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WO2025189047A1 - Formulations pour modulateurs de cftr - Google Patents

Formulations pour modulateurs de cftr

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Publication number
WO2025189047A1
WO2025189047A1 PCT/US2025/018815 US2025018815W WO2025189047A1 WO 2025189047 A1 WO2025189047 A1 WO 2025189047A1 US 2025018815 W US2025018815 W US 2025018815W WO 2025189047 A1 WO2025189047 A1 WO 2025189047A1
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WO
WIPO (PCT)
Prior art keywords
composition
hydrogen
implementations
alkyl
cellulose
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Pending
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PCT/US2025/018815
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English (en)
Other versions
WO2025189047A8 (fr
Inventor
Eric Sorscher
Andras RAB
Matthew Reed
Paul Young
Darren ZHAO
Hui Xin ONG
Juhura ALMAZI
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Emory University
Original Assignee
Emory University
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Application filed by Emory University filed Critical Emory University
Publication of WO2025189047A1 publication Critical patent/WO2025189047A1/fr
Publication of WO2025189047A8 publication Critical patent/WO2025189047A8/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems

Definitions

  • CRSwNP chronic rhinosinusitis with nasal polyps
  • CRSsNP chronic rhinosinusitis without nasal polyps
  • 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.
  • HDCF104 is a PDE4 inhibitor (PDE4i) that could be used for treating patients with Cystic Fibrosis and Non-CF chronic rhinosinusitis.
  • PDE4i PDE4 inhibitor
  • 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.
  • 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.
  • R 2 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, (alkyl) 2 amino, cyano, formyl, alkanoyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 1 is optionally substituted with one or more, the same or different, R 10 ;
  • R 3 and R 4 are each, individually and independently, hydrogen, alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, (alkyl) 2 amino, cyano, formyl, alkanoyl, benzoyl, carboxy, carbamoyl, carb
  • composition comprises the compound of Formula 1 in a concentration from 0.05-5 mg/g
  • 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.
  • compositions can be used to treat chronic rhinosinusitis.
  • 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.
  • 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.
  • Figure 1B depicts a mucosal lining.
  • Figure 2 depicts a determination of the E C50 value of HDCF104 in RPMI2650 cells.
  • Half maximal effective concentration (EC 50 ) was calculated using Non-linear fit-[Agonist] vs response to find EC 50 .
  • Figure 3A depicts a particle size distribution of raw HDCF104.
  • Figure 3B depicts a particle size distribution of micronized HDCF104.
  • Figure 4 depicts the weight of wasted and collected shots reported as the average of three individual data sets.
  • FIG. 1 depicts a total assay of an HDCF104 formulation after storage under ICH conditions (marker lines indicate ⁇ 5% theoretical).
  • 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.
  • Figure 10B depicts RPMI2650 nasal epithelial integrity and permeability; calculated apparent permeability (Papp) of the epithelial layer.
  • Figure 10C depicts RPMI2650 nasal epithelial integrity and permeability; transport study of HDCF104 through the RPMI2650 nasal epithelia cumulative mass ( ⁇ g) of HDCF104 transported over 4 hours.
  • the dose-response curve shows formulated HDCF104 with a low micromolar EC 50 (3.57 ⁇ 1.122 ⁇ M with 95% CI (1.275 ⁇ M to 5.870 ⁇ M)).
  • GraphPad Prism 10 software was utilized to calculate EC 50 .
  • Data presented as the mean ⁇ SEM. (n 4).
  • DETAILED DESCRIPTION [0037]
  • chronic sinusitis 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.
  • compositions disclosed herein may be provided in the form of acceptable salts, for example pharmaceutically acceptable salts.
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • heteroaryl includes N-alkylated derivatives such as a 1-methylimidazol-5-yl substituent.
  • 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).
  • Alkoxy refers to an alkyl group as defined above attached through an oxygen bridge.
  • alkoxy examples 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.
  • Alkylamino refers an alkyl group as defined above attached through an amino bridge.
  • An example of an alkylamino is methylamino, (i.e., -NH-CH 3 ).
  • ⁇ Attorney Docket No. 10029-122WO1
  • halogen and halo refer to fluorine, chlorine, bromine, and iodine.
  • stable 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.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 o C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • 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.
  • 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.
  • 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.
  • C 1-6 alkyl is intended to encompass C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.
  • 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
  • heteroarylene is the divalent moiety of heteroaryl (each of which parent groups as defined herein).
