Intranasal preparations for treating obstructive sleep apnea

Abstract

This disclosure relates to a nasal pharmaceutical composition for the treatment of obstructive sleep apnea, a combination of drug and device for intranasal delivery of the pharmaceutical composition, and a method of treatment. In one embodiment, this disclosure provides a pharmaceutical composition comprising 2'-{[2-(4-methoxyphenyl)-acetylamino]-methyl}biphenyl-2-carboxylic acid (2-pyridine-3-yl-ethyl)-amide (compound 1) or a pharmaceutically acceptable salt thereof, and a mucosal adhesive polymer.

Description

[Technical Field]

[0001] 1. Background of the Invention Obstructive sleep apnea (OSA), also known as obstructive sleep apnea-hypopnea syndrome (OSAHS), is estimated to affect one-third of the adult population, with an estimated global prevalence of approximately 1 billion people. Obstructive sleep apnea causes daily debilitation, including excessive daytime sleepiness, and in the longer term, increases the risk of various adverse sequelae, including hypertension and cardiometabolic syndrome.

[0002] Treatment for OSA has changed little over the past few decades, with the vast majority of patients being treated with positive airway pressure, primarily continuous positive airway pressure (CPAP). CPAP compliance is poor. Oral appliances to advance the mandible during sleep have poor compliance and uncertain effectiveness. Surgical procedures to open the airway (e.g., surgical removal of oral or oropharyngeal soft tissue and maxillofacial advancement surgery) are invasive and expensive and not suitable for the anatomical structure of all patients.

[0003] Therefore, new treatments are needed to reduce the severity of OSA.

[0004] Intranasal administration of potassium channel blockers to increase the activity of pharyngeal dilating muscles, particularly the genioglossus muscle, has been proposed as a potentially pharmacological approach to treating OSA. In 2013, Wirth et al. reported that local administration of the potassium channel blocker AVE0118 (2'-{[2-(4-methoxyphenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid (2-pyridine-3-yl-ethyl)-amide (compound 1)) into the upper airway of anesthetized pigs increased sensitivity to negative pressure reflex (NPR), shifted the mechanoreceptor response threshold of the genioglossus muscle toward positive pressure, and dose-dependently suppressed upper airway collapse (Wirth et al., SLEEP, 36(5):699-708 (2013)). There have been no published human clinical trials regarding compound 1 in OSA. However, Gaisl et al., Eur.Respir.J.58:2101937(2021) describes a phase 2 clinical trial in which intranasal administration of the potassium channel blocker BAY2253651 was attempted. However, it was concluded that a single intranasal application did not result in a reduction of the apnea-hypoxia index (AHI) in people with moderate to severe OSA who were not using CPAP. More recently, Osman et al., Chest 163(4):953-965(2023) investigated the use of different K in 12 selected patients. + A small clinical trial using the blocking agent BAY2586116 has been described, reporting an average improvement of approximately 2 cmH2O in pharyngeal collapse in OSA patients with intranasal administration of BAY2586116 compared to placebo. However, this is far from the 4-6 cm change achievable with dental instruments, and Bayer is not currently actively developing BAY2586116 (bayer.com / sites / default / files / ph-rd-pipeline-2023-08-final-new.pdf). There is still a need for medications that can treat OSA. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Wirth et al.,SLEEP,36(5):699-708(2013) [Non-Patent Document 2] Gaisl et al.,Eur.Respir.J.58:2101937(2021) [Non-Patent Document 3] Osman et al., Chest 163(4):953-965(2023) [Non-Patent Document 4] bayer.com / sites / default / files / ph-rd-pipeline-2023-08-final-new.pdf [Overview of the Initiative]

[0006] 2. Outline of the Invention Despite reports of unsuccessful intranasal potassium channel blockers in the 10 years since Wirth's initial report, a phase 2 clinical trial of intranasal administration of AVE-118 (compound 1) was conducted in human OSA patients. As reported in Example 1 herein, this trial failed to meet the primary efficacy endpoint, and no significant improvement in obstructive sleep apnea was demonstrated after intranasal administration of compound 1.

