the compositions also include benzalkonium chloride and sodium chloride.

[0011] In certain aspects the compositions are administered via a spray intranasally.

[0012] In one aspect the disclosed compositions can be used to treat rhinosinusitis, chronic obstructive pulmonary disease, nasal polyposis, bronchiectasis, Sjogren’s syndrome, asthma, chronic bronchitis, allergic bronchopulmonary aspergillosis, primarily ciliary dyskinesia, anosmia, xerostomia, xerophthalmia, lacrimal disorders or combination thereof. In an exemplary aspect, the compositions can be used to treat chronic rhinosinusitis.

[0013] In one aspect the compositions include 3-(2-bromo-5-methoxyphenyl)-6-isopropyl- 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine or a pharmaceutically acceptable salt thereof. In another aspect the compositions include 6-(3,4-dimethoxyphenyl)-3-ethyl-7H- [1,24]triazolo[3,4-b][1,3,4thiadiazine, or a pharmaceutically acceptable salt thereof.

[0014] Additional advantages of the disclosed subject matter will be set forth in part in the description that follows and the Figure, and in part will be obvious from the description or can be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. ^^Attorney Docket No. 10029-122WO1 BRIEF DESCRIPTION OF THE FIGURES

[0015] The accompanying figure, which is incorporated in and constitutes a part of this specification, illustrates several aspects described below.

[0016] Figure 1A is an anatomical depiction of the nose and nasal cavities.

[0017] Figure 1B depicts a mucosal lining.

[0018] Figure 2 depicts a determination of the EC50value of HDCF104 in RPMI2650 cells. Half maximal effective concentration (EC50) was calculated using Non-linear fit-[Agonist] vs response to find EC50.

[0019] Figure 3A depicts a particle size distribution of raw HDCF104.

[0020] Figure 3B depicts a particle size distribution of micronized HDCF104.

[0021] Figure 4 depicts the weight of wasted and collected shots reported as the average of three individual data sets. Criteria are set as 0.1 mg ± 15% (assumes 100 µL valve delivers a shot weight of 0.1 mg if density of formulation = 1 g / cm3).

[0022] Figure 5 depicts the spray content uniformity at the beginning, middle, and last portion of the composition reported as the average of three individual data sets.

[0023] Figure 6A depicts volume undersize parameters for AVICELTM.

[0024] Figure 6B depicts volume undersize parameters for Polysorbate 80.

[0025] Figure 7 depicts time-elapsed (time = 0, 1 min, 5 min, 60 min) photographs of an HDCF104 formulation.

[0026] Figure 8 depicts a total assay of an HDCF104 formulation after storage under ICH conditions (marker lines indicate ± 5% theoretical). Data represents mean ± STDev, n=3.

[0027] Figure 9A depicts a delivered dose of HDCF104 via VP7 pump at time zero. Marker lines indicate ± 15% target delivered dose. Data represents mean ± STDev, n=3.

[0028] Figure 9B depicts a delivered dose of HDCF104 via VP7 pump after three months of storage under refrigerated conditions. Marker lines indicate ± 15% target delivered dose. Data represents mean ± STDev, n=3.

[0029] Figure 9C depicts a delivered dose of HDCF104 via VP7 pump after three months of storage under ambient conditions. Marker lines indicate ± 15% target delivered dose. Data represents mean ± STDev, n=3.

[0030] Figure 9D depicts a delivered dose of HDCF104 via VP7 pump after three months of storage under accelerated stability testing conditions. Marker lines indicate ± 15% target delivered dose. Data represent mean ± STDev, n=3. ^^Attorney Docket No. 10029-122WO1

[0031] Figure 10A depicts RPMI2650 nasal epithelial integrity and permeability; measurement of the transepithelial electrical resistance (TEER) which is an indication of the tight junction formation of the nasal epithelial layer indicating nasal integrity.

[0032] Figure 10B depicts RPMI2650 nasal epithelial integrity and permeability; calculated apparent permeability (Papp) of the epithelial layer.

[0033] Figure 10C depicts RPMI2650 nasal epithelial integrity and permeability; transport study of HDCF104 through the RPMI2650 nasal epithelia cumulative mass (µg) of HDCF104 transported over 4 hours.

[0034] Figure 10D depicts RPMI2650 nasal epithelial integrity and permeability; Amount of HDCF104 detected on top of the cell (ON) and inside the cells (IN) after 4 hours. The ON between HDCF104 formulation and HDCF104 in propellant shows significant difference (p value = 0.000015). Statistical significance was calculated using multiple unpaired t tests with the two-stage step-up method of Benjamin, Krieger and Yekutieli Dunnett’s multiple comparisons post-test.^

[0035] Figure 11A depicts the dose-response of formulated HDCF104 in human bronchial epithelial cells on WT CFTR background. Representative tracing of transepithelial chloride transport measurement depicts dose-dependent CFTR activation in hBE cells carrying WT CFTR. Vehicle-treated samples demonstrate negligible CFTR activation.

[0036] Figure 11B depicts the dose-response of formulated HDCF104 in human bronchial epithelial cells on WT CFTR background. The dose-response curve shows formulated HDCF104 with a low micromolar EC50(3.57 ± 1.122 ^M with 95% CI (1.275 ^M to 5.870 ^M)). GraphPad Prism 10 software was utilized to calculate EC50. Data presented as the mean ± SEM. (n=4). DETAILED DESCRIPTION

[0037] Before the present methods and systems are disclosed and described, it is to be understood that the methods and systems are not limited to specific synthetic methods, specific components, or to particular compositions. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0038] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0039] Ranges may be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment ^^Attorney Docket No. 10029-122WO1 includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0040] “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0041] Throughout the description and claims of this specification, the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps. “Exemplary” means “an example of” and is not intended to convey an indication of a preferred or ideal embodiment. “Such as” is not used in a restrictive sense, but for explanatory purposes.

[0042] Disclosed are components that can be used to perform the disclosed methods and systems. These and other components are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these components are disclosed that while specific reference of each various individual and collective combinations and permutation of these may not be explicitly disclosed, each is specifically contemplated and described herein, for all methods and systems. This applies to all aspects of this application including, but not limited to, steps in disclosed methods. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods.

[0043] As used herein, the term “chronic” refers to the persistence of a condition or disease for 12 weeks or longer, with or without acute exacerbations.

[0044] As used herein, the term “chronic sinusitis,” “CS,” chronic rhinosinusitis “CRS,” and “chronic rhinosinusitis without nasal polyps” (CRSsNP) are used synonymously in the present disclosure and are generally used interchangeably in the field to emphasize the condition associated with an anatomic finding of chronic inflammation inside the sinuses (irrespective of nasal pathology), while the terms “nasal polyps” (NP) and “chronic rhinosinusitis with nasal polyps” (CRSwNP) are used synonymously and are intended to refer to the presence of polyps in the nasal cavities (irrespective of sinus pathology), recognizing ^^Attorney Docket No. 10029-122WO1 that these conditions can be overlapping, exist on a continuum, and can be accompanied by some degree of diffuse sino-nasal inflammation.

[0045] Compounds disclosed herein may be provided in the form of acceptable salts, for example pharmaceutically acceptable salts. Examples of such salts are acid addition salts formed with inorganic acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids and the like; salts formed with organic acids such as acetic, oxalic, tartaric, succinic, maleic, fumaric, gluconic, citric, malic, methanesulfonic, p-toluenesulfonic, napthalenesulfonic, and polygalacturonic acids, and the like; salts formed from elemental anions such as chloride, bromide, and iodide; salts formed from metal hydroxides, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, and magnesium hydroxide; salts formed from metal carbonates, for example, sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate; salts formed from metal bicarbonates, for example, sodium bicarbonate and potassium bicarbonate; salts formed from metal sulfates, for example, sodium sulfate and potassium sulfate; and salts formed from metal nitrates, for example, sodium nitrate and potassium nitrate.

[0046] As used herein, "alkyl" means a noncyclic straight chain or branched, unsaturated or saturated hydrocarbon such as those containing from 1 to 10 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n- septyl, n-octyl, n-nonyl, and the like; while saturated branched alkyls include isopropyl, sec- butyl, isobutyl, tert-butyl, isopentyl, and the like. Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl" or "alkynyl", respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3- dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1- pentynyl, 2-pentynyl, 3- methyl-1-butynyl, and the like.

[0047] Non-aromatic mono or polycyclic alkyls are referred to herein as "carbocycles," "carbocyclyl," or “cycloalkyl” groups. Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated carbocycles include cyclopentenyl and cyclohexenyl, and the like.

[0048] "Heterocarbocycles" or heterocarbocyclyl" groups are carbocycles which contain from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur which may be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen ^^Attorney Docket No. 10029-122WO1 heteroatom may be optionally quaternized. Heterocarbocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0049] "Aryl" means an aromatic carbocyclic monocyclic or polycyclic ring such as phenyl or naphthyl. Polycyclic ring systems may, but are not required to, contain one or more non- aromatic rings, as long as one of the rings is aromatic.

[0050] As used herein, "heterocycle" or "heterocyclyl" refers to mono- and polycyclic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom. The mono- and polycyclic ring systems may be aromatic, non-aromatic or mixtures of aromatic and non-aromatic rings. Heterocycle includes heterocarbocycles, heteroaryls, and the like.

[0051] As used herein, "heteroaryl" or “heteroaromatic” refers an aromatic heterocarbocycle having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and polycyclic ring systems. Polycyclic ring systems may, but are not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic. Representative heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. It is contemplated that the use of the term "heteroaryl" includes N-alkylated derivatives such as a 1-methylimidazol-5-yl substituent.

[0052] "Alkylthio" refers to an alkyl group as defined above attached through a sulfur bridge. An example of an alkylthio is methylthio, (i.e., -S-CH3).

[0053] "Alkoxy" refers to an alkyl group as defined above attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, s-butoxy, t-butoxy, n- pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, s-butoxy, t-butoxy.

[0054] "Alkylamino" refers an alkyl group as defined above attached through an amino bridge. An example of an alkylamino is methylamino, (i.e., -NH-CH3).

[0055] "Alkanoyl" refers to an alkyl as defined above attached through a carbonyl bridge (i.e., -(C=O)alkyl). ^^Attorney Docket No. 10029-122WO1

[0056] "Alkylsulfonyl" refers to an alkyl as defined above attached through a sulfonyl bridge (i.e., -S(=O)2alkyl) such as mesyl and the like, and "Arylsulfonyl" refers to an aryl attached through a sulfonyl bridge (i.e., - S(=O)2aryl).

[0057] "Alkylsulfinyl" refers to an alkyl as defined above with the indicated number of carbon atoms attached through a sulfinyl bridge (i.e., -S(=O)alkyl).

[0058] The terms "halogen" and "halo" refer to fluorine, chlorine, bromine, and iodine.

[0059] The term “sulfamoyl” refers to the amide of sulfonic acid (i.e., -S(=O)2NRR’).

[0060] As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this disclosure are those combinations that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40oC or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0061] As used herein, the term “derivative” refers to a structurally similar compound that retains sufficient functional attributes of the identified analogue. The derivative may be structurally similar because it is lacking one or more atoms, contains an enriched atomic isotope, substituted, a salt, in different hydration / oxidation states, or because one or more atoms within the molecule are switched, such as, but not limited to, replacing an oxygen atom with a sulfur atom or replacing an amino group with a hydroxy group. A derivative may be when two alkoxy groups are bound to the same atom or adjacent atoms, the two alkoxy groups form a ring together with the atom(s) to which they are bound. The derivative may be a prodrug. Derivatives may be prepared by any variety of synthetic methods or appropriate adaptations presented in synthetic or organic chemistry textbooks, such as those provide in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition (2007) Michael B. Smith or Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F. Tietze, hereby incorporated by reference.

[0062] The term "prodrug" refers to an agent that is converted into a biologically active form in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and ^^^Attorney Docket No. 10029-122WO1 metabolic hydrolysis. Typical prodrugs are pharmaceutically acceptable esters. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of an alcohol or acetamide, formamide, methanesulfonate, and benzamide derivatives of an amine functional group in the active compound and the like.

[0063] The term "substituted" refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are "substituents." The molecule may be multiply substituted. In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced. Example substituents within this context may include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, - NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb, - NRaSO2Rb, -C(=O)Ra, - C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, -SORa, -S(=O)2Ra, -OS(=O)2Ra and -S(=O)2ORa. Ra and Rb in this context may be the same or different and independently hydrogen, halogen hydroxy, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl.

[0064] When a range of values is listed, it is intended to encompass each value and sub- range within the range. For example, "C1-6alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0065] Affixing the suffix "-ene" to a group indicates the group is a polyvalent moiety, e.g., boned to two or more groups. Alkylene is the polyvalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl (each of which parent groups as defined herein).

[0066] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, and a mixture of isomers, such as a racemic ^^^Attorney Docket No. 10029-122WO1 or scalemic mixture. Unless stated to the contrary, a formula depicting one or more stereochemical features does not exclude the presence of other isomers.

[0067] Paranasal sinuses are four pairs of air-filled cavities connecting to the nasal passage. The paranasal sinuses are named after the cranial bones in which they are located: the frontal sinuses, the maxillary sinuses, the ethmoid sinuses, and the sphenoid sinuses (Figure 1A). A membrane lining the paranasal sinuses secretes mucus, which drains into the nasal passage through a small channel in each sinus. Healthy sinuses likely contain healthy commensal bacteria, and the nasal passage normally contains many bacteria that enter through the nostrils as a person breathes.

[0068] As shown in Figure 1B, several factors and processes are involved in maintaining healthy sinuses. The mucus secreted by the membrane lining must be fluid but sticky, to flow freely and absorb pollutants and entrap bacteria. It must also contain enough bacteria- fighting substances such as antibodies. Additionally, small hair-like projections called cilia, located in the nostril, must beat in unison to propel mucus toward the throat, to swallow or expel bacteria and other particles. Moreover, the mucous membranes themselves must be intact, and the sinus passages must be open to allow drainage and the circulation of air through the nasal passage. When one or more of these processes or factors are amiss, causing obstruction of the sinus passage, an infection called sinusitis develops.

[0069] Sinusitis is an inflammation of the mucous membrane lining one or more paranasal sinuses. Rhinitis is an inflammation of the mucous membrane lining the nasal passage. Rhinitis and sinusitis usually coexist and are concurrent in most individuals; thus, most guidelines and experts now have adopted the term rhinosinusitis.

[0070] Disclosed herein are pharmaceutical compositions including a compound of Formula (1):[Formula (1)], or a pharmaceutically acceptable salt thereof, wherein R1is alkyl, aryl or heterocyclyl, wherein R1is optionally substituted with one or more, the same or different, R10; ^^^Attorney Docket No. 10029-122WO1 R2is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R1is optionally substituted with one or more, the same or different, R10; R3and R4are each, individually and independently, hydrogen, alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R3and R4are optionally substituted with one or more, the same or different, R10; R10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, alkanoyl, benzoyl, carbocyclyl, aryl, or heterocyclyl, wherein R10is optionally substituted with one or more, the same or different, R11; and R11is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl- N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N- dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N- diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl.

[0071] In some implementations, R1is phenyl optionally substituted with one or more, the same or different, R10.

[0072] In some implementations, R2is alkyl, for example C1-6alkyl, optionally substituted with one or more, the same or different, R10.

[0073] In some implementations, R2is a branched alkyl of six or less carbons.

[0074] In some implementations, R1is phenyl optionally substituted with one or more, the same or different, R10and R2is alkyl optionally substituted with one or more, the same or different, R10. In certain implementations R2is an unsubstituted C1-6alkyl or C1-4alkyl.

[0075] In some implementations, R2is carbocyclyl for example C3-6carbocylyl, optionally substituted with one or more, the same or different, R10.

[0076] In some implementations, R2is a cyclopropyl or methylcyclopropyl.

[0077] In some implementations, R3and R4are hydrogen. ^^^Attorney Docket No. 10029-122WO1

[0078] In some implementations, R1is phenyl optionally substituted with one or more, the same or different, R10, and R3and R4are hydrogen.

[0079] In some implementations, R2is alkyl optionally substituted with one or more, the same or different, R10, and R3and R4are hydrogen.

[0080] In certain embodiments, R2is a branched alkyl of six or less carbons, and R3and R4are hydrogen.

[0081] In certain embodiments, R2is carbocyclyl, for example C3-6carbocylyl, optionally substituted with one or more, the same or different, R10, and R3and R4are hydrogen.

[0082] In certain embodiments, R2is a cyclopropyl or methylcyclopropyl, and R3and R4are hydrogen.

[0083] In certain embodiments, R1is phenyl optionally substituted with one or more, the same or different, R10, R2is alkyl optionally substituted with one or more, the same or different, R10, and R3and R4are hydrogen.

[0084] In certain embodiments, R1is phenyl optionally substituted with one or more, the same or different, R10, R2is a linear or branched alkyl of six or less carbons, and R3and R4are hydrogen.