  • 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.
  • a formula depicting one or more stereochemical features does not exclude the presence of other isomers.
  • 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.
  • 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.
  • 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.
  • compositions including a compound of Formula (1): [Formula (1)], or a pharmaceutically acceptable salt thereof, wherein R 1 is alkyl, aryl or heterocyclyl, wherein R 1 is optionally substituted with one or more, the same or different, R 10 ; ⁇ Attorney Docket No.
  • R 2 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 1 is optionally substituted with one or more, the same or different, R 10 ; R 3 and R 4 are each, individually and independently, hydrogen, alkyl, halogen, hydroxy, alkoxy, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3 and R 4 are optionally substituted with one or more, the same or different, R 10 ; R 10 is alkyl, halogen, nitro, cyano,
  • R 1 is phenyl optionally substituted with one or more, the same or different, R 10 .
  • R 2 is alkyl, for example C1-6alkyl, optionally substituted with one or more, the same or different, R 10 .
  • R 2 is a branched alkyl of six or less carbons.
  • R 1 is phenyl optionally substituted with one or more, the same or different, R 10 and R 2 is alkyl optionally substituted with one or more, the same or different, R 10 .
  • R 2 is an unsubstituted C 1-6 alkyl or C 1-4 alkyl.
  • R 2 is carbocyclyl for example C 3-6 carbocylyl, optionally substituted with one or more, the same or different, R 10 .
  • R 2 is a cyclopropyl or methylcyclopropyl.
  • R 3 and R 4 are hydrogen. ⁇ Attorney Docket No. 10029-122WO1
  • R 1 is phenyl optionally substituted with one or more, the same or different, R 10 , and R 3 and R 4 are hydrogen.
  • R 2 is alkyl optionally substituted with one or more, the same or different, R 10 , and R 3 and R 4 are hydrogen.
  • R 2 is a branched alkyl of six or less carbons, and R 3 and R 4 are hydrogen.
  • R 2 is carbocyclyl, for example C 3-6 carbocylyl, optionally substituted with one or more, the same or different, R 10 , and R 3 and R 4 are hydrogen.
  • R 2 is a cyclopropyl or methylcyclopropyl, and R 3 and R 4 are hydrogen.
  • R 1 is phenyl optionally substituted with one or more, the same or different, R 10 , R 2 is alkyl optionally substituted with one or more, the same or different, R 10 , and R 3 and R 4 are hydrogen.
  • R 1 is phenyl optionally substituted with one or more, the same or different, R 10 , R 2 is a linear or branched alkyl of six or less carbons, and R 3 and R 4 are hydrogen.
  • R 1 is phenyl optionally substituted with one or more, the same or different, R 10 , R 2 is carbocyclyl, for example C 3-6 carbocylyl, optionally substituted with one or more, the same or different, R 10 , and R 3 and R 4 are hydrogen.
  • R 1 is phenyl optionally substituted with one or more, the same or different, R 10 , R 2 is a cyclopropyl or methylcyclopropyl, and R 3 and R 4 are hydrogen.
  • one of R 1 and R 2 is phenyl substituted by one or more R 10 , and the other is C1-6alkyl, optionally substituted by one or more R 10 .
  • one of R 1 and R 2 is 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.
  • 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
  • the pharmaceutical composition includes a compound of Formula (1a) or Formula (1b): [Formula (1a)] [Formula (1b), or a pharmaceutically acceptable salt thereof, wherein: R 1a is hydrogen, halogen, or alkyl, for example C1-6alkyl; R 2a is hydrogen, halogen, or alkyl; for example C1-6alkyl; or R 1a and R 2a and the attached atom form a carbocyclic ring; R 3a is hydrogen, halogen, or alkyl; for example C1-6alkyl; or R 1a , R 2a , and R 3a and the attached atom form a carbocyclic ring, for example adamantanyl; R 4a is hydrogen, halogen or alkoxy, for example C 1-6 alkoxy; R 5a is hydrogen, halogen or alkoxy, for example C 1-6 alkoxy; R 6a is hydrogen, halogen or alkoxy, for example C 1-6 alkoxy; and
  • R 1a is methyl, and R 2a and R 3a are hydrogen. In some implementations R 1a and R 2a are methyl, and R 3a is hydrogen. [0091] In certain implementations of the compound of Formula (1a) R 1a and R 2a are methyl, and R 3a is hydrogen. In certain implementations of the compound Formula (1b) R 1a is methyl, and R 2a and R 3a are hydrogen. [0092] In certain implementations two of R 4a , R 5a , R 6a , and R 7a are selected from halogen and alkoxy, for example C 1-3 alkoxy, and the other two of R 4a , R 5a , R 6a , and R 7a are hydrogen.