[0007] There are many possible reasons why this trial was unsuccessful, but considering that there is no in vitro test that can model (i) sufficient deposition of channel blockers proximal to the genioglossal nerve endings in the nasopharynx, followed by (ii) entry into cells, and (iii) 8-hour persistence at the nerve endings, further development would have been hindered if Wirth's pig model did not have applicability to human OSA. However, as described in Example 3, we were able to demonstrate the applicability of Wirth's pig model.

[0008] By using a modified Wirth pig OSA model, we were able to determine whether the failure of the Phase 2 trial was attributable to the use of a suspension formulation of compound 1 in the trial. When pigs were placed vertically and intranasally administered a solution formulation containing 0.3 mg of compound 1, upper airway collapse was completely suppressed, and the duration of effectiveness was longer than that obtained with the Phase 2 suspension formulation. See Example 4. However, when nasal irrigation was performed after intranasal administration of compound 1 to model the continuous flow of mucus during lying down and sleep, the effect of compound 1 in the solution formulation was rapidly and completely neutralized. See Example 5.

[0009] In this pig model, neither the suspension nor the solution formulation could alleviate upper airway collapse over an 8-hour period. However, a microparticle suspension of compound 1 in a formulation containing various mucosal-adhering polymers was found to effectively treat OSA in a vertical pig model, tolerate nasal irrigation after administration, and reduce upper airway collapse. See Example 6. These properties enable the treatment of OSA by intranasal administration of potassium channel blockers, particularly pan-K channel inhibitors such as compound 1.

[0010] Accordingly, in one embodiment, the present disclosure provides a pharmaceutical composition comprising 2'-{[2-(4-methoxyphenyl)-acetylamino]-methyl}biphenyl-2-carboxylic acid (2-pyridine-3-yl-ethyl)-amide (compound 1) or a pharmaceutically acceptable salt thereof, and a mucosal adhesive polymer.

[0011] In another embodiment, the Disclosure provides a method for treating obstructive sleep apnea in a subject requiring treatment, comprising administering an effective amount of the pharmaceutical composition described herein to the subject before sleep. In certain embodiments, the composition is administered intranasally by a drug device combination product comprising a nasal delivery device and one or more doses of the pharmaceutical composition described herein.

[0012] In another embodiment, the Disclosure provides a pharmaceutical composition described herein for use in a method for treating obstructive sleep apnea in a subject requiring treatment, the method comprising administering an effective amount of the pharmaceutical composition described herein to the subject before sleep. In certain embodiments, the composition is administered intranasally by a drug device combination product comprising a nasal delivery device and one or more doses of the pharmaceutical composition described herein.

[0013] 3. Brief explanation of the drawing These and other features, aspects and advantages of the present invention will be better understood with reference to the following description and accompanying drawings. [Brief explanation of the drawing]

[0014] [Figure 1] This is a schematic diagram of the Phase 2 clinical trial design described in Example 1 below.

[0015] [Figure 2] The mean change (±95% confidence interval) of the apnea-hypoxia index (AHI) from baseline in the protocol-compliant (PP: per-protocol) population in the clinical trial described in Example 1 is plotted.

[0016] [Figure 3] This is a plot of individual AHI values ​​in the protocol-fit (PP) population in the clinical trial described in Example 1.

[0017] [Figure 4] This study demonstrates the efficacy of intravenous administration of oxybutynin with a 20 μg / kg bolus and 12.5 μg / kg / h infusion, followed by 4 hours of intravenous administration of atomoxetine with a 1 mg / kg bolus and 275 μg / kg / h infusion, in an anesthetized pig model of upper airway collapse.

[0018] [Figure 5] This example demonstrates the effect of intranasal administration of a 0.3 mg (400 μl / nostril) solution formulation of Compound 1 in an anesthetized pig model on upper airway collapse.