[0085] In certain embodiments, R1is phenyl optionally substituted with one or more, the same or different, R10, R2is carbocyclyl, for example C3-6carbocylyl, optionally substituted with one or more, the same or different, R10, and R3and R4are hydrogen.

[0086] In certain embodiments, R1is phenyl optionally substituted with one or more, the same or different, R10, R2is a cyclopropyl or methylcyclopropyl, and R3and R4are hydrogen.

[0087] In certain implementations, one of R1and R2is phenyl substituted by one or more R10, and the other is C1-6alkyl, optionally substituted by one or more R10. In further implementations, one of R1and R2is phenyl substituted by one or more times by halogen, C1-3alkoxy, or combination thereof, and the other is unsubstituted C1-6alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0088] In certain embodiments, the composition includes the compound 3-(2,3- dichlorophenyl)-6-(tert-pentyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (HDCF 83) as the free base or a pharmaceutically acceptable salt thereof, 6-(tert-butyl)-3-(2,4- dichlorophenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (HDCF 89) as the free base or a pharmaceutically acceptable salt thereof, 3-(2-bromo-5-methoxyphenyl)-6-isopropyl-7H- [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (HDCF104) as the free base or a pharmaceutically acceptable salt thereof, 3-(2-bromo-5-chlorophenyl)-6-(tert-butyl)-7H-[1,2,4]triazolo[3,4- ^^^Attorney Docket No. 10029-122WO1 b][1,3,4]thiadiazine (HDCF 95)as the free base or a pharmaceutically acceptable salt thereof, or 6-(3,4-dimethoxyphenyl)-3-ethyl-7H-[1,24]triazolo[3,4-b][1,3,4thiadiazine (uHTS-159), a pharmaceutically acceptable salt thereof or free base.

[0089] In some implementations, the pharmaceutical composition includes a compound of Formula (1a) or Formula (1b):[Formula (1a)] [Formula (1b), or a pharmaceutically acceptable salt thereof, wherein: R1ais hydrogen, halogen, or alkyl, for example C1-6alkyl; R2ais hydrogen, halogen, or alkyl; for example C1-6alkyl; or R1aand R2aand the attached atom form a carbocyclic ring; R3ais hydrogen, halogen, or alkyl; for example C1-6alkyl; or R1a, R2a, and R3aand the attached atom form a carbocyclic ring, for example adamantanyl; R4ais hydrogen, halogen or alkoxy, for example C1-6alkoxy; R5ais hydrogen, halogen or alkoxy, for example C1-6alkoxy; R6ais hydrogen, halogen or alkoxy, for example C1-6alkoxy; and R7ais hydrogen, halogen or alkoxy, for example C1-6alkoxy.

[0090] In certain implementations R1ais methyl, and R2aand R3aare hydrogen. In some implementations R1aand R2aare methyl, and R3ais hydrogen.

[0091] In certain implementations of the compound of Formula (1a) R1aand R2aare methyl, and R3ais hydrogen. In certain implementations of the compound Formula (1b) R1ais methyl, and R2aand R3aare hydrogen.

[0092] In certain implementations two of R4a, R5a, R6a, and R7aare selected from halogen and alkoxy, for example C1-3alkoxy, and the other two of R4a, R5a, R6a, and R7aare hydrogen.

[0093] In certain implementations of the compound of Formula (1a) R4ais halogen, preferably Br, R7ais OC1-3alkyl, preferably OCH3, and R5aand R6aare each hydrogen. ^^^Attorney Docket No. 10029-122WO1

[0094] In certain implementations of the compound of Formula (1b) R5aand R6aare each OC1-3alkyl, preferably OCH3, and R4aand R7aare each hydrogen.

[0095] In some implementations, the composition includes the compound 3-(2-bromo-5- methoxyphenyl)-6-isopropyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine, or a pharmaceutically acceptable salt thereof. In the some implementations the composition includes the compound 3-(2-bromo-5-methoxyphenyl)-6-isopropyl-7H-[1,2,4]triazolo[3,4- b][1,3,4]thiadiazine as the free base. In some implementations the composition includes the compound 6-(3,4-dimethoxyphenyl)-3-ethyl-7H-[1,24]triazolo[3,4-b][1,3,4thiadiazine, or a pharmaceutically acceptable salt thereof. In some implementations the composition 6-(3,4- dimethoxyphenyl)-3-ethyl-7H-[1,24]triazolo[3,4-b][1,3,4thiadiazine free base.

[0096] In some implementations, the composition is formulated for intranasal administration.

[0097] In some implementations, the composition includes water. In some implementations concentration of the compound of Formula (1), Formula (1a), or Formula (1b) in the aqeuous composition is from 0.05-5 mg / g, from 0.05-2.5 mg / g, from 0.05-1 mg / g, from 0.05-0.5 mg / g, from 0.1-0.5 mg / g, from 0.1-0.25 mg / g, from 0.25-0.5 mg / g, from 0.2-0.4 mg / g, or from 0.25-0.35 mg / g. When the compound of Formula (1) or Formula (1a) is present as a pharmaceutically acceptable salt, the concentration of the compound is determined using the free base equivalent.

[0098] In some implementations, the composition includes water, the compound of Formula (1), Formula (1a), or Formula (1b), and no additional excipients. In other implementations, the composition includes water, the compound of Formula (1), Formula (1a), or Formula (1b), and one or more pharmaceutically acceptable excipients.

[0099] In some implementations, the composition includes water as the only solvent. In other implementations, the composition includes water, the compound of Formula (1), Formula (1a), or Formula (1b), and one or more additional solvents, for example, ethanol, glycerin, propylene glycol, or a combination thereof. In some implementations the composition can include the additional solvent(s) in an amount from 1-30 wt.%, from 1-25 wt.%, from 1-20 wt.%, from 1-15 wt.%, from 1-10 wt.%, from 1-5 wt.%, from 5-30 wt.%, from 10-30 wt.%, from 15-30 wt.%, from 20-30 wt.%, from 10-20 wt.%, or from 5-10 wt.%, relative to the total weight of the composition.

[0100] In some implementations, the composition can include one or more antioxidants, for example butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, methionine, sodium ascorbate, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, ^^^Attorney Docket No. 10029-122WO1 ascorbyl palmitate, thioglycerol, alpha tocopherol (vitamin E), cysteine hydrochloride, citric acid, sodium citrate, and combinations thereof. The antioxidant(s) can be present in a total concentration from 0.005-5 wt.%, from 0.005-2.5 wt.%, from 0.005-1 wt.%, from 0.005-0.5 wt.%, from 0.05-0.5 wt.%, from 0.05-1 wt.%, from 0.1-1 wt.%, from 0.5-2.5 wt.%, or from 1-2 wt.%, relative to the total weight of the composition.

[0101] In some implementations, the composition can include one or more preservatives, for example benzoyl alcohol, phenyl ethyl alcohol, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, sodium benzoate, chlorobutanol, thioglycerol, benzalkonium chloride, citric acid, ethylenediaminetetraacetic acid (EDTA), sodium citrate, propyl gallate, 8-hydroxyquinoline, boric acid, histidine, and combinations thereof. The preservative can be present in a total concentration from 0.005-5 wt.%, from 0.005-2.5 wt.%, from 0.005-1 wt.%, from 0.005-0.5 wt.%, from 0.05-0.5 wt.%, from 0.05-1 wt.%, from 0.1-1 wt.%, from 0.5-2.5 wt.%, or from 1-2 wt.%, relative to the total weight of the composition. In some implementations, the composition includes benzalkonium chloride in an amount from 0.005-1 wt.%, from 0.005-0.5 wt.%, from 0.05-0.5 wt.%, from 0.01-0.05 wt.%, from 0.01- 0.025 wt.%, or from 0.015-0.025 wt.%.

[0102] In some implementations, the composition can include polyvinylpyrrolidone, polyvinyl alcohol, or a combination thereof. In some implementations the composition can include polyvinylpyrrolidone, polyvinyl alcohol, or a combination thereof in an amount from 0.1-5 wt.%, from 0.1-0.5 wt.%, from 0.5-1 wt.%, from 1-2 wt.%, from 2-3 wt.%, from 3-4 wt.%, or from 4-5 wt.%, relative to the total weight of the composition.

[0103] In some implementations, the composition can include cellulose, a cellulose derivative, or a combination thereof. Exemplary cellulose derivatives include carboxymethyl cellulose sodium, hydroxypropyl methylcellulose (“HPMC”), methylcellulose, and hydroxyethyl cellulose. In some implementations, the cellulose and / or cellulose derivative can be present in a total concentration from 0.1-5 wt.%, from 0.1-0.5 wt.%, from 0.5-1 wt.%, from 1-2 wt.%, from 2-3 wt.%, from 3-4 wt.%, or from 4-5 wt.%. In some implementations, the composition includes cellulose, for example microcrystalline cellulose, in combination with carboxymethyl cellulose sodium, and is present in a combined concentration from 0.5-2.5 wt.%, from 0.5-2.0 wt.%, from 0.5-1.5 wt.%, from 0.75-1.25 wt.%, from 1-1.5 wt.%., from 1-1.25 wt.%, from 1-1.3 wt.%, or from 1.1-1.3 wt.%.

[0104] In some implementations, the composition can include a surfactant, for example, a positively charged oligosaccharide, cationic surfactant, anionic surfactant, amphoteric ^^^Attorney Docket No. 10029-122WO1 surfactant, non-ionic surfactants, or a combination thereof. In some implementations, the composition can include methyl chitosan, chitosan oligosaccharides, polysorbates, saponins, polyoxyethylene-9-lauryl ether, sodium lauryl sulfate, glyceryl oleate, dipalmitoyl phosphatidyl choline, soybean lecithin, or phosphatidylcholine. In some implementations, the composition can include a fatty acid such as caproic acid, caprylic acid, enanthic acid, pelargonic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, oleic acid, stearic acid, linolenic acid, arachidonic acid, combinations thereof, or a salt thereof. In some implementations the surfactant can be present in a concentration from 0.001-10 wt.%, from 0.001-1 wt.%, from 1-5 wt.%, from 5-10 wt.%, from 0.001-0.1 wt.%, from 0.001-0.01 wt.%, from 0.005-0.05 wt.%, from 0.01-0.1 wt.%, from 0.01-0.05 wt.%, or from 0.02-0.05 wt.%.

[0105] In some implementations, the composition includes a polysorbate surfactant. Polysorbate surfactants are polyoxyethylene (20) sorbitan mono fatty acid esters. Suitable fatty acid esters include laurate, palmitates, stearates, oleates, myristates, caprylates, and caprates. In some implementations, the surfactant is polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, or polyoxyethylene (20) sorbitan monooleate. Polyoxyethylene (20) sorbitan monooleate is designated polysorbate 80. In some implementations, the polysorbate surfactant, e.g., polysorbate 80, can be present at a concentration from 0.001-1 wt.%, from 0.001-0.1 wt.%, from 0.001-0.01 wt.%, from 0.005-0.05 wt.%, from 0.01-0.1 wt.%, from 0.01-0.05 wt.%, or from 0.02-0.05 wt.%.

[0106] In some implementations, the composition includes an isotonicity agent, for example sodium chloride, dextrose, glycerin, sucrose, urea, propylene glycol, boric acid, phenobarbital, zinc sulfate, magnesium sulfate, sodium sulfate, zinc chloride, calcium bromide, sodium phosphate, sodium citrate, sodium borate, and potassium borate. In some embodiments, the isotonicity agent is present in the composition in an amount from 0.1-5 wt.%, from 0.1-0.5 wt.%, from 0.5-1 wt.%, from 1-2 wt.%, from 2-3 wt.%, from 3-4 wt.%, or from 4-5 wt.% relative to the total weight of the composition. In some implementations the composition includes sodium chloride in an amount from 0.1-5 wt.%, from 0.1-0.5 wt.%, from 0.5-1.5 wt.%, from 0.5-1 wt.%, from 1-2 wt.%, from 2-3 wt.%, from 3-4 wt.%, or from 4-5 wt.% relative to the total weight of the composition.

[0107] In certain implementations, the composition can include one more additional excipients selected from benzethonium chloride, benzethonium bromide, cetylpyridium chloride, edetate disodium dihydrate, sodium desoxycholate, sodium deoxyglycolate, ^^^Attorney Docket No. 10029-122WO1 sodium glycocholate, sodium taurocholate, sodium deoxycholate sodium, glycodeoxycholate, sodium taurocholate, sodium hydroxybenzoyal amino caprylate, dodecyl dimethyl aminopropionate, an amino acid, for example L-lysine, glycerol oleate, glyceryl monostearate, citric acid, peppermint oil, cyclodextrins, methylated cyclodextrins, or a combination thereof. The additional excipient(s) can be present in an amount from 0.1- 10 wt.%, from 0.1-5 wt.%, from 0.1-2.5 wt.%, from 1-10 wt.%, from 1-5 wt.%, from 1-2.5 wt.%, from 2.5-10 wt.%, or from 5-10 wt.%., relative to the total weight of the composition.

[0108] The compositions of the present disclosure can be formulated with a variety of pH ranges. For example, the compositions can have a pH from 2.0-8.0, from 3.0-7.0, from 3.0- 6.5, from 3.5-6.5, from 4.5-6.5, from 5.0-6.5, from 5.5-6.5, from 6.0-6.5, from 3.0-6.0, from 3.0-6.0, from 3.5-6.0, from 4.5-6.0, from 5.0-6.0, from 5.5-6.0, from 3.0-5.5, from 3.5-5.5, from 4.0-5.5, from 4.5-5.5, or from 5.0-5.5. In an embodiment, the compositions of the present disclosure are at a pH from about 5.0 to about 6.0. In other embodiments, the pH of the composition is from about 7 to about 8. In further embodiments, the pH of the composition is from about 6 to about 7. pH levels are determined at 23 °C. As needed the pH can be controlled by inclusion of the appropriate amount of a suitable acid, base, or buffer system such as hydrochloric acid, citric acid, fumaric acid, lactic acid, malic acid, tartaric acid, succinic acid, sodium hydroxide, sodium citrate, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, sodium carbonate, ammonium carbonate, and combinations thereof.

[0109] In certain implementations, the composition is aqueous Composition 1 that includes:

[0110] In certain implementations Composition 1 includes a compound of Formula (1a). In some implementations Composition 1 includes 3-(2-bromo-5-methoxyphenyl)-6-isopropyl- 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine or a pharmaceutically acceptable salt thereof. In certain implementations Composition 1 includes 3-(2-bromo-5-methoxyphenyl)-6- isopropyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine free base. ^^^Attorney Docket No. 10029-122WO1

[0111] In certain implementations Composition 1 includes a compound of Formula (1b). In some implementations Composition 1 includes 6-(3,4-dimethoxyphenyl)-3-ethyl-7H- [1,24]triazolo[3,4-b][1,3,4thiadiazine, or a pharmaceutically acceptable salt thereof. In some implementations Composition 1 includes 6-(3,4-dimethoxyphenyl)-3-ethyl-7H- [1,24]triazolo[3,4-b][1,3,4thiadiazine free base.

[0112] In certain implementations, Composition 1 also includes sodium chloride, benzalkonium chloride, or a combination thereof.

[0113] In certain implementations of Composition 1 the cellulose and / or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose. In certain implementations of Composition 1 the polysorbate is polysorbate 80. In further implementations of Composition 1 the cellulose and / or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose and the polysorbate is polysorbate 80.

[0114] In certain implementations, the composition is aqueous Composition 2 that includes:

[0115] In certain implementations Composition 2 includes a compound of Formula (1a). In some implementations Composition 2 includes 3-(2-bromo-5-methoxyphenyl)-6-isopropyl- 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine or a pharmaceutically acceptable salt thereof. In certain implementations Composition 2 includes 3-(2-bromo-5-methoxyphenyl)-6- isopropyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine free base.

[0116] In certain implementations Composition 2 includes a compound of Formula (1b). In some implementations Composition 2 includes 6-(3,4-dimethoxyphenyl)-3-ethyl-7H- [1,24]triazolo[3,4-b][1,3,4thiadiazine, or a pharmaceutically acceptable salt thereof. In some implementations Composition 2 includes 6-(3,4-dimethoxyphenyl)-3-ethyl-7H- [1,24]triazolo[3,4-b][1,3,4thiadiazine free base.

[0117] In certain implementations, Composition 2 also includes sodium chloride and benzalkonium chloride. ^^^Attorney Docket No. 10029-122WO1

[0118] In certain implementations of Composition 2 the cellulose and / or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose. In certain implementations of Composition 2 the polysorbate is polysorbate 80. In further implementations of Composition 2 the cellulose and / or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose and the polysorbate is polysorbate 80.

[0119] In certain implementations, the composition is aqueous Composition 3 that includes:

[0120] In certain implementations, Composition 3 includes a compound of Formula (1a). In some implementations Composition 3 includes 3-(2-bromo-5-methoxyphenyl)-6- isopropyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine or a pharmaceutically acceptable salt thereof. In certain implementations, Composition 3 includes 3-(2-bromo-5- methoxyphenyl)-6-isopropyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine free base.