  • R 4a is halogen, preferably Br
  • R 7a is OC 1-3 alkyl, preferably OCH 3
  • R 5a and R 6a are each hydrogen.
  • R 5a and R 6a are each OC1-3alkyl, preferably OCH3, and R 4a and R 7a are each hydrogen.
  • 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.
  • 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.
  • 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.
  • the composition 6-(3,4- dimethoxyphenyl)-3-ethyl-7H-[1,24]triazolo[3,4-b][1,3,4thiadiazine free base.
  • the composition is formulated for intranasal administration.
  • the composition includes water.
  • 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.
  • concentration of the compound is determined using the free base equivalent.
  • the composition includes water, the compound of Formula (1), Formula (1a), or Formula (1b), and no additional excipients.
  • the composition includes water, the compound of Formula (1), Formula (1a), or Formula (1b), and one or more pharmaceutically acceptable excipients.
  • the composition includes water as the only solvent.
  • 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.
  • 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.
  • 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 hydrochlor
  • 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.
  • 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.
  • 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
  • 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.
  • 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.%.
  • the composition can include polyvinylpyrrolidone, polyvinyl alcohol, or a combination thereof.
  • 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.
  • 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.
  • 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.%.
  • 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.%.
  • the composition can include a surfactant, for example, a positively charged oligosaccharide, cationic surfactant, anionic surfactant, amphoteric ⁇ Attorney Docket No.
  • 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.
  • 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.
  • 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.
  • 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.%.
  • 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.
  • 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.
  • the polysorbate surfactant e.g., polysorbate 80
  • the polysorbate surfactant 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.%.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compositions of the present disclosure can be formulated with a variety of pH ranges.
  • 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.
  • the compositions of the present disclosure are at a pH from about 5.0 to about 6.0.
  • the pH of the composition is from about 7 to about 8.
  • the pH of the composition is from about 6 to about 7. pH levels are determined at 23 °C.
  • 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.
  • 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.
  • 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,
  • 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).
  • 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.
  • the polysorbate is polysorbate 80.
  • the cellulose and/or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose and the polysorbate is polysorbate 80.
  • the composition is aqueous Composition 2 that includes: [0115]
  • Composition 2 includes a compound of Formula (1a).
  • 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.
  • 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.
  • 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.
  • the composition is aqueous Composition 3 that includes: [0120]
  • Composition 3 includes a compound of Formula (1a).
  • 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.
  • Composition 3 includes 3-(2-bromo-5- methoxyphenyl)-6-isopropyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine free base.
  • Composition 3 includes a compound of Formula (1b).
  • 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.
  • the polysorbate is polysorbate 80.
  • the cellulose and/or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose and the polysorbate is polysorbate 80.
  • the composition is aqueous Composition 4 that includes: ⁇ Attorney Docket No. 10029-122WO1 [0125]
  • Composition 4 includes a compound of Formula (1a).
  • 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.
  • 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.
  • Composition 4 includes 6-(3,4-dimethoxyphenyl)-3-ethyl-7H- [1,24]triazolo[3,4-b][1,3,4thiadiazine free base.
  • the cellulose and/or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose.
  • the polysorbate is polysorbate 80.
  • the cellulose and/or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose and the polysorbate is polysorbate 80.
  • the composition is aqueous Composition 5 that includes: ⁇ Attorney Docket No.
  • 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).
  • 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.
  • the cellulose and/or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose and the polysorbate is polysorbate 80.
  • the composition is aqueous Composition 6 that includes: [0133]
  • Composition 6 includes a compound of Formula (1a).
  • 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.
  • 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.
  • Composition 6 includes 6-(3,4-dimethoxyphenyl)-3-ethyl-7H- [1,24]triazolo[3,4-b][1,3,4thiadiazine free base.
  • the cellulose and/or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose.
  • the polysorbate is polysorbate 80.
  • the cellulose and/or cellulose derivative is a mixture of microcrystalline cellulose and carboxymethylcellulose and the polysorbate is polysorbate 80.