[0019] [Figure 6] This example demonstrates the effect of intranasal administration of a 12 mg (200 μl / nostril) suspension formulation of compound 1 (3% w / w) as described in Example 4 on upper airway collapse in an anesthetized pig model.

[0020] [Figure 7] This example demonstrates the effect of nasal irrigation following intranasal administration of a 0.3 mg (400 μl / nostril) solution formulation of Compound 1 in an anesthetized pig model of upper airway collapse.

[0021] [Figure 8] This example demonstrates the effect of nasal irrigation following intranasal administration of a 3 mg (400 μl / nostril) solution of compound 1 in an anesthetized pig model on upper airway collapse.

[0022] [Figure 9] This example demonstrates the effect of nasal irrigation following intranasal administration of a 24 mg (400 μl / nostril) suspension formulation of Compound 1 (3% w / w) in an anesthetized pig model of upper airway collapse.

[0023] [Figure 10] This example demonstrates the effect of nasal irrigation following intranasal administration of a 24 mg (400 μl / nostril) suspension formulation of Compound 1 (3% w / w) in an anesthetized pig model of upper airway collapse.

[0024] [Figure 11] This example demonstrates the effect of nasal irrigation after intranasal administration of a 18 mg (400 μl / nostril) suspension of compound 1 (2.25% w / w) as described in Example 4 on upper airway collapse in an anesthetized pig model.

[0025] [Figure 12] The average time to onset of action for each formulation of Compound 1 tested at three test negative pressure levels: -50 cm, -100 cm, and -150 cmH2O, in an anesthetized pig model.

[0026] [Figure 13] This report shows the average duration of action for each formulation of Compound 1 tested at three test negative pressure levels: -50 cm, -100 cm, and -150 cmH2O, in an anesthetized pig model. The observation period ended at 480 minutes.

[0027] [Figure 14] This report presents individual pig data for the time to onset and duration of action for each formulation of Compound 1 tested at three test negative pressure levels: -50 cm, -100 cm, and -150 cmH2O, in an anesthetized pig model. [Figure 15] This report presents individual pig data for the time to onset and duration of action for each formulation of Compound 1 tested at three test negative pressure levels: -50 cm, -100 cm, and -150 cmH2O, in an anesthetized pig model. [Figure 16] This report presents individual pig data for the time to onset and duration of action for each formulation of Compound 1 tested at three test negative pressure levels: -50 cm, -100 cm, and -150 cmH2O, in an anesthetized pig model. [Figure 17] This report presents individual pig data for the time to onset and duration of action for each formulation of Compound 1 tested at three test negative pressure levels: -50 cm, -100 cm, and -150 cmH2O, in an anesthetized pig model. [Figure 18] This report presents individual pig data for the time to onset and duration of action for each formulation of Compound 1 tested at three test negative pressure levels: -50 cm, -100 cm, and -150 cmH2O, in an anesthetized pig model. [Figure 19] This report presents individual pig data for the time to onset and duration of action for each formulation of Compound 1 tested at three test negative pressure levels: -50 cm, -100 cm, and -150 cmH2O, in an anesthetized pig model. [Figure 20]This report presents individual pig data for the time to onset and duration of action for each formulation of Compound 1 tested at three test negative pressure levels: -50 cm, -100 cm, and -150 cmH2O, in an anesthetized pig model. [Figure 21] This report presents individual pig data for the time to onset and duration of action for each formulation of Compound 1 tested at three test negative pressure levels: -50 cm, -100 cm, and -150 cmH2O, in an anesthetized pig model.

[0028] [Figure 22] An exemplary nasal device used for dispensing a composition of compound 1 is shown. The device's fluid dispenser pump is in the resting position.

[0029] [Figure 23] An exemplary nasal device used for dispensing a composition of compound 1 is shown. The device's fluid dispenser pump is in the operating position.

[0030] [Figure 24] Representative microscopic images (100x and 400x) of the Phase II formulation (3% compound 1) at t=0 are shown.