[0121] In certain implementations, Composition 3 includes a compound of Formula (1b). In some implementations, Composition 3 includes 6-(3,4-dimethoxyphenyl)-3-ethyl-7H- [1,24]triazolo[3,4-b][1,3,4thiadiazine, or a pharmaceutically acceptable salt thereof. In some implementations, Composition 3 includes 6-(3,4-dimethoxyphenyl)-3-ethyl-7H- [1,24]triazolo[3,4-b][1,3,4thiadiazine free base.

[0122] In certain implementations, Composition 3 also includes sodium chloride and benzalkonium chloride.

[0123] In certain implementations of Composition 3, the cellulose and / or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose. In certain implementations of Composition 3, the polysorbate is polysorbate 80. In further implementations of Composition 3, the cellulose and / or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose and the polysorbate is polysorbate 80.

[0124] In certain implementations, the composition is aqueous Composition 4 that includes:^^^Attorney Docket No. 10029-122WO1

[0125] In certain implementations Composition 4 includes a compound of Formula (1a). In some implementations Composition 4 includes 3-(2-bromo-5-methoxyphenyl)-6-isopropyl- 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine or a pharmaceutically acceptable salt thereof. In certain implementations Composition 4 includes 3-(2-bromo-5-methoxyphenyl)-6- isopropyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine free base.

[0126] In certain implementations Composition 4 includes a compound of Formula (1b). In some implementations Composition 4 includes 6-(3,4-dimethoxyphenyl)-3-ethyl-7H- [1,24]triazolo[3,4-b][1,3,4thiadiazine, or a pharmaceutically acceptable salt thereof. In some implementations Composition 4 includes 6-(3,4-dimethoxyphenyl)-3-ethyl-7H- [1,24]triazolo[3,4-b][1,3,4thiadiazine free base.

[0127] In certain implementations of Composition 4 the cellulose and / or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose. In certain implementations of Composition 4 the polysorbate is polysorbate 80. In further implementations of Composition 4 the cellulose and / or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose and the polysorbate is polysorbate 80.

[0128] In certain implementations, the composition is aqueous Composition 5 that includes:^^^Attorney Docket No. 10029-122WO1

[0129] In certain implementations Composition 5 includes a compound of Formula (1a). In some implementations Composition 5 includes 3-(2-bromo-5-methoxyphenyl)-6-isopropyl- 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine or a pharmaceutically acceptable salt thereof. In certain implementations Composition 5 includes 3-(2-bromo-5-methoxyphenyl)-6- isopropyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine free base.

[0130] In certain implementations Composition 5 includes a compound of Formula (1b). In some implementations Composition 5 includes 6-(3,4-dimethoxyphenyl)-3-ethyl-7H- [1,24]triazolo[3,4-b][1,3,4thiadiazine, or a pharmaceutically acceptable salt thereof. In some implementations Composition 5 includes 6-(3,4-dimethoxyphenyl)-3-ethyl-7H- [1,24]triazolo[3,4-b][1,3,4thiadiazine free base.

[0131] In certain implementations of Composition 5 the cellulose and / or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose. In certain implementations of Composition 5 the polysorbate is polysorbate 80. In further implementations of Composition 5 the cellulose and / or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose and the polysorbate is polysorbate 80.

[0132] In certain implementations, the composition is aqueous Composition 6 that includes:

[0133] In certain implementations, Composition 6 includes a compound of Formula (1a). In some implementations Composition 6 includes 3-(2-bromo-5-methoxyphenyl)-6- isopropyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine or a pharmaceutically acceptable salt thereof. In certain implementations, Composition 6 includes 3-(2-bromo-5- methoxyphenyl)-6-isopropyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine free base.

[0134] In certain implementations, Composition 6 includes a compound of Formula (1b). In some implementations, Composition 6 includes 6-(3,4-dimethoxyphenyl)-3-ethyl-7H- [1,24]triazolo[3,4-b][1,3,4thiadiazine, or a pharmaceutically acceptable salt thereof. In ^^^Attorney Docket No. 10029-122WO1 some implementations, Composition 6 includes 6-(3,4-dimethoxyphenyl)-3-ethyl-7H- [1,24]triazolo[3,4-b][1,3,4thiadiazine free base.

[0135] In certain implementations of Composition 6, the cellulose and / or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose. In certain implementations of Composition 6, the polysorbate is polysorbate 80. In further implementations of Composition 6, the cellulose and / or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose and the polysorbate is polysorbate 80.

[0136] In some implementations, the compound of Formula (1), Formula (1a), or Formula (1b), e.g., 3-(2-bromo-5-methoxyphenyl)-6-isopropyl-7H-[1,2,4]triazolo[3,4- b][1,3,4]thiadiazine or 6-(3,4-dimethoxyphenyl)-3-ethyl-7H-[1,24]triazolo[3,4- b][1,3,4thiadiazine, is present in the composition in micronized form. In certain implementations, the compound of Formula (1), Formula (1a), or Formula (1b) has a particle size Dv50 from 0.5-5 µm, from 0.5-3 µm, from 0.5-2.5 µm, from 1-2.5 µm, from 1- 2 µm, or from 1.5-2.5 µm. In certain implementations, the compound of Formula (1), Formula (1a), or Formula (1b) has a particle size Dv90 from 3-10 µm, from 3-8 µm, from 3- 6 µm, from 3-5 µm, or from 4-5 µm. In certain implementations, the compound of Formula (1), Formula (1a), or Formula (1b) has a particle size Dv10 from 0.05-1 µm, from 0.05-0.5 µm, from 0.05-0.25 µm, from 0.1-0.5 µm, from 0.2-0.4 µm, or from 0.25-0.35 µm. In some implementations the compound of Formula (1), Formula (1a), or Formula (1b) is 3-(2- bromo-5-methoxyphenyl)-6-isopropyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine or a pharmaceutically acceptable salt thereof. In certain implementations, the Compound of Formula (1) or (1a) is 3-(2-bromo-5-methoxyphenyl)-6-isopropyl-7H-[1,2,4]triazolo[3,4- b][1,3,4]thiadiazine free base. In some implementations, the compound of Formula (1), Formula (1a), or Formula (1b) is 6-(3,4-dimethoxyphenyl)-3-ethyl-7H-[1,24]triazolo[3,4- b][1,3,4thiadiazine or a pharmaceutically acceptable salt thereof. In certain implementations, the compound of Formula (1), Formula (1a), or Formula (1b) is 6-(3,4- dimethoxyphenyl)-3-ethyl-7H-[1,24]triazolo[3,4-b][1,3,4thiadiazine free base. As used herein, particle size distributions refer to the proportion of equivalent sphere diameters as determined by Malvern Mastersizer MS3000 with Aero S apparatus.

[0137] In certain implementations, the compositions disclosed herein provide enhanced storage stability, for instance as measured using accelerated stability test, including when compared to prior art compositions. ^^^Attorney Docket No. 10029-122WO1

[0138] In certain implementations, the compositions disclosed herein provide enhanced transport across certain membranes, including nasal epithelia and other tissue types found in the respiratory tract, including when compared to prior art compositions. In some implementations, the compositions provide an enhanced rate of transport of the active ingredient across the membranes. In some implementations the compositions provide a greater fraction of the delivered dose across the membrane. In some implementations, the compositions provide an enhanced rate of transport of the active ingredient across the membranes and a greater fraction of the delivered dose across the membrane.

[0139] In certain implementations, the compositions disclosed herein provided enhanced tissue distribution, for instance providing the active ingredient selectively to the upper respiratory tract, including when compared to prior art compositions.

[0140] In certain implementations, the compositions disclosed herein provide increased mucosal penetration and residence time for the active ingredient relative to the unformulated versions of the active ingredient, e.g., HDCF104.

[0141] The compositions disclosed herein may be intranasally administered to a patient in need thereof using a suitable spray device. Nasal spray devices known in the art, such as a “ready-to-use” device, wherein minimal or no manipulations are required to use the device and administer the composition into a nostril. The device can comprise a reservoir and means for expelling a portion of the composition in the form of a spray, where a bulk quantity of the composition is contained within the reservoir. In an embodiment, the device, which can be suitable for expelling a single or multiple doses, can include a metering pump, which can be finger or hand-actuated. It may be designed to administer the intended dose with multiple sprays, e.g., two sprays, e.g., one spray in each nostril, or as a single spray, e.g., in one nostril, or to vary the dose in accordance with the body weight or maturity of the patient.

[0142] In some implementations are provided nasal drug delivery devices including a pharmaceutical composition or formulation described herein. The benefits of nasal delivery include needle-free, drug delivery, especially when rapid absorption and effect at the target tissue site are desired. In addition, nasal delivery may help address issues related to poor bioavailability, slow absorption, drug degradation, and adverse events (AEs) in the gastrointestinal tract and avoids the first-pass metabolism in the liver.

[0143] The liquid nasal formulations described herein may be aqueous solutions, suspensions or emulsions. In certain delivery systems, antimicrobial preservatives may be included to maintain microbiological stability. ^^^Attorney Docket No. 10029-122WO1

[0144] Earlier approaches to nasal drug delivery include irrigation and nasal drops. Nasal irrigation is primarily used to deliver saline solutions to remove debris, sources of inflammation and to improve mucociliary clearance. Nasal drops are often used to deliver systemically acting agents. Neither nasal irrigation nor nasal drops are precise and often require head and body maneuvering to assure delivery to the olfactory region. The lack of dose precision tends to limit these delivery options as they may complicate regulatory approval and patient adherence. In some implementations, the nasal formulations disclosed herein can be delivered by nasal irrigation. In some implementations, the nasal formulations disclosed herein can be delivered by nasal drops.

[0145] Aqueous, metered nasal spray pumps were developed to overcome some of the dosing limitations of nasal irrigation and nasal drops. Metered or mechanical spray pumps are the most used nasal delivery systems, and many off-the-shelf options and bespoke options are available. Nasal spray drug products contain therapeutically active ingredients (drug substances) dissolved or suspended in solutions or mixtures of excipients (e.g., preservatives, viscosity modifiers, emulsifiers, buffering agents) in non-pressurized dispensers that deliver a spray containing a metered dose of the active ingredient. The dose can be metered by the spray pump or could have been pre-metered during manufacture. A nasal spray unit can be designed for unit dosing or can discharge up to several hundred metered sprays of a formulation containing the drug substance. Nasal sprays are applied to the nasal cavity for local and / or systemic effects. The formulation and the container closure system (container, closure, pump, and any protective packaging) collectively constitute the drug product. Current container closure system designs for inhalation spray drug products include both pre-metered and device-metered presentations using mechanical or power assistance and / or energy from patient inspiration for production of the spray plume. Pre- metered presentations contain previously measured doses or a dose fraction in some type of units (e.g., single or multiple blisters or other cavities) that are subsequently inserted into the device during manufacture or by the patient before use. In some implementations, the nasal formulations described herein are delivered by pre-metered device unit. Typical device-metered spray pumps have a reservoir containing formulation sufficient for multiple doses that are delivered as metered sprays by the device itself when activated by the patient. In some implementations, the nasal formulations described herein are delivered by a device- metered nasal spray pump. In some implementations, the device-metered spray pump replaces the emitted liquid formulation with air. In some implementations, the formulations include a preservative. In some implementations, the device-metered spray pump uses a ^^^Attorney Docket No. 10029-122WO1 collapsible bag, a movable piston, or a compressed gas to compensate for the emitted liquid volume. In some implementations, the device-metered spray pump replaces the emitted liquid nasal formulation with air filtered through an aseptic air filter. In some implementations, the device-metered spray pump has a ball valve at the tip to prevent contamination of the liquid inside the applicator tip.

[0146] In some implementations, device-metered spray pumps deliver multiple doses. In some implementations, device-metered spray pumps require priming and some degree of overfill to maintain dose conformity for the labeled number of doses. In some implementations, the device-metered spray pump delivers two doses. In some implementations, the device-metered spray pump delivers one dose.

[0147] The metered spray pumps typically deliver 25-200 µl per spray. In some implementations, 25 µl of the nasal formulation described herein is delivered by a device- metered spray pump. In some implementations, 50 µl of the nasal formulation described herein is delivered by a device-metered spray pump. In some implementations, 75 µl of the nasal formulation described herein is delivered by a device-metered spray pump. In some implementations, 100 µl of the nasal formulation described herein is delivered by a device- metered spray pump. In some implementations, 125 µl of the nasal formulation described herein is delivered by a device-metered spray pump. In some implementations, 150 µl of the nasal formulation described herein is delivered by a device-metered spray pump. In some implementations, 175 µl of the nasal formulation described herein is delivered by a device- metered spray pump. In some implementations, 200 µl of the nasal formulation described herein is delivered by a device-metered spray pump.

[0148] In some implementations, the spray device administers a volume of the composition that is from about 25-500 µL, from about 50-500 µL, from about 100-500 µL, from about 200-500 µL, from about 300-500 µL, from about 400-500 µL, from about 25-400 µL, from about 50-400 µL, from about 100-400 µL, from about 200-400 µL, from about 300-400 µL, from about 25-300 µL, from about 50-300 µL, from about 100-300 µL, from about 200-300 µL, from about 25-200 µL, from about 50-200 µL, from about 100-200 µL, from about 25- 100 µL, from about 50-100 µL, or from about 25-50 µL.

[0149] In some implementations, the spray device delivers from 10-50 µg of the compound of Formula (1), Formula (1a), or Formula (1b) per individual spray. In some implementation, the spray device delivers from 20-40 µg or from 25-35 µg of the compound of Formula (1), Formula (1a), or Formula (1b) per individual spray. In some implementations, the compound of Formula (1), Formula (1a), or Formula (1b) is 3-(2- ^^^Attorney Docket No. 10029-122WO1 bromo-5-methoxyphenyl)-6-isopropyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine or a pharmaceutically acceptable salt thereof. In certain implementations, the Compound of Formula (1) or (1a) is 3-(2-bromo-5-methoxyphenyl)-6-isopropyl-7H-[1,2,4]triazolo[3,4- b][1,3,4]thiadiazine free base. In some implementations, the Compound of Formula (1), Formula (1a), or Formula (1b) is 6-(3,4-dimethoxyphenyl)-3-ethyl-7H-[1,24]triazolo[3,4- b][1,3,4thiadiazine or a pharmaceutically acceptable salt thereof. In certain implementations, the Compound of Formula (1), Formula (1a), or Formula (1b) is 6-(3,4- dimethoxyphenyl)-3-ethyl-7H-[1,24]triazolo[3,4-b][1,3,4thiadiazine free base.

[0150] Non-limiting examples of device metered spray pumps include the VP3 Multi-Dose Spray Pump (Aptar), the VP6 Multi-dose Spray Pump (Aptar), the VP7 Multi-Dose Spray Pump (Aptar), the APF Futurity Nasal Spray Pump (Aptar), the CPS Multidose System (Aptar), the Advaspray Unidose system (Aptar), the Unidose Liquid Spray System (Aptar), the Bag-on-Valve Multidose System (Aptar), the APF Advanced Preservative Free System (Aptar), the Bidose Liquid Nasal Spray System (Aptar), the E-Lockout Multidose System (Aptar), NasaDose Unit Dose device (Bespak), the Exhalation Delivery Device (Optinose) and Accuspray (Becton Dickinson Technologies).

[0151] In some implementations, the nasal formulation described herein is delivered in a liquid, nebulized, or aerosolized form. In some implementations, the nasal formulation described herein is delivered by a powered nebulizer. Powered nebulizers use compressed gases or ultrasonic or mechanical power to break up nasal formulations into small aerosol droplets that can be directly inhaled into the mouth or nose. In some implementations, the nasal formulation described herein is delivered by an atomizer. Non-limiting examples of nebulizers include Slow Spray HFA (3M), VibrENT (PARI Pharma GmbH), and the Aeroneb Solo (Aerogen).

[0152] In some implementations, the systems are terminally sterilized. Products may be filled and sealed in a controlled environment to minimize the microbial and particulate content of the in-process product and to help ensure that the subsequent sterilization process is successful. In some implementations, the product in its final container is then subjected to a sterilization process such as heat or irradiation. In an aseptic process, the drug product, container, and closure may be first subjected to sterilization methods separately, as appropriate, and then brought together.

[0153] Also disclosed herein are methods of treating respiratory diseases and conditions in a subject in need thereof by administering the disclosed compositions to the subject. In certain implementations, the composition is administered to the subject intranasally. In ^^^Attorney Docket No. 10029-122WO1 some implementations the subject is a pediatric subject, i.e., a human less than 18 years old. In some implementations the subject is an adult aged from 18-65 years. In some implementations the subject is greater than 65 years old. In some implementations, the subject has CFTR deficiency. In some implementations the subject has the mutated CFTR. In other implementations the subject does not have mutated CFTR. In some implementations, the subject is diagnosed with cystic fibrosis. In other implementations, the subject is not diagnosed with cystic fibrosis.