  • the compound of Formula (1), Formula (1a), or Formula (1b) has a particle size Dv50 from 0.5-5 ⁇ m, from 0.5-3 ⁇ m, from 0.5-2.5 ⁇ m, from 1-2.5 ⁇ m, from 1- 2 ⁇ m, or from 1.5-2.5 ⁇ m. In certain implementations, the compound of Formula (1), Formula (1a), or Formula (1b) has a particle size Dv90 from 3-10 ⁇ m, from 3-8 ⁇ m, from 3- 6 ⁇ m, from 3-5 ⁇ m, or from 4-5 ⁇ m.
  • the compound of Formula (1), Formula (1a), or Formula (1b) has a particle size Dv10 from 0.05-1 ⁇ m, from 0.05-0.5 ⁇ m, from 0.05-0.25 ⁇ m, from 0.1-0.5 ⁇ m, from 0.2-0.4 ⁇ m, or from 0.25-0.35 ⁇ m.
  • 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.
  • 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.
  • 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.
  • 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.
  • particle size distributions refer to the proportion of equivalent sphere diameters as determined by Malvern Mastersizer MS3000 with Aero S apparatus.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the liquid nasal formulations described herein may be aqueous solutions, suspensions or emulsions.
  • antimicrobial preservatives may be included to maintain microbiological stability.
  • Previously 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.
  • 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.
  • the nasal formulations disclosed herein can be delivered by nasal irrigation.
  • 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 collectively constitute the drug product.
  • 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.
  • 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.
  • the nasal formulations described herein are delivered by a device- metered nasal spray pump.
  • the device-metered spray pump replaces the emitted liquid formulation with air.
  • the formulations include a preservative.
  • 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.
  • the device-metered spray pump replaces the emitted liquid nasal formulation with air filtered through an aseptic air filter.
  • 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.
  • 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 ⁇ l per spray. In some implementations, 25 ⁇ l of the nasal formulation described herein is delivered by a device- metered spray pump. In some implementations, 50 ⁇ l of the nasal formulation described herein is delivered by a device-metered spray pump. In some implementations, 75 ⁇ l of the nasal formulation described herein is delivered by a device-metered spray pump.
  • 100 ⁇ l of the nasal formulation described herein is delivered by a device- metered spray pump. In some implementations, 125 ⁇ l of the nasal formulation described herein is delivered by a device-metered spray pump. In some implementations, 150 ⁇ l of the nasal formulation described herein is delivered by a device-metered spray pump. In some implementations, 175 ⁇ l of the nasal formulation described herein is delivered by a device- metered spray pump. In some implementations, 200 ⁇ l of the nasal formulation described herein is delivered by a device-metered spray pump.
  • the spray device administers a volume of the composition that is from about 25-500 ⁇ L, from about 50-500 ⁇ L, from about 100-500 ⁇ L, from about 200-500 ⁇ L, from about 300-500 ⁇ L, from about 400-500 ⁇ L, from about 25-400 ⁇ L, from about 50-400 ⁇ L, from about 100-400 ⁇ L, from about 200-400 ⁇ L, from about 300-400 ⁇ L, from about 25-300 ⁇ L, from about 50-300 ⁇ L, from about 100-300 ⁇ L, from about 200-300 ⁇ L, from about 25-200 ⁇ L, from about 50-200 ⁇ L, from about 100-200 ⁇ L, from about 25- 100 ⁇ L, from about 50-100 ⁇ L, or from about 25-50 ⁇ L.
  • the spray device delivers from 10-50 ⁇ g of the compound of Formula (1), Formula (1a), or Formula (1b) per individual spray. In some implementation, the spray device delivers from 20-40 ⁇ g or from 25-35 ⁇ g 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • the nasal formulation described herein is delivered in a liquid, nebulized, or aerosolized form.
  • 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.
  • 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).
  • 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.
  • the product in its final container is then subjected to a sterilization process such as heat or irradiation.
  • a sterilization process such as heat or irradiation.
  • the drug product, container, and closure may be first subjected to sterilization methods separately, as appropriate, and then brought together.
  • 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.
  • the composition is administered to the subject intranasally.
  • 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.
  • 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.
  • the compositions can be used to induce salivation or to induce tearing.
  • the respiratory disease or disorder is rhinosinusitis.
  • the respiratory disease or disorder is chronic rhinosinusitis.
  • the respiratory disease or disorder is rhinosinusitis accompanied by nasal polyps.
  • 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.
  • CST1/2, PRDX5 Peroxiredoxin-5
  • GP6 Platinum glycoprotein VI
  • 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.