[0031] [Figure 25] Representative microscopic images (400x magnification) of SU28 (9% (w / w) compound 1) and SU41 (9% (w / w) compound 1) at t=0 and t=4 after 4 weeks of storage at 40°C are shown.

[0032] [Figure 26] Representative microscopic images (100x magnification) of SU40 (9% (w / w) compound 1) and SU45 (9% (w / w) compound 1) at t=0 and at t=4 after 4 weeks of storage at 25°C and 40°C are shown.

[0033] [Figure 27](From left to right) The precipitation rates of SU28, SU41, SU40, and SU45 are shown. All formulations contain 9% (w / w) of compound 1.

[0034] [Figure 28] The scintigraphy study design for Example 8 is shown. TV1 = Treatment visit 1 (SU2810), TV2 = Treatment visit 2 (SU4510), TV3 = Treatment visit 3 (SU4110), and TV4 = Treatment visit 4 (SU4530). All formulations contain 9% (w / w) of compound 1. [Modes for carrying out the invention]

[0035] 4. Detailed Description of the Invention 4.1. Definition In describing embodiments of this disclosure, the following terms, if present, have the meanings set forth below unless otherwise specified. Unless otherwise defined, the terms have the conventional meanings in the relevant technical field.

[0036] As will be obvious to those skilled in the art, the terms used in this specification, and especially in the claims (e.g., the body of the claims), are generally intended to be "non-restrictive" terms (for example, the term "including" should be interpreted as "including but not limited to," the term "having" should be interpreted as "having at least one," and the term "includes" should be interpreted as "includes but is not limited to"). Furthermore, as will be obvious to those skilled in the art, if a specific number of claimed features to be introduced is intended, such intention is clearly stated in the claim; if such statement is absent, such intention does not exist. For example, to aid understanding, the following claims may include the use of the introductory phrases "at least one" and "one or more" to introduce claimed features. However, the use of such phrases should not be interpreted as implying that a particular claim containing such introduced claimed features is limited to embodiments containing only one such feature (even if the claim contains an introductory phrase such as "one or more" or "at least one" and an indefinite article such as "a" or "an"), due to the introduction of the claimed feature with the indefinite article "a" or "an" (for example, "a" and / or "an" should be interpreted as meaning "at least one" or "one or more"). The same applies to the use of definite articles used to introduce claimed features. Furthermore, it will be understood by those skilled in the art that even if a specific number of claimed features to be introduced is explicitly stated, such statement should be interpreted as meaning at least the stated number (for example, the statement "two features" without other modifying phrases means at least two features or two or more features).Furthermore, when expressions such as "at least one of A, B, and C, etc." are used, such constructions are generally intended to have the meaning of that expression as understood by those skilled in the art (for example, "a system having at least one of A, B, and C" includes, but is not limited to, systems having A alone, B alone, C alone, both A and B, both A and C, both B and C, and / or all of A, B, and C). When expressions such as "at least one of A, B, or C, etc." are used, such constructions are generally intended to have the meaning of that expression as understood by those skilled in the art (for example, "a system having at least one of A, B, or C" includes, but is not limited to, systems having A alone, B alone, C alone, both A and B, both A and C, both B and C, and / or all of A, B, and C). Furthermore, as is obvious to those skilled in the art, substantially any disjunctive word and / or phrase indicating two or more disjunctive terms should be understood in the specification, claims, or drawings to presuppose the possibility of including one of the terms, either of the terms, or both of the terms. For example, the phrase “A or B” shall be understood to include the possibilities of “A” or “B” or “A and B.”

[0037] Furthermore, if any feature or aspect of this disclosure is described as a Markush group, it will be understood by those skilled in the art that this disclosure is also described as an individual component or a subgroup of a component of the Markush group.