[0154] In some implementations, the respiratory disease or disorder includes rhinosinusitis, chronic obstructive pulmonary disease, cystic fibrosis, or bronchiectasis. In some implementations, the respiratory disease or disorder includes rhinosinusitis, chronic obstructive pulmonary disease, nasal polyposis, primary ciliary dyskinesia bronchiectasis, Sjogren’s syndrome, asthma, chronic bronchitis, allergic bronchopulmonary aspergillosis, primarily ciliary dyskinesia, anosmia, xerostomia, xerophthalmia, lacrimal disorders or combination thereof. In certain implementations, the compositions can be used to induce salivation or to induce tearing.

[0155] In certain implementations, the respiratory disease or disorder is rhinosinusitis. In certain implementations, the respiratory disease or disorder is chronic rhinosinusitis. In certain implementations, the respiratory disease or disorder is rhinosinusitis accompanied by nasal polyps.

[0156] In some implementations, a subject having chronic rhinosinusitis is identified and treated by administration to the subject of an effective amount of the compositions described herein. The subject having chronic rhinosinusitis can be identified by one of skill in the art based on known methods, e.g., based on detection of the presence of symptoms, by endoscopy, or by computed tomography, or using a method described herein, e.g., detection of CST1 / 2, PRDX5 (Peroxiredoxin-5); and / or GP6 (Platelet glycoprotein VI), e.g., in mucus derived exosomes, (whole) nasal mucus, or nasal biopsy tissue. See, e.g., McClay et al., Nasal Polyps, emedicine.medscape.com / article / 994274-overview (Dec.14, 2017); Newton and Ah-See, Ther Clin Risk Manag.2008 April; 4(2): 507-512, the contents of which are incorporated herein by reference. The efficacy of the treatment may be monitored by methods known in the art, e.g., by monitoring symptoms, by endoscopy or computed tomography. Improvements of the subject include a better symptom score, e.g., a better SNOT-22 or VAS score; a reduction in inflammation or nasal polyp burden as revealed by endoscopy, e.g. a better Lund-Kennedy score; or a reduction in mucosal thickening or sinus opacification as revealed by computed tomography (CT), e.g. a better ^^^Attorney Docket No. 10029-122WO1 Lund-Mackay score. The 22-item Sinonasal Outcomes Test (SNOT-22) is a questionnaire encompassing 22 major symptoms on rhinosinusitis and nasal polyps and serves as a valuable tool to measure the severity of a subject's symptoms and their impact on health- related quality of life (Quintanilla-Dieck, et al., International Forum of Allergy & Rhinology 2012; 2(6):437-443), the contents of which are incorporated herein by reference. The SNOT-22 assessed 12 nasal- and sinus-related symptoms (nasal blockage, loss of sense of taste and smell; need to blow nose, sneezing, runny nose, cough, postnasal discharge, thick nasal discharge, ear fullness, dizziness, ear pain, and facial pain / pressure) and 10 psychological and behavioral symptoms (difficulty falling asleep, waking up at night, lack of a good night's sleep, waking up tired, fatigue, reduced productivity, reduced concentration, frustrated / restless / irritable, sad, and embarrassed) with participants scoring each symptom on a scale of 0 (absent) to 5 (severe) on average for the last week, for a total score range of 0 to 100. The SNOT-22 score is the mean for the 22 scores (Piccirillo et al., Otolaryngol Head Neck Surg 2002; 126:41-47), the contents of which are incorporated herein by reference. The 10-symptom visual analog (VAS) scale is a questionnaire based on the major and minor symptom diagnostic criteria for CRS as described by the American Academy of Otolaryngology—Head and Neck Surgery TFR. The VAS assessed subject- reported severity of each of the following symptoms on average experienced during the prior week: nasal drainage of pus, nasal obstruction / congestion, impaired sense of smell, facial pressure / pain, headache, bad breath, weakness / fatigue, dental pain, ear fullness / pain, and cough (Ryan, et al., Laryngoscope 2011; 121:674-678), the contents of which are incorporated herein by reference. The Lund-Kennedy endoscopy scoring system quantifies the pathologic states of the nose and paranasal sinuses as assessed by nasal endoscopy, focusing on the presence of polyps, discharge, edema, scarring or adhesions, and crusting. The Lund Mackay CT scoring system is the most widely used CT grading system for chronic rhinosinusitis. This scoring system consists of a scale of 0-2 dependent on the absence (0), partial (1) or complete (2) opacification of the sinus system and the osteomeatal complex as assessed by CT imaging (Hopkins et al., Otolaryngology—Head and Neck Surgery 2007; 137:555-561), the contents of which are incorporated herein by reference.

[0157] Also disclosed herein are methods of treating rhinosinusitis in a patient in need thereof by administering to the patient the disclosed compositions, wherein the method provides clinical improvement of symptoms as measured by one or more change from baseline surveys. ^^^Attorney Docket No. 10029-122WO1

[0158] In some implementations, the disclosed compositions can be administered to a patient to produce a change from baseline (CFBL) in the 7-day average using the composite score of 3 cardinal symptoms (3CS) in participants without nasal polyps. The 3CS are nasal blockage / obstruction / congestion, anterior / posterior nasal discharge, and facial pain / pressure. Each symptom is rated on a 4-point (0-3) scale where 0=absent symptoms and 3=severe symptoms. The composite score of 3CS is the sum of the three cardinal symptom scores. In some implementations, administration of the disclosed compositions provides a reduction in 3CS score in a patient by at least 1, at least 2, at least 3, or 4 composite score points.

[0159] In some implementations, the disclosed compositions can be administered to a patient to produce a change from baseline in Chronic Sinusitis Symptom Scores at time intervals (7-day, Week 4, Week 24, etc.) - Participants score their CS symptoms on a 4- point scale as follows: 0 = absent symptoms (no sign / symptom evident), 1 = mild symptoms (sign / symptom present but minimal awareness; easily tolerated), 2 = moderate symptoms (definite awareness of sign / symptom that is bothersome but tolerable), 3 = severe symptoms (sign / symptom that is hard to tolerate; causes interference with activities of daily living and / or sleeping). The scores are summed and averaged over the proceeding 7 days; higher scores indicate higher severity of symptoms of CS. In some implementations, administration of the disclosed compositions provides a score reduction in a patient by at least 1, at least 2, at least 3, or 4 points, after 7 days. In some implementations, administration of the disclosed compositions provides a score reduction in a patient by at least 1, at least 2, at least 3, or 4 points, after 4 weeks. In some implementations, administration of the disclosed compositions provides a score reduction in a patient by at least 1, at least 2, at least 3, or 4 points, after 24 weeks.

[0160] In some implementations, the disclosed compositions can be administered to a patient to produce a change from baseline to week 4 in each of the 4 Individual Cardinal Chronic Rhinosinusitis (CRS) Symptoms (AM, Instantaneous). The 4 individual CRS symptoms are: congestion, facial pain or pressure sensation, nasal discharge (anterior and / or posterior), and sense of smell. The range of scores for each nasal symptom isnone, 1 = mild, 2 = moderate, 3 = severe. The scores at baseline and week 4 are calculated by averaging the score reported for the individual symptom over 7 days prior to the timepoint. The value provided in the results is calculated by subtracting the score at week 4 from the score at baseline; therefore, scores reported here can range from -3 to 3. In some ^^^Attorney Docket No. 10029-122WO1 implementations, administration of the disclosed compositions provides a score reduction in a patient by at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, or 7 points.

[0161] In some implementations, the disclosed compositions can be administered to a patient to produce a change from baseline in the 22-item Sino-Nasal Outcome Test (SNOT- 22) total score at week 24 - The SNOT-22 questionnaire is a 22-item disease-specific quality of life instrument. Each symptom is scored on a 6-point scale where 0 = no problem and 5 = problem as bad as it can be. The total SNOT-22 score is the sum of the 22 items and can range from 0 to 110 with higher scores indicating worse symptoms. In some implementations, administration of the disclosed compositions provides a reduction in a patient by at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 score points.

[0162] In some implementations, the disclosed compositions can be administered to a patient to produce a change from baseline as measured by a composite score for each symptom of nasal congestion, facial pain or pressure sensation, and nasal discharge (anterior and / or posterior) at the end of week 4 - Change from baseline to the end of Week 4 in average total instantaneous AM scores (evaluation of symptom severity immediately preceding the time of scoring) for each symptom: nasal congestion, nasal discharge (anterior and / or posterior), facial pain / pressure sensation. Baseline scores are the averaged total instantaneous AM scores over the last 7 days of the single blind run-in period, and the end of week 4, scores are averaged over the 7 days from the subject diary. The range of scores for each nasal symptom is 0= none, 1 = mild, 2 = moderate, 3 = severe. Composite score is a sum of the 3 symptom scores and will range from 0 to 9. In some implementations, administration of the disclosed compositions provides a reduction in in a patient by at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or 10 score points.

[0163] In some implementations, the compositions can be provided to reduce sinus opacification in a patient. Sinus opacification refers to a clouding or lightening of the paranasal sinuses, which are the hollow spaces in the bones of the head and face that surround the nasal cavity. Sinus opacification can be diagnosed using a computed tomography (CT) scan or magnetic resonance imaging (MRI). These imaging tests can show the size, shape, and extent of the opacification. Sinus opacification can be assessed in the 3-D volumetric CT score at week 20. The percent opacification of the bilateral anterior and posterior ethmoids will be assessed by 3-D volumetric CT analysis at baseline and week 20. Each sinus is assessed using the Bilateral Zinreich Score; i.e., assigned a score based on ^^^Attorney Docket No. 10029-122WO1 the percentage of opacification as follows: 0 = 0%, 1 = 1% to 25%, 2 = 26% to 50%, 3 = 51% to 75%, 4 = 76 % to 99%, 5 = 100% or completely occluded. Each sinus pair has a bilateral score in the range of 0 to 10. Higher scores indicate higher severity of sinus opacification. In some implementations, administration of the disclosed compositions provides a reduction in the Zinreich score of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or 10 points.

[0164] In some implementations the disclosed compositions are administered to produce a change in the Week 24 / Early Termination (ET) in the Average Percent of the Volume Opacified (APOV) in the ethmoid and maxillary sinuses. Change from baseline to Week 24 / ET in the average percent of ethmoid and maxillary sinus volume opacified as measured by CT. Percent volume opacified can range from 0% to 100%. The outcome measure is the percentage change from percent opacification at baseline to percent opacification at Week 24; therefore, change in opacification volume can range from -100% to 100%. For example, if baseline opacification was 68.22% and Week 24 opacification was 66.11%, then the change would be reported as -2.11%. In some implementations, administration of the disclosed compositions provides a reduction of at least 1%, at least 2%, at least 5%, at least 10%, or at least 20%.

[0165] In some implementations, the disclosed compositions are administered to produce a change from baseline to week 24 / ET in the average percent of sinus volume occupied by disease in the worst maxillary sinus, as measured by CT scan assessment. The percentage volume opacified of the worst maxillary sinus can range from 0% to 100%. The outcome measure is the percentage change from percent opacification of the worst maxillary sinus at baseline to the percent opacification of the same maxillary sinus at Week 24; therefore, change in opacification volume can range from -100% to 100%. In some implementations, administration of the disclosed compositions provides a reduction of at least 1%, at least 2%, at least 5%, at least 10%, or at least 20%.

[0166] In some implementations, the disclosed compositions are administered to produce a change from baseline to week 24 / ET in the Lund-Mackay Staging System Total Score - Lund-Mackay Staging System: Lund-Mackay (LM) system (Lund and Mackay, 1993) assigns to each of 10 sinus cavities (left and right maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal) a score of 0 (no opacification), 1 (partial opacification), or 2 (total opacification), plus a 0-2 score for each of the left and right ostiomeatal complex (OMC). The total LM score for a CT scan ranges from 0-24. In some implementations, ^^^Attorney Docket No. 10029-122WO1 administration of the disclosed compositions provides a reduced score in in a patient by at least 5, at least 10, at least 15, or at least 20 points.

[0167] In some implementations, the disclosed compositions can be administered to a patient to increase the time to first acute exacerbation of chronic sinusitis relative to patients not receiving the compositions. An exacerbation of chronic sinusitis is defined as a worsening of symptoms that require escalation of treatment. In some implementations, the disclosed compositions can be administered to a patient to reduce the number and severity of acute exacerbations of chronic sinusitis.

[0168] In some implementations, the disclosed compositions can be administered to a patient to produce a change from baseline as measured by the Pittsburgh Sleep Quality Index (PSQI) - The PSQI is a validated, self-rated questionnaire which assesses sleep quality and disturbances over a 1-month time interval. Nineteen individual items generate 7 "component" scores (each ranging between 0 and 3): subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of scores for these 7 components yields 1 global score ranging between 0 and 21. Higher values represent a worse outcome. In some implementations, administration of the disclosed compositions provides a reduction in in a patient by at least 2, at least 4, at least 6, at least 8, at least 10, at least 12, at least 14, at least 16, at least 18, or at least 20 points.

[0169] In some implementations, the disclosed compositions are administered to produce a change in overall health from baseline to week 4 and week 24 / ET as measured by the percent of subjects improved as indicated by the Patient Global Impression of Change (PGIC). Global impression of change will be assessed using a subject-completed PGIC scale range: 1 - Very much improved, 2 - Much improved, 3 - Minimally improved, 4 - No change, 5 - Minimally worse, 6 - Much worse, 7. In some implementations, administration of the disclosed compositions provides a patient score of 3 or less, 2 or less, or 1. -

[0170] In some implementations, the disclosed compositions are administered to produce a change in baseline to week 24 / ET as measured by the Short-Form 36 Health Survey, Version 2 (SF-36v2) - The SF-36v2 is a multipurpose, 36-item subject-completed validated questionnaire that measures 8 domains of health: physical functioning, role limitations due to physical health (RP), bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. The SF-36v2 survey with a 4-week recall will be used. It yields scale scores for each of these 8 health domains, each of which is scored from 0 to 100. Higher scores indicate better health status, with 100 ^^^Attorney Docket No. 10029-122WO1 representing the highest level of functioning possible. In some implementations, administration of the disclosed compositions provides an increased score in in a patient by at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or 100 points.

[0171] In some implementations, the disclosed compositions are administered to produce a change in the 36-Item Short Form Health Survey Version 2 (SF-36v2) Mental Component Score (MCS). Change from baseline to Week 24 / ET on the MCS of the 36-Item Short Form Health Survey version 2 (SF-36v2). The SF-36v2 is a multipurpose, scaled, 36-item, subject-completed validated questionnaire. The scale range is from 0-100. A lower score means more disability and a higher score means less disability. Result values are calculated by subtracting the score reported at week 24 from the score reported at baseline. In some implementations, administration of the disclosed compositions provides an increased score in a patient by at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or 100 score points.

[0172] In some implementations, the disclosed compositions are administered to produce a change in olfactory impairment from baseline to week 24 / ET as measured by the Smell Identification Test (SIT)™. The SIT is a test comprised of 4 booklets each containing 10 microencapsulated (scratch and sniff) odors. Forced choice response alternatives accompany each test item. Each correct response is assigned a score of 1 and incorrect responses are assigned a score of 0. The total score is calculated by summing the scores of each individual odor for a total possible score ranging from 0-40. The higher the score, the better the individual's sense of smell. The test provides an absolute indication of smell loss (anosmia; mild, moderate or severe hyposmia) as well as an index to detect malingering. In some implementations, administration of the disclosed compositions provides an increased score in in a patient by at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, or 40 points.

[0173] In certain implementations, the disclosed compositions may be administered to the subject once a day or twice a day. In some implementations the disclosed compositions are administered more than twice a day, e.g., 3x, 4x, or 5x. In certain implementations, the composition is administered intranasally to the subject once a day, wherein the subject receives a single spray to one nostril, or a single spray to each nostril, delivered at approximately the same time. In certain implementations, the composition is administered to the subject twice a day, wherein the first administration is a single spray to one nostril, and the second administration is a single spray to the other nostril administered a later time ^^^Attorney Docket No. 10029-122WO1 in the day. In certain implementations, the composition is administered to the subject twice a day, wherein the first administration and second administration are both a single spray to each nostril (i.e., four sprays per day).

[0174] In certain implementations, the subject has previously received one or more different therapeutics for the treatment of the respiratory disease or disorder, prior to being administered the compositions disclosed herein.

[0175] In certain implementations the subject is administered one or more additional therapeutic agents along with the disclosed compositions. In certain implementations, the subject is administered a bronchodilator, corticosteroid, PDE4 inhibitor, CFTR activator antimuscarinic, cyclic AMP activator, cromolyn, antibiotic, or a combination thereof.

[0176] In some implementations, the subject is administered a ^-2 agonist in combination with the disclosed compositions. In some implementations, the ^-2 agonist includes salbutamol, salmeterol, formoterol and vilanterol or an anticholinergic, such as ipratropium, tiotropium, aclidinium, or glycopyrronium, or an antimuscarinic such as atropine or scopolamine.