  • 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 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.
  • 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.
  • the composite score of 3CS is the sum of the three cardinal symptom scores.
  • 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.
  • 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).
  • CRS Individual Cardinal Chronic Rhinosinusitis
  • the 4 individual CRS symptoms are: congestion, facial pain or pressure sensation, nasal discharge (anterior and/or posterior), and sense of smell.
  • 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.
  • 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.
  • 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 total SNOT-22 score is the sum of the 22 items and can range from 0 to 110 with higher scores indicating worse symptoms.
  • 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.
  • 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.
  • Composite score is a sum of the 3 symptom scores and will range from 0 to 9.
  • 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.
  • 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.
  • each sinus pair has a bilateral score in the range of 0 to 10. Higher scores indicate higher severity of sinus opacification.
  • 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.
  • 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.
  • 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%.
  • 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%.
  • 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%.
  • 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%.
  • 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.
  • ⁇ 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.
  • 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.
  • the disclosed compositions can be administered to a patient to reduce the number and severity of acute exacerbations of chronic sinusitis.
  • the disclosed compositions can be administered to a patient to produce a change from baseline as measured by the Pittsburgh Sleep Quality Index (PSQI) -
  • PSQI Pittsburgh Sleep Quality Index
  • 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.
  • 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.
  • 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.
  • administration of the disclosed compositions provides a patient score of 3 or less, 2 or less, or 1.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)TM.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • the subject is administered one or more additional therapeutic agents along with the disclosed compositions.
  • the subject is administered a bronchodilator, corticosteroid, PDE4 inhibitor, CFTR activator antimuscarinic, cyclic AMP activator, cromolyn, antibiotic, or a combination thereof.
  • the subject is administered a ⁇ -2 agonist in combination with the disclosed compositions.
  • 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.
  • the subject is administered a mucolytic agent in combination with the disclosed compositions.
  • 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.
  • NAC N-acetylcysteine
  • the subject is administered a PDE4 inhibitor such as apremilast, crisaborole, or roflumilast agonist in combination with the disclosed compositions.
  • 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).
  • the subject is administered a CFTR activator agonist in combination with the disclosed compositions.
  • 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.
  • the subject is administered the disclosed compositions in combination with tezacaftor with ivacaftor.
  • the subject is administered the disclosed compositions in combination with tezacaftor with elexacaftor and ivacaftor.
  • the subject is administered the disclosed compositions in combination with tezacaftor with vanzacaftor and deutivacaftor.
  • the subject is administered a cyclic AMP activator (for example forskolin, H89, KT-5720, and dibutyryl-cAMP) in combination with the disclosed compositions.
  • the subject is administered cromolyn agonist in combination with the disclosed compositions.
  • 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, triam
  • the subject is administered the disclosed composition in combination with dexamethasone, prednisone, prednisolone, triamcinolone, cortisol, budesonide, mometasone, fluticasone, flunisolide, betamethasone, or a combination thereof.
  • the subject is administered the disclosed composition in combination with a decongestant, for example in combination with pseudoephedrine, ⁇ Attorney Docket No.
  • 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
  • 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, moxif
  • 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.
  • macrolides e.g., ⁇ Attorney Docket No. 10029-122WO1 erythromycin
  • penicillins e.g., amoxicillin, beta-lactam, ampicillin
  • tetracyclines e.g., doxycycline, tetracycline
  • sulfonamides
  • 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.
  • antifungals including but limited to, allylamines and thiocarbamates like terbinafine, naftifine, to
  • 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,
  • the subject is administered the disclosed composition in combination with one or more additional rhinosinusitis treatments.
  • 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.
  • temperature is °C or is at ambient temperature, and pressure is at or near atmospheric.
  • process conditions 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.
  • RPMI2650 cells were treated with the concentrations range of 1- 1000 ⁇ M 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).
  • EC 50 was calculated to be 101.5 ⁇ M.
  • 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.
  • HDCF104 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
  • 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).
  • Example 4 Preparation of the HDCF104 Nasal Formulation [0202] The optimal concentration of AVICEL TM RC-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 AVICEL TM with water.
  • AVICEL TM /water dispersion was made initially and an IKA ULTRA-TURRAX homogenizer was used to activate AVICEL TM at >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 AVICEL TM /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.
  • HDCF104 Quantification by HPLC was 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 ⁇ m, 100 ⁇ , Phenomenex, Torrance, USA).