[0038] As is obvious to those skilled in the art, all scopes disclosed herein, regardless of the purpose, including the provision of written explanations, encompass all possible sub-scopes and combinations of sub-scopes of that scope. Each scope presented is readily apparent and readily understood to be fully explainable and permissible as being divided into at least two, three, four, five, ten, and so on. As a non-limiting example, each scope described herein can easily be divided into a lower third, a middle third, and an upper third, and so on. Again, as is obvious to those skilled in the art, all terms such as “up to,” “at least,” “greater than,” and “less than” include the stated numbers and refer to scopes that can continue to be divided into sub-scopes as described above. Finally, as is obvious to those skilled in the art, a scope includes each individual component. Therefore, for example, a group having 1 to 3 items refers to a group having 1, 2, or 3 items. Similarly, a group having 1 to 5 items refers to a group having 1, 2, 3, 4, or 5 items, and so on.

[0039] As used herein, the term “effective dose” means the amount of a compound or composition sufficient to produce the desired utility when administered to a subject. Thus, the term “effective dose” refers to the amount of a compound or composition sufficient to promote a particular effect when administered to a subject in need of treatment. In certain embodiments, the effective dose includes the amount of a compound or composition sufficient to prevent or delay the onset of disease symptoms, alter the course of disease symptoms (e.g., slow the progression of disease symptoms), or improve disease symptoms. Naturally, in any case, a suitable “effective dose” can be determined by a person skilled in the art using standard experiments. For example, when administered clinically, such a compound or composition would contain an effective amount of the active ingredient to achieve the desired result.

[0040] As used herein, “mucosal adhesion” refers to the ability of a substance (e.g., a polymer) or composition to adhere to mucous membranes for extended periods.

[0041] As used herein, the term “pharmaceutically acceptable salt” means a salt that, within the bounds of proper medical judgment, is suitable for use in contact with human and lower animal tissues without causing excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable benefit-risk ratio. pharmaceutically acceptable salts are well known in the art. pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate. Examples include lactobionate, lactate, laurate, lauryl sulfate, malic acid, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N+(C1-4 alkyl) 4 salts. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium.Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylic acids, sulfuric acids, phosphoric acids, nitric acids, lower alkyl sulfonic acids, and aryl sulfonic acids.

[0042] As used herein, “Subject” refers to a human or organism to which the composition is administered or intended to be administered. Therefore, the subjects of the present invention may include, but are not limited to, mammals, such as humans, and other primates, such as chimpanzees and other apes and monkey species. In preferred embodiments, the subject is human. The term subject includes humans or organisms of any age, weight, or other physical characteristics, including adults, adolescents, children, infants, or neonates.

[0043] As used herein, “to treat” or “treatment” has the broadest meaning generally recognized in the art of treating sleep apnea and hypopnea, and therefore cure or remission is not necessarily required. These terms include, for example, the suppression or improvement of symptoms associated with the condition the subject is suffering from, and this suppression or improvement is used in a broad sense to refer to at least a reduction in the severity of parameters associated with the condition being treated, such as obstructive sleep apnea. Thus, treatment also includes situations in which the condition is completely suppressed, for example, its occurrence is prevented or halted, or it terminates, so that the subject no longer experiences the condition. Therefore, treatment includes both the prevention and management of the condition.

[0044] In typical embodiments, this disclosure is intended to encompass the compounds disclosed herein, as well as pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomers, polymorphs, and prodrugs of such compounds. In specific embodiments, this disclosure includes pharmaceutically acceptable addition salts, pharmaceutically acceptable esters, solvates (e.g., hydrates) of addition salts, tautomers, polymorphs, enantiomers, mixtures of enantiomers, stereoisomers, or mixtures of stereoisomers (as pure, racemic, or non-racemic) of the compounds described herein.