[0177] In some implementations, the subject is administered a mucolytic agent in combination with the disclosed compositions. In certain implementations, the mucolytic is acetylcysteine, also known as N-acetylcysteine (NAC), this drug is available under the brand names Mucomyst and Acys-5, this drug is delivered by a nebulizer; carbocisteine, available under the brand name Availnex, this drug is available as a tablet, chewable tablet, and inhaler; erdosteine, available under the brand name Ectrin, this drug is available as a capsule, tablet, granules, and powder; dornase alfa, available under the brand name Pulmozyme, this drug is delivered by nebulizer; and ambroxol, available under the brand names Mucosolvan, Lasolvan or Mucoangin.

[0178] In some implementations the subject is administered a PDE4 inhibitor such as apremilast, crisaborole, or roflumilast agonist in combination with the disclosed compositions. In some implementations the PDE4 inhibitor is ibudilast (MN-166, MediciNova), BI 1015550 (Boehringer Ingelheim), tanimilast (CH-6001, Chiesi Pharmaceuticals), GSK256066 (GlaxoSmithKline), cilomilast (GlaxoSmithKline), oglemilast (Glenmark Pharmaceuticals), tetomilast (Otsuka) or ensifentrine (Ohtuvayre, Verona Pharmaceuticals).

[0179] In some implementations, the subject is administered a CFTR activator agonist in combination with the disclosed compositions. In some implementations, the subject is administered the disclosed compositions in combination with tezacaftor, ivacaftor, ^^^Attorney Docket No. 10029-122WO1 elexacaftor, vanzacaftor, deutivacaftor, lumacaftor, or a combination thereof. In some implementations, the subject is administered the disclosed compositions in combination with tezacaftor with ivacaftor. In some implementations, the subject is administered the disclosed compositions in combination with tezacaftor with elexacaftor and ivacaftor. In some implementations, the subject is administered the disclosed compositions in combination with tezacaftor with vanzacaftor and deutivacaftor.

[0180] In some implementations, the subject is administered a cyclic AMP activator (for example forskolin, H89, KT-5720, and dibutyryl-cAMP) in combination with the disclosed compositions.

[0181] In some implementations, the subject is administered cromolyn agonist in combination with the disclosed compositions.

[0182] In some implementations, the subject is administered the disclosed composition in combination with an anti-inflammatory agent such as a corticosteroid, fluticasone, or salts thereof. Suitable anti-inflammatory compounds include both steroidal and non-steroidal structures. Suitable non-limiting examples of steroidal anti-inflammatory compounds are corticosteroids such as hydrocortisone, cortisol, triamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoximetasone, desoxycorticosterone acetate, dexamethasone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluocinolone acetonide, fluocinonide, fluocortin butyl ester, fluocortolone, fluprednidene acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, fludrocortisone, fludrocortisone, fluocinolone, medrysone, betamethasone and the balance of its esters, chloroprednisone, dichlorisone, flunisolide, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortamate, prednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, and triamcinolone. Mixtures of the above steroidal anti-inflammatory compounds may also be used.

[0183] In some implementations, the subject is administered the disclosed composition in combination with dexamethasone, prednisone, prednisolone, triamcinolone, cortisol, budesonide, mometasone, fluticasone, flunisolide, betamethasone, or a combination thereof.

[0184] In some implementations, the subject is administered the disclosed composition in combination with a decongestant, for example in combination with pseudoephedrine, ^^^Attorney Docket No. 10029-122WO1 phenylephrine, propylhexedrine, ephedrine, levmetamfetamine, L-desoxyephedrine, naphazoline, xylometazoline, or oxymetazoline.

[0185] In some implementations, the subject is administered the disclosed composition in combination with one or more antibiotics. Suitable antibiotics include, without limitation, such as 2,4-diaminopyrimidines, including baquiloprim, brodimoprim, iclaprim, ormetoprim, pyrimethamine, tetroxoprim, trimethoprim; aminocoumarins, including novobiocin; aminocyclitols, including spectinomycin; aminoglycosides, including amikacin, apramycin, arbekacin, bekanamycin, butirosin, dibekacin, dihydrostreptomycin, etimicin, fortimicins, astromicin, framycetin, gentamicin, hygromycin B, isepamicin, kanamycin, micronomicin, neomycin, netilmicin, paromomycin, plazomicin, ribostamycin, sisomicin, streptomycin, tobramycin; aminomethylcyclines, including omadacycline; amphenicols, including azidamfenicol, chloramphenicol, florfenicol, thiamphenicol; ansamycins, including rifabutin, rifampicin, rifapentine, rifaximin; antitubercular agents, including cycloserine, delamanid, ethambutol, ethionamide, morinamide, p-aminosalicylic acid (PAS), protionamide, pyrazinamide, terizidone, thioacetazone; bacteriocins, including nisin; b-lactam carbapenems, including loracarbef biapenem, doripenem, ertapenem, faropenem, imipenem, meropenem, panipenem, razupenem, sulopenem, tebipenem, tomopenem; b- lactam cephalosporins, including cefacetrile, cefaclor, cefadroxil, cefalexin, cefalonium, cefaloridine, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefcapene, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, cefoselis, cefotaxime, cefotiam, cefovecin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefradine, cefroxadine, cefsulodin, ceftaroline, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftizoxime, ceftobiprole, ceftolozane, ceftriaxone, cefuroxime, cefuzonam; b-lactam cephamycin, including cefbuperazone, cefmetazole, cefotetan, cefoxitin; b-lactam monobactams, including aztreonam, carumonam, tigemonam; b-lactam oxacephems, including flomoxef, latamoxef, moxalactam; b-lactam penicillins, including amdinocillin, amoxicillin, ampicillin, apalcillin, azidocillin, azlocillin, bacampicillin, carbenicillin, ciclacillin, clemizole penicillin, cloxacillin, cyclacillin, dicloxacillin, epicillin, fenbenicillin, floxacillin, hetacillin, mecillinam, metampicillin, methicillin sodium, mezlocillin, nafcillin, oxacillin, penamecillin, penethamate hydroiodide, penicillin G, penicillin G benzathine, penicillin G procaine, penicillin N, penicillin O, penicillin V, phenethicillin potassium, piperacillin, pivampicillin, pivmecillinam, propicillin, quinacillin, sultamicillin, talampicillin, temocillin, ticarcillin; b-lactam in combination with b-lactamase inhibitors, ^^^Attorney Docket No. 10029-122WO1 including avibactam, clavulanic acid, relebactam, sulbactam, tazobactam, vaborbactam, zidebactam; bicyclomycins, including bicozamycin; bis-benzimidazoles including ridinilazole; cyclic esters, including fosfomycin; fluoroquinolones, including avarofloxacin, balofloxacin, besifloxacin, cinoxacin, ciprofloxacin, clinafloxacin, danofloxacin, delafloxacin, difloxacin, enoxacin, enrofloxacin, finafloxacin, fleroxacin, flumequine, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, marbofloxacin, miloxacin, moxifloxacin, nadifloxacin, norfloxacin, ofloxacin, orbifloxacin, pazufloxacin, pefloxacin, pradofloxacin, prulifloxacin, rosoxacin, rufloxacin, sarafloxacin, sitafloxacin, sparfloxacin, temafloxacin, tosufloxacin, trovafloxacin, zabofloxacin; fusidane-type, including helvolic acid, fusidic acid and cephalosporin; glycolipodepsipeptides, including ramoplanin; glycopeptides, including avoparcin, dalbavancin, norvancomycin, oritavancin, teicoplanin, telavancin, vancomycin; glycylcyclines, including tigecycline; hybrids, oxazolidinone-quinolone; lincosamides, including clindamycin, lincomycin, pirlimycin; lipopeptides, including daptomycin, surotomycin; macrolides, including azithromycin, cethromycin, clarithromycin, dirithromycin, erythromycin, fidaxomicin, flurithromycin, gamithromycin, josamycin, kitasamycin, leucomycin, miocamycin, oleandomycin, primycin, rokitamycin, rosaramicin, roxithromycin, solithromycin, spiramycin, telithromycin, tildipirosin, tilmicosin, troleandomycin, tulathromycin, tylosin, tylvalosin; nitrofurans, including furaltadone, furazidin, furazolidone, nifuroxazide, nifurtoinol, nifurzide, nitrofural, nitrofurantoin, nitrofurazone; nitroimidazoles, including dimetridazole, metronidazole, ornidazole, secnidazole, tinidazole; oligosaccharides, including avilamycin, everninomicin; polymyxins, including polymyxin E (colistin), polymyxin B; polypeptides, including amphomycin, bacitracin, capreomycin, enduracidin, enramycin, gramicidin(s), ristocetin, tuberactinomycin, tyrocidine, tyrothricin, viomycin; pseudomonic acids including mupirocin; quinoxalines including carbadox, olaquindox; sulfonamides including acetyl sulfamethoxypyrazine, chloramine-B, chloramine-T, dichloramine T, mafenide, sulfacetamide, sulfadiazine, sulfadimidine, sulfamethazine, sulfamethizole, sulfapyridine, sulfathiazole, sulfisomidine, sulfisoxazole; sulfones, including dapsone sodium, sulfanilic acid; tetracycline including chlortetracycline, clomocycline, demeclocycline, doxycycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, rolitetracycline, tetracycline; triazaacenaphthylene including gepotidacin, or any combination thereof.

[0186] In some implementations the subject is administered the disclosed composition in combination with one or more antibiotics, including, but not limited to macrolides, e.g., ^^^Attorney Docket No. 10029-122WO1 erythromycin; penicillins, e.g., amoxicillin, beta-lactam, ampicillin; tetracyclines, e.g., doxycycline, tetracycline; sulfonamides, e.g. mafenide, sulfacetamide; fluoroquinolones; and cephalosporins, e.g., ceftaroline fosamil, ceftobiprole.

[0187] In certain implementations the subject is administered the disclosed composition in combination with one or more antifungals, including but limited to, allylamines and thiocarbamates like terbinafine, naftifine, tolnaftate, or liranaftate, azoles like tioconazole, clotrimazole, exonazole, miconazole, ketoconazole, fluconazole, itraconazole, terconazole, voriconazole, and posaconazole, polyenes like amphotericin B, natamycin, and nystatin, pyrimidines like flucytosine, echinocandins like caspofungin, micafungin, and andulafungin, oxaboroles like ciclopiroxolamine, and antibiotic antifungals like griseofluvin.

[0188] In certain implementations the subject is administered the disclosed composition in combination with one or more of acrisorcin, ambruticin, amphotericin b, azaconazole, azaserine, basifungin, bifonazole, biphenamine hydrochloride, bispyrithione magsulfex, butoconazole nitrate, calcium undecylenate, candicidin, carbol-fuchsin, chlordantoin, ciclopirox, ciclopirox olamine, cilofungin, cisconazole, clotrimazole, cuprimyxin, denofungin, dipyrithione, doconazole, econazole, econazole nitrate, enilconazole, ethonam nitrate, fenticonazole nitrate, filipin, fluconazole, flucytosine, fungimycin, griseofulvin, hamycin, isoconazole, itraconazole, kalafungin, ketoconazole, lomofimgin, lydimycin, mepartricin, miconazole, miconazole nitrate, monensin, monensin sodium, naftifine hydrochloride, neomycin undecylenate, nifuratel, nifurmerone, nitralamine hydrochloride, nystatin, octanoic acid, orconazole nitrate, oxiconazole nitrate, oxifungin hydrochloride, parconazole hydrochloride, partricin, potassium iodide, proclonol, pyrithione zinc, pyrrolnitrin, rutamycin, sanguinarium chloride, saperconazole, scopafungin, selenium sulfide, sinefungin, sulconazole nitrate, terbinafine, terconazole, thiram, ticlatone, tioconazole, tolciclate, tolindate, tolnaftate, triacetin, triafungin, undecylenic acid, viridofulvin, zinc undecylenate, or zinoconazole hydrochloride.

[0189] In further implementations, the subject is administered the disclosed composition in combination with one or more additional rhinosinusitis treatments. In certain embodiments, the treatments are selected from fluticasone proprionate (Xhance, Optinose), brensocatib (INS-1007, Insmed), rimegepant (BHV-300, Nurtec, Pfizer), LYR-210 (Lyra Therapeutics), LY-220 (Lyra Therapeutics), dupilumab (Dupixent, Sanofi), GLS-1200 (Gene One Life Sciences), Oticara (betamethasone diproprionate nasal cream), tezepelumab (Astra Zeneca and Amgen), UPB-101 (Upstream Bio), CSL787 (CSL Behring), benralizumab (Astra ^^^Attorney Docket No. 10029-122WO1 Zeneca), ALT-09 (Alistair Pharmaceuticals), CHF-6333 (Chiesi Pharmaceuticals), ARINA- 1 (Renovion) and BI 1291583 (Boehringer Ingelheim). EXAMPLES

[0190] To further illustrate the principles of the present disclosure, the following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compositions, articles, and methods claimed herein are made and evaluated. They are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.); however, some errors and deviations should be accounted for. Unless indicated otherwise, temperature is °C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of process conditions that can be used to optimize product quality and performance. Only reasonable and routine experimentation can be required to optimize such process conditions.

[0191] The following reagents and equipment were used unless otherwise stated. LaboMill (S / N: FPS0447); Mastersizer (Malvern MS3000 with Aero S apparatus); Raw and Micronized HDCF104 (Batch: Xun-3-200); Super Refined Polysorbate 80-LQ-(MH), SR48833 (Croda Batch: 0001662791); Benzalkonium chloride (Sigma Lot#BCCD6587); Sodium chloride (Sigma Lot#SLBV9983); AVICELTMRC-591 (IMCD Australia Pty Ltd, Batch# 2173829530); Milli-Q water; ULTRA-TURRAX homogenizer (IKATMT25); Ultrasonic cleanser (Purerrific Model: GS0410); VP7 / 100 nasal spray pump – 18 / 415 TP 120.00 mm, Poussoirs 232 NA / B / R, Cap B63 Clip - (APTAR Pharma, actuation volume is 100 µL). Spraytec (Malvern, UK – model: STP3315, serial number: MAL 1072981, software v3.30). Amber glass vial (Schott, Hungary, Fiolax amber screw neck, Lot 6105850542). Example 1: Cyclc AMP Detection

[0192] The cyclic AMP (cAMP) detection and measurement was conducted using the cAMP-Glo™Max Assay (Promega, Alexandria, NSW, AUS) using manufacture’s protocol. Briefly, 1 x 105cells / well were seeded in a white 96-well microplate with clear bottom and incubated at 37°C with 5% CO2for 24 h. Cells were washed with only MEM to remove serum and other additives. Cells were treated with HDCF104 in MEM supplemented with 25mM MgCl2with the concentration range of 1^M –1000µM for 15 minutes. Following the ^^^Attorney Docket No. 10029-122WO1 cAMP-Glo™Max Assay protocol, the luminescence was measured using the Spectramax iD3 microplate reader, Molecular Devices, San Jose, CA, USA).

[0193] The PDE4 inhibitory function of the HDCF104 compound was determined by the cyclic adenosine monophosphate (cAMP) detection assay in the nasal epithelial cell model RPMI2650. The inhibition of PDE4 would result in decreased degradation of cAMP. RPMI2650 cells were treated with the concentrations range of 1- 1000 µM of HDCF104 and cAMP levels were measured after 15 min exposure. HDCF104 demonstrates a concentration dependent increase of cAMP in RPMI2650 cells within 15 min of exposure (Figure 2). EC50was calculated to be 101.5 µM. Example 2: Micronization of HDCF104 raw materials

[0194] Raw HDCF104 (Batch No. Xun-3-200) was pre-sieved using a stainless-steel sieve (1.0 mm pore size). The pre-sieved HDCF104 were fed to the LaboMill jet mill feeder with a consistent feed rate of approximately 20 mg / s. The air pressures of feeding and grinding were both 4 bar. The micronized powder was collected from the sample collecting bowl. Sample yield was calculated based on the following equation: ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Sample yield = ^^^^^^^^^^^^^^^^^^^^^^^ ^^^^

[0195] To formulate HDCF104 as a nasal spray product, the initial size distribution of the raw material was determined and based on the results, an in-house micronizer was used to reduce the particle size and obtain a narrow size distribution. Figure 3A shows that the raw HDCF104 has a wide size distribution with multiple peaks.

[0196] HDCF 104 was then micronized using a feeding pressure of 4 bar and grinding pressure of 4 bar with the resultant size distribution of the micronized powder shown in Figure 3A-B and the table. The size distribution of the resultant micronized HDCF 104 powder was found to be narrower compared to raw powder (Figure 3B). Example 3: Size Distribution Measurements of Primary HDCF104 Particles ^^^Attorney Docket No. 10029-122WO1

[0197] The size distributions of the raw and micronized HDCF104 powder were measured using laser diffraction via a Malvern Mastersizer equipped with a dry dispersion system (Aero S apparatus). A small aliquot of micronized sample was transferred to the feeder in the dry dispersion system of the Mastersizer. The distance of the feeder was set to 0.7mm and feeding rate to 50%. Feeding air pressures were set to 0.1 bar, 0.5 bar, 1 bar, 2 bar and 4 bar to establish optimum settings for size analysis.