  • HPLC high-performance liquid chromatography
  • 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.
  • 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.
  • 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).
  • Example 7 Formulation Robustness
  • concentrations of AVICEL TM RC591 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.
  • the Spraytec was set up at a 45° inhalation cell, open bench measurement with air extractor on.
  • 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.
  • 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%).
  • FIGS 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>.
  • 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
  • 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 cm 2 ⁇ 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.
  • MEM Minimum Essential Media
  • FBS fetal bovine serum
  • FBS fetal bovine serum
  • 1% (v/v) non-essential amino acids solution 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.
  • ALI air-liquid interface
  • cells were seeded at a density of 5 ⁇ 10 5 ⁇ cells/insert on a Snapwell polyester inserts (1.12 cm 2 ⁇ growth area) containing 200 ⁇ L 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.
  • 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 EVOM2 TM ⁇ 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.
  • HBSS Balanced Salt Solution
  • TEER ⁇ cm2
  • ⁇ the measured potential resistance difference between the apical and basolateral sides
  • ⁇ the measured potential resistance difference between the apical and basolateral sides
  • TEER ⁇ ( ⁇ cm 2 ) (Resistance test ⁇ Resistance blank ) ⁇ Area ⁇ of ⁇ well ⁇ insert
  • 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 (3 ⁇ g) 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.
  • NTI next generation impactor
  • 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.
  • 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.
  • the HDCF104 in the formulation if more effectively transported through the nasal epithelia compared to direct deposition with propellant.
  • Example 12 Sodium Fluorescein Paracellular Permeability
  • 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.
  • 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% CO 2 – 95% air atmosphere on inserts until they formed a well-polarized airway epithelial stage, typically 4 weeks from seeding.
  • ALI air-liquid interface
  • the temperature of bathing solutions was maintained at 37 °C and stirred by bubbling through 5% CO 2 /95% O 2 .
  • 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.
  • CFTR (inh)-172 (10 ⁇ M; MilliporeSigma C2992) was administered to the apical side to inhibit CFTR-mediated current.
  • UTP VWR, 0145
  • Isc short circuit current
  • 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 EC 50 in 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).
  • HDCF-104 Intranasal Dose Range Finding Studies in Male and Female Sprague Dawley Rats
  • 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).
  • NCE chronic Rhinosinusitis
  • HDCF-104 functions by activating the cystic fibrosis transmembrane conductance regulator (CFTR) through inhibiting of phosphodiesterase enzyme 4 (PDE4).
  • CFTR cystic fibrosis transmembrane conductance regulator
  • PDE4 phosphodiesterase enzyme 4
  • 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.
  • 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.
  • terminal brain and nasal turbinate samples were taken from 3 animals / group / time point at 75min, 5, and 24 hours post dose administration.
  • Three male and three female Main Study animals per group were euthanized after a 48-hour observations period. No tissues were collected.
  • 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.
  • 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.
  • 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.
  • 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.
  • HDCF-104 Intranasal Dose Range Finding Studies in Male and Female Beagle Dogs
  • 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).
  • NCE cystic fibrosis transmembrane conductance regulator
  • PDE4 phosphodiesterase enzyme 4
  • 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.
  • 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.
  • 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.
  • 200 ⁇ l TA administrations were separated by approximately 80min.
  • 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).
  • Intranasal dosing of the TA was well tolerated in both phases of the study.
  • 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.
  • 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.
  • 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.
  • 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.

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Abstract

L'invention concerne des compositions pharmaceutiques pour le traitement de maladies et de troubles respiratoires, y compris la rhinosinusite. Selon certains aspects, les compositions fournissent une administration sélective aux voies respiratoires supérieures et facilitent un transport efficace des agents actifs à travers les membranes.
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US20080045514A1 (en) * 2006-07-18 2008-02-21 Cytovia, Inc. 3-Aryl-6-aryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and analogs as activators of caspases and inducers of apoptosis and the use thereof

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Publication number Priority date Publication date Assignee Title
US20080045514A1 (en) * 2006-07-18 2008-02-21 Cytovia, Inc. 3-Aryl-6-aryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and analogs as activators of caspases and inducers of apoptosis and the use thereof

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WU ET AL.: "Recent research progress on preparation and application of N,N,N-trimethyl chitosan", CARBOHYDRATE RESEARCH, vol. 434, 2016, pages 27 - 32, XP029771889, DOI: 10.1016/j.carres.2016.08.002 *

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