[0198] The resultant HDCF104 formulation was successfully prepared and had an opaque viscous suspension (Figure 7). Using an Aptar VP7 pump with 100µL delivering volume, the delivered mass uniformity with the prepared formulation was evaluated. The weights of all the shots including wasted shots (1-6, 17-40, 51-70 and 81-last) and the weight of collected shots (7-16, 41-50 and 71-80) were recorded to ensure that the pump delivery was consistent throughout. Figure 4 shows the shot weight through the entire life of the formulation with a target mass of 0.1 mg assuming a formulation density of 1 g / cm3.

[0199] From the results in Figure 4, the pump delivery of the shots at the beginning increased over the first 4 shots and started to produce consistent shot weights by shot number 5. This is due to the priming requirements of a new unused VP7 pump, dip tube and valve. Hence, six priming shots to waste were implemented as this would ensure consistent dosing and was included as a standard protocol for testing and potentially included as instructions to patients in the future. However, tailing started to occur after shot 90 as the liquid reaches the bottom of the container. Therefore, the current bottle / valve configuration could consistently deliver 80 shots with a 12 ml fill, which will ensure consistent dosing.

[0200] The shot weights at the beginning, middle and end of life as well as all shots through life are within the broad mass-based acceptance criteria of (0.1 mg ± 15%). However, it is important to note that assumptions were made of the formulation density where the density was assumed to be similar to that of water and does not take into consideration the presence of excipients in which this is a complex suspension formulation with different excipients used. The average shot weight across 3 valves from shot 7-80 (n=222 measurements) was 107 mg ± 3 mg (RSD = 3%) indicating good dose reproducibility. Based on a 107 mg shot weight and formulation mass of 30 µg per 100 mg this would mean that the effective dose should be 32 µg per shot. Spray content uniformity at the three phases of beginning, middle, and end of life is shown in Figure 5.

[0201] Analysis of the data indicated that the dose was reproducible throughout the product life. The average target was reported to be 31.94 µg ± 15%. This value is calculated based on the average mean µg delivered dose across the entire life of the product for three ^^^Attorney Docket No. 10029-122WO1 replicate devices. Based on Figure 4Error! Reference source not found., it was determined that the delivered dose of HDCF104 using VP7100 µl valves was 31.94 ± 0.12 µg with an RSD of 0.36%. Therefore, it is concluded that the specification for the formulation dose delivered using these valves 32 µg per dose. Example 4: Preparation of the HDCF104 Nasal Formulation

[0202] The optimal concentration of AVICELTMRC-591 in water dispersion was determined to be 1.2% w / w. Sodium chloride is used to adjust tonicity of the formulation, while no salt can be presented to disperse the AVICELTMwith water. To prepare the formulation, a 2.4% w / w AVICELTM / water dispersion was made initially and an IKA ULTRA-TURRAX homogenizer was used to activate AVICELTMat >8,000 rpm for 5 min. Aqueous solutions that contain double the desired concentration (w / w) of polysorbate 80, sodium chloride and benzalkonium chloride were prepared by mixing with a magnetic stirrer. This mixture was then mixed with equal mass of the AVICELTM / water dispersion using the homogenizer at ~3000 rpm for 1 min to form a homogeneous liquid. HDCF104 powder was then added to the mixture and using the mixing methods of sonicating and stirring to form a homogenous suspension formulation. The resultant HDCF104 formulation was successfully prepared and had an opaque viscous suspension (Figure 7). Example 5: HDCF104 Quantification by HPLC

[0203] HDCF104 detection and quantification were conducted using a high-performance liquid chromatography (HPLC) system equipped with SPD-20A UV–Vis detector, an LC- 20AT liquid chromatography, an SIL-20A HT autosampler (Shimadzu) and a Luna C18 column (150×3 mm, 3 µm, 100Å, Phenomenex, Torrance, USA). The mobile phase consisted of acetonitrile / H2O 45 / 55 % v / v. Samples were analyzed at 290 nm, a flow rate of 1mL / minute and an injection volume of 10 ^L. Linearity was obtained between 0.1 and 100 ^g / mL (R2=0.99) with a retention time of 4.11 min.

[0204] Example 6: Through Life Delivered Mass and Spray Content Uniformity Studies

[0205] 12mL of HDCF104 formulation was filled in a glass vial attached to an Aptar VP7 pump, which is an equivalent of 120 shots. Using a 4-figure balance, the filled bottle was weighed and the weight of the bottle after each shot was recorded to exhaustion to measure the through-life delivered mass. An acceptable range of the delivered mass was ±15% (between priming and tailing) of the target delivered mass.

[0206] Simultaneously, the spray content uniformity (SCU) of the formulation was evaluated whereby after actuating 6 shots to waste, the spray bottle was shaken 3 times and ^^^Attorney Docket No. 10029-122WO1 shots 7 to 16 (Phase 1-beginning shots) were collected into a separate 50 mL centrifuge conical tubes places horizontally. After the shots in Phase 1 were collected, a further 24 shots were fired to waste before shots 41 to 50 were collected (Phase 2-middle of life shots). Then, a further 20 shots were fired to waste and shots 71 to 80 were collected (Phase 3-end of life shots). The collected samples were analyzed by HPLC to determine the mass of the HDCF104 for each shot (delivered dose). An acceptable range of the delivered dose was ±15% of the target delivered dose.

[0207] Example 7: Formulation Robustness

[0208] The concentrations of AVICELTMRC591 and polysorbate 80 in the proposed formulation were changed slightly to test the robustness of the formulation. The robustness study allows the understanding of the optimal concentrations of the excipients. It also gives information about how much they would impact droplet size if the excipients concentrations changed during manufacture. The robustness of the formulation was determined by using Spraytec to measure the size distribution of the aerosolized formulation through VP7 pump.

[0209] The Spraytec was set up at a 45° inhalation cell, open bench measurement with air extractor on. Analysis settings as follows: Droplet: Water equivalent (RI = 1.33; density = 0.00); Dispersant: Air (RI = 1).

[0210] Five different concentrations of polysorbate and five different concentrations of AVICELTMwere analyzed:

[0211] A robustness study of the HDCF104 nasal suspension formulation was performed by evaluating concentration deviations of the two major components of the optimized ^^^Attorney Docket No. 10029-122WO1 formulation, which are Polysorbate 80 and Avicel that has been optimized at 0.01 % w / w and 1.2 %w / w, respectively. The first component is Avicel which can change the viscosity of the formulation while the other component that could affect droplet size is polysorbate 80, which can change the surface tension of the formulation. The percentile volume undersize for the aerosols generated from formulations containing different percentages of Avicel Figure 6A.

[0212] Analysis of the droplet size distributions of HDCF104 formulations as a function of varying Avicel concentrations revealed no significant differences in Dv50 over a range of 1- 1.4% w / w with respect to the target concentration of 1.2% (w / w). Analysis of Dv90 droplet size distributions indicated significant differences over a range of 1-1.4% w / w Avicel with a peak droplet size around 1.2% (w / w) having criticality with respect to droplet size. Multiple comparison analysis indicated that there was no significant difference between 1.2 and 1.1 and 1.2 and 1.3% w / w indicating relative robustness around the target Avicel concentration.

[0213] The percentile volume undersize for the aerosols generated from formulations containing different percentages of Polysorbate 80 components are shown in Figure 6B. Analysis of the impact of other polysorbate 80 concentrations on droplet size indicated no significant differences on both Dv50 and Dv90 values when considering the target formulation concentration of 0.02% (w / w) polysorbate 80.

[0214] No significant impact on Dv10 and Dv50 values were observed when changing the concentrations of both Avicel and polysorbate 80. For Avicel the Dv90, the extreme values 1.0 and 1.4% (w / w) showed statistical significance when compared to the target concentration (1.2%w / w). Furthermore, decreasing the polysorbate 80 concentration from 0.02 to 0.01% (w / w) resulted in a higher standard deviation for both Dv50 and Dv90 values.

[0215] Based on these findings, it was therefore concluded that the maximum tolerance for Avicel concentration in the HDCF 104 nasal suspension formulation was between 1.1 to 1.3 % (w / w), while for Polysorbate 80 is between 0.02 % to 0.05% (w / w). Example 8: HDCF104 Short-term Stability Study

[0216] A short-term stability study was conducted on the HDCF104 suspension and was evaluated based on three different aspects: (a) Visual examination which was the first and easiest way to test the formulation’s stability.10mL of HDCF104 was filled in a transparent glass vial and photos were taken at time zero, 1 minute, 5 minutes and 1 hour time point to compare. Figure 7 shows the photos of the HDCF104 formulation suspension that was taken over a period of 1 min to 1-hour intervals to determine any sedimentation or phase separation. No obvious separation was noticed over the 1-hour period. However, it was ^^^Attorney Docket No. 10029-122WO1 difficult to determine if any drug sedimentation occurred during the period due to the opaque nature of the suspension. (b) The second aspect to test the formulation stability was the total assay content where the formulations were stored in three different conditions according to ICH guideline Q1A(R2). The three conditions were: 2-8 °C refrigerated condition; 25°C / 60%RH ambient condition; and 40°C / 75%RH accelerated condition. HPLC was used to measure the total assay of the formulation at time zero, week-1, week-2, week-3, week-8 and week-12. The accepted total assay criteria to be considered stable needs to be within the range of 100 ± 5%. The average total assay results were found to be within the theoretical range of 95% - 105%, except for the month-3 timepoint in the refrigerated condition, where the total Assay were slightly higher than the nominal dose (105.7 ± 0.7%). Both ambient and accelerated conditions showed that the formulation was stable for 3 months (Figure 8). In general, the HDCF104 formulation is considered stable within the period of the stability study. Based on the accelerated stability condition, it is postulated that the formulation will continue to be stable at room temperature for up to 6 months, which is in accordance with requirements set out by the Stability Testing Guidelines: Stability Testing of New Drug Substances and Products (Revision 2) [CPMP / ICH / 2736 / 99 (Q1A)]. The results are shown in Figures 9A-D. The final aspect of the stability test is the delivered dose the formulation when actuated using the VP7 pump. After priming, 10 shots were actuated into the conical falcon tube and were collected and analyzed by HPLC. The acceptable delivered dose should be within the ±15% of the target dose. Figures 9A-D show the dose uniformity data of HDCF104 formulation upon manufacture and after storage under different ICH conditions up to 3 months. The mean delivered dose at time 0 and the end of the stability study at 3 months in the different conditions were shown to be uniform based on the criteria addressed in USP <601>. In general, the newly developed HDCF104 suspension nasal formulation has shown to be stable over the 3 months study period demonstrating reproducible total assay content in the different storage conditions and consistent delivered dose at the beginning and the end of the study. Example 9: Cell Culture and Air-Liquid Interface (ALI) Model

[0217] The epithelial cancer-derived RPMI2650 cell line (ATCC, CCL-30) was chosen as an in vitro nasal epithelium model. Cells were cultured between passages 26 to 36 in 75 cm2^flasks containing Minimum Essential Media (MEM) supplemented with 10% (v / v) fetal bovine serum (FBS), 1% (v / v) non-essential amino acids solution and 1% (v / v) L-glutamine solution. Cells were maintained in a humidified 95% air, 5% CO2^atmosphere at 37 °C until ^^^Attorney Docket No. 10029-122WO1 confluency was reached. The media was replaced three times a week and cells were passaged according to American Type Culture Collection Recommendations—ATCC guidelines. This cell line has been well characterized previously as an appropriate model for the nasal epithelium when grown at an air-liquid interface (ALI) culture. For the ALI model, cells were seeded at a density of 5 × 105^cells / insert on a Snapwell polyester inserts (1.12 cm2^growth area) containing 200 µL in the apical chamber and 2 mL in the basolateral chamber. The medium from the apical chamber was removed after 24 h from seeding and every day afterwards until an ALI was achieved, while the medium from the basolateral chamber was replaced every second day up to 14 days of culture. Example 10: Transepithelial Electrical Resistance (TEER)

[0218] Transepithelial electrical resistance (TEER) of RPMI2650 cells in ALI culture was measured. Briefly, pre-warmed Hanks’ Balanced Salt Solution (HBSS) was added to the apical chamber and allowed to equilibrate for 30 min at 37 °C under 5% CO2.^TEER was measured using EVOM2TM^epithelial volt / ohm meter (World Precision Instruments, Sarasota, FL, USA) connected to STX-2 chopstick electrodes at the annotated conditions. Blank controls (cell-free inserts containing HBSS) and untreated controls (inserts of cells in medium) were included in the study. Experiments were performed in triplicate. TEER (^ cm2) was calculated from the measured potential resistance difference (^) between the apical and basolateral sides, normalized by subtracting the blank insert and multiplying by the surface area of the Transwell or Snapwell inserts, according to the equation: TEER^(^ cm2) = (Resistancetest^^^Resistanceblank) ×^Area^of^well^insert

[0219] To better understand the impact of formulation on the nasal epithelia, RPMI2650 cells were grown in air-liquid interface culture and the effect of the deposited formulation on the epithelial integrity (Figure 10A-B) was determined. The formulation did not affect the integrity of the nasal epithelia, where there was no significance difference between the cell treated with HDCF104 formulation and its excipients compared to untreated control. Example 11: Transport Studies in ALI Model

[0220] The deposition of HDCF104 nasal suspension formulation onto the RPMI2650 epithelia was achieved either by direct exposure of product through pipetting the drug suspension (3µg) or by using 3 shots in a modified expansion nasal chamber with a custom- built 3D-printed inserts to house the Snapwell inserts allowing direct deposition of product aerosol attached to a next generation impactor (NGI) with a flow rate of 15L / min. Additionally, the milled HDCF104 was also deposited on the nasal epithelia using the propellant (2H,3H perfluoropentane, HPFP) in order to see how the transport was affected ^^^Attorney Docket No. 10029-122WO1 without excipients. The propellant of choice was used for consistency of dosing. After aerosol deposition, the Snapwell inserts were transferred to the culture plates containing pre-warmed HBSS in the basolateral chamber. At predetermined time points, 200 ^L samples were collected from the basolateral chamber and replaced by fresh HBSS to maintain sink conditions. After 4h, the apical surface was washed twice with 200 ^L of HBSS and combined to quantify the remaining HDCF104 on top of the epithelial layer. The epithelial layer was disturbed using a micropipette tip and the cells were washed with 400 ^L of HBSS to remove mucus. The cells were pelleted using centrifugation (1000 x g, 10 min) and lysed using cell lysis buffer to quantify the amount of HCDF104 inside the cells. The transport of the HDCF104 through the nasal epithelia was also determined (Figure 10C) in formulation compared to deposition of the HDCF104 only without excipient via propellant (HPFP). The transport study showed that the nasal formulation of HDCF104 were transported more effectively through the nasal epithelium compared to the HDCF104 when delivered without the presence of any excipients. In the first 30 min, 58% of the HDCF104 in the formulation was transported while in the propellant deposition, only 24.62% was transported. At the end of the transport study (4h), 79% of the HDCF104 in formulation was transported across the nasal epithelia while the propellant deposited HDCF104 only had 51% of the drug transported. The amount of HDCF104 remaining on top of the epithelia (ON) and inside the cells (IN) were also quantified (Figure 10D). The ON samples had 14% and 43% in the formulation and HPFP depositions respectively and the IN samples had 7% and 5.5% in the formulation and HPFP depositions respectively. Thus, the HDCF104 in the formulation if more effectively transported through the nasal epithelia compared to direct deposition with propellant. This observation suggests that that the excipient mixture could contribute to the increase in absorption of the HDCF104 through an improved solubility of HDCF104 in the surface airway liquid on the nasal epithelium. Example 12: Sodium Fluorescein Paracellular Permeability

[0221] The functionality of tight junctions and paracellular permeability of the cell layer was investigated using the sodium fluorescein permeability assay. Briefly, HDCF104 formulation was deposited on top of the epithelial layer as described in the transport study and incubated at 37 °C for 4h, sodium fluorescein (2.5 mg / mL) (Sigma Aldrich) was added to the apical chamber and pre-warmed HBSS was added to the basolateral chamber. Snapwells with the nasal epithelia were incubated for 4 h at 37 °C with 5% CO2, with ^^^Attorney Docket No. 10029-122WO1 basolateral samples (100 µL) collected at 15 min intervals for 1h to measure the rate of transport (flux) of the sodium fluorescein from the apical chamber to the basolateral chamber. For analysis, the collected basolateral sample fluorescence was measured using the SpectraMax iD3 plate reader (excitation: 485 nm; emission: 538 nm). The permeation coefficient (Papp) was calculated according to the equation: Papp = (V / AC0) (dC / dt), where^V is the volume in the basolateral chamber,^A^is the surface area of the Snapwells membrane,^C0 is the initial concentration in the apical chamber, and^dC / dt is flux (cumulative) of Na-Flu through the membrane. To better understand the impact of formulation on the nasal epithelia, RPMI2650 cells were grown in air-liquid interface culture and the effect of the deposited formulation on the epithelial permeability (Figure 10B) was determined. The formulation did not affect the permeability of the nasal epithelia, where there was no significance difference between the cell treated with HDCF104 formulation and its excipients compared to untreated control. Example 13: Electrophysiological Studies (Ussing Assay)

[0222] Primary human bronchial epithelial cells carrying WT CFTR were obtained from (Lifeline Cell Technology; FC-0035). Cells were expanded using PneumaCult-Ex Plus medium (Stemcell Technology; 05040) on collagen-coated flask and seeded to collagen- coated Transwell inserts to establish ALI epithelial monolayers for functional studies. Cells on inserts were cultured for 2-4 days under submerged conditions, then the monolayers were transitioned to ALI (air-liquid interface) condition utilizing PneumaCult ALI medium (StemCell Technology; 05001). Cells were maintained at 37C° under humidified, 5% CO2– 95% air atmosphere on inserts until they formed a well-polarized airway epithelial stage, typically 4 weeks from seeding.

[0223] Primary human bronchial epithelial monolayers were mounted onto EasyMount Ussing Chamber System (Physiologic Instruments) and bathed apically in low chloride Ringer`s solution: 140mM Na-gluconate, 1.2mM NaCl, 25mM NaHCO3, 3.33mM KH2PO4, 0.83mM K2HPO4, 1.2mM CaCl2, 1.2mM MgCl2, and 10mM D-glucose (pH 7.4) whereas the basolateral solution contained 120mM NaCl, 25mM NaHCO3, 3.33mM KH2PO4, 0.83mM K2HPO4, 1.2mM CaCl2, 1.2mM MgCl2, and 10mM D-glucose (pH 7.4) to establish chloride gradient. The temperature of bathing solutions was maintained at 37 °C and stirred by bubbling through 5% CO2 / 95% O2. Once the baseline stabilized, 100^M amiloride (MilliporeSigma, A7410) was applied to both apical and basolateral sides to inhibit epithelial sodium channel (ENaC). Formulated HDCF104 (0.3mg / g) were applied directly ^^^Attorney Docket No. 10029-122WO1 to the apical bath in increasing concentration. Equivalent volume of vehicle was administered to control assays. Maximal CFTR protein activation was achieved by applying 10^M forskolin (MilliporeSigma, F3917) to both sides after reaching maximal activation by HDCF104. At the end of each recording, CFTR (inh)-172 (10^M; MilliporeSigma C2992) was administered to the apical side to inhibit CFTR-mediated current. After maximal CFTR inhibition, UTP (VWR, 0145) were applied to evaluate the quality of monolayers. Across the experiments, short circuit current (Isc) was recorded under voltage clamp conditions and the change in Isc induced by the acute treatment was calculated and expressed as mean ± SEM.

[0224] The data are presented as mean ± standard deviation (STDev) of at least three independent experiments. Statistical analysis was performed using Prism software version 9.4.0 (GraphPad, San Diego, USA). Means were evaluated using ANOVA statistical analysis and Multiple unpaired t tests followed by multiple comparison.

[0225] HDCF104 effectively increases cAMP level in human primary cells as demonstrated in Figure 11A, attributable to PDE4 inhibition. Accordingly, formulated HDCF104 activates CFTR protein at the cell surface in a dose-dependent manner with 80% maximal activation that is achievable with forskolin, an adenylate cyclase activator used to maximally stimulate CFTR in in vitro experiments (Figure 11A). Furthermore, HDCF104 exhibitS EC50in a low micromolar range (3.57 ± 1.122 ^M with 95% CI (1.275 ^M to 5.870 ^M)) toward stimulating WT CFTR. (Figure 11B). Example 14: HDCF-104: Intranasal Dose Range Finding Studies in Male and Female Sprague Dawley Rats

[0226] The purpose of this study was to evaluate HDCF-104 suspension (Test Article / TA), for intranasal tolerance and systemic pharmacokinetics after single escalating and up to 7 repeat daily doses in male and female Sprague Dawley rats. HDCF-104 is a novel new chemical entity (NCE) for the treatment of Chronic Rhinosinusitis (CRS). HDCF-104 functions by activating the cystic fibrosis transmembrane conductance regulator (CFTR) through inhibiting of phosphodiesterase enzyme 4 (PDE4).

[0227] This study was conducted in two (2) phases: a terminal, single, acute dose escalation phase and a terminal 7-day repeat dose phase. Twelve male [3 Main Study (toxicology) and 9 toxicokinetics (TK)] and three female Main Study (toxicology) rats per dose group (Low, Mid, and High TA) were assigned to the acute phase. In the repeat dose phase, twenty-one male and twenty-one female rats were included in Low, Mid, and High TA dose groups [3 Main Study per sex (toxicology) and 9 TK-“First Dose” and 9 TK “Last Dose” per sex] and ^^^Attorney Docket No. 10029-122WO1 twelve male and twelve female rats [3 Main Study (Toxicology) and 9 toxicokinetics (TK)] were included in the control group.

[0228] Control rats (repeat dose phase only) were administered normal saline. All other rats were administered TA consisting of 0.3 mg / g micronized HDCF104, 1.2 wt% Avicel, 0.9 wt% NaCl, 0.02 wt% Polysorbate 80, and 0.02 wt% benzalkonium chloride. Throughout the study, saline control and TA were administered via intranasal (IN) instillation by pipetting 10 ^L volumes of saline or TA into each nare (20 ^L total). Saline, Low, Mid, and High animals received, 60 ^L, 20 ^L, 40 ^L, and 60 ^L per daily dose split over three, one, two, and three 20^L dose administrations respectively. The latter corresponded to HCDF-104 target dose levels of 0 (saline), 6 (Low), 12 (Mid), and 18 (High) micrograms. Daily 20^L administration intervals of saline and TA were separated by a minimum target of 80 minutes.

[0229] In the acute phase, TK blood was collected for bioanalyses (plasma) and TK analyses following the last 20 ^L intranasal administration at 3 animals / group / time point at targets of 5 min (±2), 25 min (±5), 50 min (±5), 75 min (±5), 100 min (±10), 150 min (±10), 225 min (±10), 5 hours (±10 min), and 24 hours (±30 min) for each of the Low, Mid and High dose groups. In addition, terminal brain and nasal turbinate samples were taken from 3 animals / group / time point at 75min, 5, and 24 hours post dose administration.

[0230] Three male and three female Main Study animals per group were euthanized after a 48-hour observations period. No tissues were collected. Observations were performed during and after dosing on all animals. The results from the acute tolerance phase were used to determine doses for the repeated dosing phase.

[0231] In the repeated dosing phase, rats from the saline, Low, Mid, and High dose groups followed the daily dosing schedule described previously for either a single daily dose (Day 1 TK animals) or for 7 consecutive days (Main Study and Day 7 TK animals). Blood for bioanalyses was collected from 9 male and 9 females from each of the Low, Mid, and High TK rats on Day 1 and Day 7 respectively post the last 20^L administration [(Low, Mid and High target 5 min (±2), 25 min (±5), 50 min (±5), 75 min (±5), 5 hours (±10 min), and 24 hours (±30 min)]. Blood for bioanalyses was collected from saline TK animals on Days 1, 4 and 7 post the last 20^L administration (target 5 min (±2)] to confirm absence of HDCF- 104. Three repeat dose male and three female Main Study rats from each of the saline, Low, Mid, and High groups were dosed for (7) consecutive days followed by a terminal necropsy on Day 8. Study parameters collected and evaluated included in-life body weights, pre and post exposure observations, and detailed observations. Near terminal / terminal endpoints ^^^Attorney Docket No. 10029-122WO1 included clinical pathology, gross necropsy observations, organ weights (adrenals, brain, epididymis, heart, kidney, liver, lung, ovaries, spleen, testes, thymus, and uterus) and histopathology (gross lesions, brain, esophagus, gastrointestinal tract, heart, kidney, lacrimal gland, liver, lungs, nasal cavity, nasal turbinates, pharynx, salivary gland, and spleen).

[0232] Intranasal dosing of the TA was well tolerated all dose levels in both phases of the study. No clinical signs were observed during either phase of the study and all animals throughout both phases of the study survived until scheduled euthanasia.

[0233] Evidence of systemic exposure to HDCF-104 was observed in all treated TK rats following daily intranasal administration. No quantifiable concentration of HDCF-104 was noted in the saline animal samples. In general, HDCF-104 plasma exposure appeared to increase in a dose proportional manner on Day 1 and in a less than dose proportional manner on Day 7. Brain exposure increased in a less than dose proportional manner on Day 1 and in a dose proportional manner on Day 7. Nasal turbinate exposure increased in a greater than dose proportional manner on Day 1 and in a less than dose proportional manner on Day 7. The Day 7 plasma and brain AUC values were similar to Day 1 values suggesting minimal accumulation, while Day 7 turbinate AUC values were higher than Day 1 values suggesting some accumulation. There were negligible differences between the sexes. ^^^Attorney Docket No. 10029-122WO1 Composite Plasma TK Parameters Following Intranasal HDCF-104 Administration in Female and Male Sprague Dawley RatsComposite Turbinate TK Parameters Following Intranasal HDCF-104 Administration in Female and Male Sprague Dawley RatsComposite Brain TK Parameters Following Intranasal HDCF-104 Administration in Female and Male Sprague Dawley Rats ^^^Attorney Docket No. 10029-122WO1

[0234] Composite Brain TK Parameters Following Intranasal HDCF-104 Administration in Female and Male Sprague Dawley Rats

[0235] At Necropsy, no gross findings were observed. Postmortem organ weights were unremarkable. Weight differences were minor, lacked a consistent dose response, and were inconsistent between sexes and body or brain weight ratios. The only histologic TA related finding was a minimal mixed cell infiltrate in the larynx in one male and one female in the Mid dose group and one male and one female in the High dose group. Low dose animals were not affected. A single female in the saline group also had a minimal laryngeal mixed cell infiltrate. In all affected animals, infiltrate was very minimal, and no other changes were associated with the infiltrate. This finding was deemed non-adverse.

[0236] In summary, intranasal TA doses of up to 60 ^L [18 ^g of HCDF-104 (High dose)] for up to 7-days were well tolerated. No-TA related clinical observations were noted. Evidence of systemic exposure to HDCF-104 was observed in all treated TK rats in plasma, nasal turbinates and brain following daily intranasal administration. In general, Cmax and AUC increased with dose level. There were negligible differences between the sexes. No TA-related gross necropsy or organ weight observations were observed. ^^^Attorney Docket No. 10029-122WO1

[0237] Example 15: HDCF-104: Intranasal Dose Range Finding Studies in Male and Female Beagle Dogs

[0238] The purpose of this study was to evaluate HDCF-104 suspension (Test Article / TA), for intranasal tolerance and systemic pharmacokinetics of after single escalating and up to 7 repeat daily doses in male and female Beagle dogs. HDCF-104 is a novel new chemical entity (NCE) for the treatment of Cystic Fibrosis, HDCF-104 functions by activating the cystic fibrosis transmembrane conductance regulator (CFTR) through inhibiting of phosphodiesterase enzyme 4 (PDE4).

[0239] This study was conducted in two (2) phases: a nonterminal, single, acute dose phase, and a terminal 7-day repeat dose phase. One male and one female dog were assigned to the acute phase. In the repeat dose phase, one male and one female dog were included in Control and Low, Medium, and High TA dose groups respectively. Control dogs (repeat dose only) were administered normal saline. All other dogs were administered TA (HCDF- 104 suspension) consisting of 0.3 mg / g micronized HDCF104, 1.2 wt% Avicel, 0.9 wt% NaCl, 0.02 wt% Polysorbate 80, and 0.02 wt% benzalkonium chloride. Throughout the study, Control and TA were administered with a human intranasal spray device (Aptar VPZ) designed to deliver 100 ^l per spray. One spray per nostril (200 ^l total) was delivered per dosing interval. In the acute phase, dogs were dosed with 200 ^l of TA for Dose 1 (target of 60^g HDCF-104), 600 ^l of TA for Dose 2 (target of 180 ^g HDCF-104), and 1200 ^l of TA for Dose 3 (target of 360 ^g HDCF-104). Each dosing session was followed by a 3-day non-dosing washout period. For Dose 2 and 3, 200 ^l TA administrations were separated by approximately 80min. Observations were performed during and after dosing. Data from this portion of the study was used to determine doses for the repeated dosing study phase.

[0240] In the repeated dosing phase, Control and High TA dose group dogs received 1200 ^l total spray volume separated into 200 ^l doses with administrations performed approximately 80 min apart. The same 200 ^l dosing schedule was followed for the Mid dose with a target total spray volume of 600 ^l TA for each dog. Low dose dogs received a single 200 ^l TA administration. This daily dosing schedule was followed for all dose groups for 7 consecutive dose days. Blood samples were drawn after the first dose administration in all TA animals (initial 200 ^l administration) [Low, target 5(±2), 50(±5), and 180(±10) minutes; Mid and High, target 5(±2), 25(±5), and 75(±5) ] and after the last 200 ^l dose administration (Low, Mid and High, target 5(±2), 50(±5), and 180(±10) minutes) on Day 1 and Day 7. Pre-dose trough samples were collected on Day 2, 4, and 7. ^^^Attorney Docket No. 10029-122WO1 An additional post last dose administration 5 (±2) minutes sample was collected and analyzed from TA-dosed animals on Day 4. Plasma was isolated and analyzed for HDCF- 104 concentrations. Pharmacokinetic analyses were performed. Terminal sacrifices were conducted the day following the last dose administration for all animals (Day 8). Study parameters collected and evaluated included in-life body weight, detailed observations, and clinical pathology. Terminal endpoints included gross necropsy observations, organ weights (adrenals, brain, epididymis, heart, kidney, liver, lung, ovaries, spleen, testes, thymus, and uterus) and histopathology (gross lesions, brain, esophagus, gastrointestinal tract, heart, kidney, lacrimal gland, liver, lungs, nasal cavity, turbinates, pharynx, salivary gland, and spleen).

[0241] Intranasal dosing of the TA was well tolerated in both phases of the study. No clinical signs were observed during the acute dosing phase. Two female dogs in the low and high dose groups vomited once each during exposure on Day 1 (High dose group) and Day 5 (Low dose group) in the repeat dose phase. The relationship of this finding to TA administration treatment is unclear but may be sex dependent as it only presented in 2 female animals. Body weights in both phases of the study stayed were generally consistent with pre-dose weights and were not impacted by exposure to the TA. ^^^Attorney Docket No. 10029-122WO1

[0242] Individual Animal and Mean Plasma TK Parameters Following Intranasal HDCF-104 Administration in Female and Male Beagle Dogs

[0243] HDCF-104 plasma concentrations were low after intranasal TA administration (Cmax < 9ng / ml at all dose levels). Tmax was observed at the at the earliest sample times in all dose groups and Cmax and AUC were generally dose proportional at both Day 1 and 7 PK intervals. HDCF-104 plasma exposure varied approximately 3-fold following the initial 200 ^l (60 ^g) intranasal installation.

[0244] AUC values were similar among dose groups on Day 1 and 7 suggesting negligible accumulation. No pre-dose trough HDCF-104 concentrations were detected from any dose group. In general, no sex differences were observed in Tmax, Cmax, or AUC at Day 1 and Day 7. Histopathology evaluation resulted in minimal, non-adverse neutrophilic infiltrate in ^^^Attorney Docket No. 10029-122WO1 the pharyngeal epithelium. The latter were observed in the high dose animals, as well as the female at the mid dose. In all three animals, infiltrate was minimal with no other associated pathology findings.

[0245] In Summary, intranasal TA administration was well tolerated at up to 1200 ^l (360 ^g). Low level, dose-related exposure of HDCF-104 was observed post administration in all TA dogs. No accumulation was observed. With the exception of histopathology, no TA- related observations were noted in any parameters on study. Minimal, non-adverse neutrophilic infiltrate in the pharyngeal epithelium was observed in High dose dogs and the female Mid-dose dog. ^

[0246] The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein or less, however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated. The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non- limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of” and “consisting of” can be used in place of “comprising” and “including” to provide for more specific embodiments of the invention and are also disclosed. Other than in the examples, or where otherwise noted, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood at the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, to be construed in light of the number of significant digits and ordinary rounding approaches. ^^^

Claims

Attorney Docket No. 10029-122WO1 CLAIMS What is claimed is:

1. A pharmaceutical composition, comprising: a) a compound of Formula (1): [Formula (1)], or a pharmaceutically acceptable salt thereof, wherein R1is alkyl, aryl or heterocyclyl, wherein R1is optionally substituted with one or more, the same or different, R10; R2is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R1is optionally substituted with one or more, the same or different, R10; R3and R4are each, individually and independently, hydrogen, alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R3and R4are optionally substituted with one or more, the same or different, R10; R10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, alkanoyl, benzoyl, carbocyclyl, aryl, or heterocyclyl, wherein R10is optionally substituted with one or more, the same or different, R11; and R11is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N- ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl; b) a surfactant; ^^^Attorney Docket No. 10029-122WO1 c) cellulose, cellulose derivative, or a combination thereof, and d) water; wherein the composition comprises the compound of Formula 1 in a concentration from 0.05-5 mg / g, from 0.05-2.5 mg / g, from 0.05-1 mg / g, from 0.05-0.5 mg / g, from 0.1-0.5 mg / g, from 0.1-0.25 mg / g, from 0.25-0.5 mg / g, from 0.2-0.4 mg / g, or from 0.25-0.35 mg / g.

2. The pharmaceutical composition of claim 1, wherein the surfactant comprises a positively charged oligosaccharide, cationic surfactant, anionic surfactant, amphoteric surfactant, non-ionic surfactant, or a combination thereof.

3. The pharmaceutical composition of claim 1, wherein the surfactant comprises methyl chitosan, chitosan oligosaccharides, polysorbates, saponins, polyoxyethylene-9-lauryl ether, sodium lauryl sulfate, glyceryl oleate, dipalmitoyl phosphatidyl choline, soybean lecithin, phosphatidylcholine, a fatty acid, or salt thereof.

4. The pharmaceutical composition of claim 1 wherein the surfactant comprises polyoxyethylene (20) sorbitan mono fatty acid ester.

5. The pharmaceutical composition of claim 1, wherein the surfactant comprises polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, or polyoxyethylene (20) sorbitan monooleate, or a combination thereof.

6. The pharmaceutical composition of claim 1, wherein the surfactant comprises polyoxyethylene (20) sorbitan monooleate.

7. The pharmaceutical composition of claim 1, wherein the surfactant consists of polyoxyethylene (20) sorbitan monooleate.

8. The pharmaceutical composition of any of claims 1-7, wherein the surfactant is present in a concentration from 0.001-10 wt.%, from 0.001-1 wt.%, from 1-5 wt.%, from 5-10 wt.%, from 0.001-0.1 wt.%, from 0.001-0.01 wt.%, from 0.005-0.05 wt.%, from 0.01-0.1 wt.%, from 0.01-0.05 wt.%, or from 0.02-0.05 wt.%.

9. The pharmaceutical composition of any of claims 1-7, wherein the surfactant is present in a concentration from 0.01-0.1 wt.%, preferably from 0.02-0.05 wt.%.

10. The pharmaceutical composition of claim 1, wherein the composition comprises a cellulose derivative.

11. The pharmaceutical composition of claim 1, wherein the composition comprises a cellulose derivative comprising carboxymethyl cellulose sodium, hydroxypropyl ^^^Attorney Docket No. 10029-122WO1 methyl cellulose (“HPMC”), methyl cellulose, hydroxyethyl cellulose, or a combination thereof.

12. The pharmaceutical composition of claim 1, wherein the composition comprises carboxymethyl cellulose sodium.

13. The pharmaceutical composition of claim 1, wherein the composition comprises cellulose and a cellulose derivative.

14. The pharmaceutical composition of claim 1, wherein the composition comprises cellulose and carboxymethyl cellulose sodium.

15. The pharmaceutical composition of claim 1, wherein the composition comprises cellulose and a cellulose derivative, wherein the cellulose derivative consists of carboxymethyl cellulose sodium.

16. The composition of any of claims 1 or 10-15, wherein the composition comprises cellulose, cellulose derivative, or combination thereof in a concentration from 0.1-5 wt.%, from 0.1-0.5 wt.%, from 0.5-1 wt.%, from 1-2 wt.%, from 2-3 wt.%, from 3-4 wt.%, or from 4-5 wt.%.

17. The composition of any of claims 1 or 10-15, wherein the composition comprises cellulose, cellulose derivative, or combination thereof in a concentration from 0.5-2.5 wt.%, from 0.5-2.0 wt.%, from 0.5-1.5 wt.%, from 0.75-1.25 wt.%, from 1-1.5 wt.%, from 1-1.25 wt.%, from 1-1.3 wt.%, or from 1.1-1.3 wt.%.

18. The composition of any of claims 1 or 10-15, wherein the composition comprises cellulose and carboxymethyl cellulose sodium in a concentration from 0.5-2.5 wt.%, from 0.5-2.0 wt.%, from 0.5-1.5 wt.%, from 0.75-1.25 wt.%, from 1-1.5 wt.%, from 1-1.25 wt.%, from 1-1.3 wt.%, or from 1.1-1.3 wt.%.

19. The composition of any of claims 1 or 10-15, wherein the composition comprises the cellulose, cellulose derivative, or combination thereof in a concentration from 1-1.5 wt.%, preferably from 1.1-1.3 wt.%.

20. The composition of any of claims 1 or 10-15, wherein the composition comprises cellulose and carboxymethyl cellulose sodium in a concentration from 1-1.5 wt.%, preferably from 1.1-1.3 wt.%.

21. The composition of claim 1, wherein the composition comprises an isotonicity agent.

22. The composition of claim 1, wherein the composition comprises an isotonicity agent comprising sodium chloride, dextrose, glycerin, sucrose, urea, propylene glycol, boric acid, phenobarbital, zinc sulfate, magnesium sulfate, sodium sulfate, zinc chloride, ^^^Attorney Docket No. 10029-122WO1 calcium bromide, sodium phosphate, sodium citrate, sodium borate, and potassium borate.

23. The composition of claim 1, wherein the composition comprises an isotonicity agent comprising sodium chloride.

24. The composition of claim 1, wherein the composition comprises an isotonicity agent consisting of sodium chloride.

25. The composition of any of claims 1 or 21-24, wherein the composition comprises an isotonicity agent in a concentration from 0.1-5 wt.%, from 0.1-0.5 wt.%, from 0.5-1.5 wt.%, from 0.5-1 wt.%, from 1-2 wt.%, from 2-3 wt.%, from 3-4 wt.%, or from 4-5 wt.%.

26. The composition of any of claims 1 or 21-24, wherein the composition comprises an isotonicity agent in a concentration from 0.5-1.5 wt.%.

27. The composition of claim 1, wherein the composition comprises a preservative.

28. The composition of claim 1, wherein the composition comprises a preservative comprising benzoyl alcohol, phenyl ethyl alcohol, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, sodium benzoate, chlorobutanol, thioglycerol, benzalkonium chloride, citric acid, ethylenediaminetetraacetic acid (EDTA), sodium citrate, propyl gallate, 8-hydroxyquinoline, boric acid, histidine, or a combination thereof.

29. The composition of claim 1, wherein the composition comprises a preservative comprising benzalkonium chloride.

30. The composition of claim 1, wherein the composition comprises a preservative consisting of benzalkonium chloride.

31. The composition of any of claims 1 or 27-30, comprising a preservative in a concentration from 0.005-5 wt.%, from 0.005-2.5 wt.%, from 0.005-1 wt.%, from 0.005-0.5 wt.%, from 0.05-0.5 wt.%, from 0.05-1 wt.%, from 0.1-1 wt.%, from 0.5- 2.5 wt.%, or from 1-2 wt.%.

32. The composition of any of claims 1 or 27-30, comprising a preservative comprising benzalkonium chloride in an amount from 0.005-1 wt.%, from 0.005-0.5 wt.%, from 0.05-0.5 wt.%, from 0.01-0.05 wt.%, from 0.01-0.025 wt.%, or from 0.015-0.025 wt.%.

33. The composition of any of claims 1 or 27-30, comprising a preservative comprising benzalkonium chloride in a concentration from 0.01-0.025 wt.%.

34. The composition of claim 1, wherein the composition is Composition 1. ^^^Attorney Docket No. 10029-122WO1 35. The composition of claim 1, wherein the composition is Composition 2.

36. The composition of claim 1, wherein the composition is Composition 3.

37. The composition of claim 1, wherein the composition is Composition 4.

38. The composition of claim 1, wherein the composition is Composition 5.

39. The composition of claim 1, wherein the composition is Composition 6.

40. The composition of any of claims 1-39, wherein the composition comprises 3-(2- bromo-5-methoxyphenyl)-6-isopropyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine, or a pharmaceutically acceptable salt thereof.

41. The composition of any of claims 1-39, wherein the composition comprises 3-(2- bromo-5-methoxyphenyl)-6-isopropyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine free base.

42. The composition of any of claims 1-39, wherein the composition comprises 6-(3,4- dimethoxyphenyl)-3-ethyl-7H-[1,24]triazolo[3,4-b][1,3,4thiadiazine or a pharmaceutically acceptable salt thereof.

43. The composition of any of claims 1-39, wherein the composition comprises 6-(3,4- dimethoxyphenyl)-3-ethyl-7H-[1,24]triazolo[3,4-b][1,3,4thiadiazine free base.

44. The composition of any of claims 1-39, wherein R1is phenyl optionally substituted with one or more, the same or different, R10.

45. The composition of any of claims 1-39, wherein R2is a branched alkyl of six or less carbons.

46. The composition of any of claims 1-39, wherein R1is phenyl optionally substituted with one or more, the same or different, R10and R2is alkyl optionally substituted with one or more, the same or different, R10, preferably R2is an unsubstituted C1-4alkyl 47. The composition of any of claims 1-39, wherein R2is carbocyclyl optionally substituted with one or more, the same or different, R10.

48. The composition of any of claims 1-39, wherein R2is a cyclopropyl or methylcyclopropyl.

49. The composition of any of claims 1-39, wherein R3and R4are hydrogen.

50. The composition of any of claims 1-39, wherein R1is phenyl optionally substituted with one or more, the same or different, R10, and R3and R4are hydrogen.

51. The composition of any of claims 1-39, wherein R2is alkyl optionally substituted with one or more, the same or different, R10, and R3and R4are hydrogen.

52. The composition of any of claims 1-39, wherein R2is a branched alkyl of six or less carbons, and R3and R4are hydrogen. ^^^Attorney Docket No. 10029-122WO1 53. The composition of any of claims 1-39, wherein R2is carbocyclyl optionally substituted with one or more, the same or different, R10, and R3and R4are hydrogen.

54. The composition of any of claims 1-39, wherein R2is a cyclopropyl or methylcyclopropyl, and R3and R4are hydrogen.

55. The composition of any of claims 1-39, wherein R1is phenyl optionally substituted with one or more, the same or different, R10, R2is alkyl optionally substituted with one or more, the same or different, R10, and R3and R4are hydrogen.

56. The composition of any of claims 1-39, wherein R1is phenyl optionally substituted with one or more, the same or different, R10, R2is a branched alkyl of six or less carbons, and R3and R4are hydrogen.

57. The composition of any of claims 1-39, wherein R1is phenyl optionally substituted with one or more, the same or different, R10, R2is carbocyclyl optionally substituted with one or more, the same or different, R10, and R3and R4are hydrogen.

58. The composition of any of claims 1-39, wherein R1is phenyl optionally substituted with one or more, the same or different, R10, R2is a cyclopropyl or methylcyclopropyl, and R3and R4are hydrogen.

59. The composition of any of claims 1-39, wherein one of R1and R2is phenyl substituted by one or more R10, and the other is C1-6alkyl, optionally substituted by one or more R10.

60. The composition of any of claims 1-39, wherein one of R1and R2is phenyl substituted by one or more times by halogen, C1-3alkoxy, or combination thereof, and the other is unsubstituted C1-6alkyl, for example methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, or tert-butyl.

61. The composition of any of claims 1-39, wherein the compound of formula I is 3-(2,3- dichlorophenyl)-6-(tert-pentyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (HDCF 83), 6-(tert-butyl)-3-(2,4-dichlorophenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (HDCF 89), 3-(2-bromo-5-methoxyphenyl)-6-isopropyl-7H-[1,2,4]triazolo[3,4- b][1,3,4]thiadiazine (HDCF104), 3-(2-bromo-5-chlorophenyl)-6-(tert-butyl)-7H- [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (HDCF 95) or 6-(3,4-dimethoxyphenyl)-3- ethyl-7H-[1,24]triazolo[3,4-b][1,3,4thiadiazine (uHTS-159) 62. The composition of any of claims 1-39, wherein the compound of Formula 1 is a compound of Formula (1a) or Formula (1b): or a pharmaceutically acceptable salt thereof, wherein: ^^^Attorney Docket No. 10029-122WO1[Formula (1a)] [Formula (1b)], R1ais hydrogen, halogen, or alkyl, for example C1-6alkyl; R2ais hydrogen, halogen, or alkyl; for example C1-6alkyl; or R1aand R2aand the attached atom form a carbocyclic ring; R3ais hydrogen, halogen, or alkyl; for example C1-6alkyl; or R1a, R2a, and R3aand the attached atom form a carbocyclic ring, for example adamantanyl; R4ais hydrogen, halogen or alkoxy, for example C1-6alkoxy; R5ais hydrogen, halogen or alkoxy, for example C1-6alkoxy; R6ais hydrogen, halogen or alkoxy, for example C1-6alkoxy; and R7ais hydrogen, halogen or alkoxy, for example C1-6alkoxy 63. The composition of claim 62, wherein R1ais methyl, and R2aand R3aare hydrogen, or R1aand R2aare methyl, and R3ais hydrogen.

64. The composition of any of claims 62 or 63, wherein the composition comprises the compound of Formula (1a), wherein R1aand R2aare methyl, and R3ais hydrogen.

65. The composition of any of claims 62-64, wherein the composition comprises the compound Formula (1b) R1ais methyl, and R2aand R3aare hydrogen.

66. The composition of any of claims 62-65, wherein two of R4a, R5a, R6a, and R7aare selected from halogen and alkoxy, for example C1-3alkoxy, and the other two of R4a, R5a, R6a, and R7aare hydrogen 67. The composition of any of claims 62-66, wherein the composition comprises the compound of Formula (1a) R4ais halogen, preferably Br, R7ais OC1-3alkyl, preferably OCH3, and R5aand R6aare each hydrogen.

68. The composition of any of claims 62-66, wherein the composition comprises the compound of Formula (1b) R5aand R6aare each OC1-3alkyl, preferably OCH3, and R4aand R7aare each hydrogen 69. A method of treating a respiratory disease or disorder in a subject in need thereof, comprising administering to the subject the composition of any of claims 1-68. ^^^Attorney Docket No. 10029-122WO1 70. The method of claim 69, wherein the composition is administered by spray intranasally.

71. The method of claim 69 or 70, wherein the composition is administered intranasally to the subject once a day, twice a day, three times a day, four times a day, or five times a day, where each administration comprises a single spray to a single nostril, a single spray to each nostril, a double spray to a single nostril, a double spray to both nostrils, a triple spray to a single nostril, or a triple spray to both nostrils.

72. The method of any of claims 69-71, wherein the subject is a human that is less than 18 years old, that is between 18-65 years old, or that is greater than 65 years old.

73. The method of any of claims 69-72, wherein the subject is diagnosed with cystic fibrosis.

74. The method of any of claims 69-72, wherein the subject is not diagnosed with cystic fibrosis.

75. The method of any of claims 69-74, wherein the subject has mutated CFTR.

76. The method of any of claims 69-74, wherein the subject does not have mutated CFTR.

77. The method of any of claims 69-76, wherein the subject has nasal polyps.

78. The method of any of claims 69-77, wherein the respiratory disease or disorder comprises rhinosinusitis, chronic obstructive pulmonary disease, nasal polyposis, bronchiectasis, Sjogren’s syndrome, asthma, chronic bronchitis, allergic bronchopulmonary aspergillosis, primarily ciliary dyskinesia, anosmia, xerostomia, xerophthalmia, lacrimal disorders or combination thereof.

79. The method of any of claims 69-78, wherein the respiratory disease or disorder comprises chronic rhinosinusitis.

80. The method of any of claims 69-79, wherein the method prevents or reduces an acute exacerbation.

81. The method of any of claims 69-80, wherein subject has experienced an acute exacerbation.

82. The method of any of claims 69-81, further comprising administering one or more additional therapeutic agents to the subject.

83. The method of claim 82, wherein the additional therapeutic agent comprises a ^-2- agonist, a mucolytic agent, an anti-inflammatory, PDE4 inhibitor, an antibiotic, CFTR activator, cyclic AMP activator, or a combination thereof.

84. The method of any of claims 70-83, wherein each spray delivers the composition in an amount from about 25-500 µL, from about 50-500 µL, from about 100-500 µL, ^^^Attorney Docket No. 10029-122WO1 from about 200-500 µL, from about 300-500 µL, from about 400-500 µL, from about 25-400 µL, from about 50-400 µL, from about 100-400 µL, from about 200-400 µL, from about 300-400 µL, from about 25-300 µL, from about 50-300 µL, from about 100-300 µL, from about 200-300 µL, from about 25-200 µL, from about 50-200 µL, from about 100-200 µL, from about 25-100 µL, from about 50-100 µL, or from about 25-50 µL.

85. The method of any of claims 70-83, wherein each spray delivers the composition in an amount from about 25-50 µL. ^^^

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