[0045] The compounds described herein may contain one or more chiral centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of stereoisomer mixtures, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers may be isolated from mixtures by methods known to those skilled in the art, such as chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, and preferred isomers may be prepared by asymmetric synthesis. This disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0046] 4.2. Composition In one embodiment, the present disclosure provides a pharmaceutical composition comprising 2'-{[2-(4-methoxyphenyl)-acetylamino]-methyl}biphenyl-2-carboxylic acid (2-pyridine-3-yl-ethyl)-amide (compound 1) having the following structure or a pharmaceutically acceptable salt thereof. [ka]

[0047] The molecular formula of compound 1 is C 30 H 29It is N3O3.

[0048] The compositions described herein can be used to treat sleep disorders such as obstructive sleep apnea (OSA) and obstructive sleep apnea-hypopnea syndrome (OSAHS). This disclosure provides compositions comprising Compound 1 and a mucosal-adhering polymer.

[0049] In certain embodiments, the pharmaceutical composition provided herein is in liquid form. In certain embodiments, the pharmaceutical composition is a solution. In certain embodiments, the pharmaceutical composition is a suspension. In certain embodiments, the pharmaceutical composition is a particulate suspension.

[0050] The amount of compound 1 in the composition can vary. In a particular embodiment, the composition contains compound 1 in amounts of 0.1% (w / w) or more, for example, 0.2% (w / w) or more, 0.3% (w / w) or more, 0.4% (w / w) or more, 0.5% (w / w) or more, 0.6% (w / w) or more, 0.7% (w / w) or more, 0.9% (w / w) or more, 1% (w / w) or more, 1.25% (w / w) or more, 1.5% (w / w) or more, 1.75% (w / w) or more, 2% (w / w) or more, 2.25% (w / w) or more, 2.5% (w / w) or more, 2.75% (w / w) or more, 3% (w / w) or more, 3.25% (w / w) or more. Above, 3.5% (w / w) or more, 3.75% (w / w%) or more, 4% (w / w) or more, 4.25% (w / w) or more 4.5% (w / w) or more, 4.75% (w / w) or more, 5% (w / w) or more, 5.25% (w / w) or more, 5.5% (w / w) or more, 5.75% (w / w) 6% (w / w) or more, 6.25% (w / w) or more, 6.5% (w / w) or more, 6.75% (w / w) or more, 7% (w / w) or more, 7.25% (w / w) or more, 7.5% (w / w) or more, 7.75% (w / w) or more, 8% (w / w) or more, 8.25% (w / w) or more Above, 8.5% (w / w) or more, 8.75% (w / w) or more, 9% (w / w) or more, 9.25% (w / w) or more, 9.5% (w / w) or more, 9.75% (w / w) or more, 10% (w / w) or more, 10.25% (w / w) or more, 10.5% (w / w) or more, 10.75% ( w / w) or more, 11% (w / w) or more, 11.25% (w / w) or more, 11.5% (w / w) or more, 11.75% (w / w) or more, 12% (w / w) or more, 12.25% (w / w) or more, 12.5% ​​(w / w) or more, 12.75% (w / w) or more, 13% (w / w) or more Above, 13.25% (w / w) or more, 13.5% (w / w) or more, 13.75% (w / w) or more, 14% (w / w) or more, 14.25% (w / w) or more, 14.5% (w / w) or more, 14.75% (w / w) or more, 15% (w / w) or more, 15.25% (w / w) or more, 15.5% (w / w) or more, 15.75% (w / w) or more, 16% (w / w) or more, 16.25% (w / w) or more, 16.5% (w / w) or more, 16.75% (w / w) or more, 17% (w / w) or more, 17.25% (w / w) or more, 17.5% (w / w) or more, 17.Contains in amounts of 75% (w / w) or more, 18% (w / w) or more, 18.25% (w / w) or more, 18.5% (w / w) or more, 18.75% (w / w) or more, 19% (w / w) or more, 19.25% (w / w) or more, 19.5% (w / w) or more, 19.75% (w / w) or more, or 20% (w / w) or more.

[0051] In a specific mechanism, compound 1 can be added in concentrations of 0.1% (w / w) to 20% (w / w), for example, 0.1% (w / w) to 15% (w / w), 0.1% (w / w) to 10% (w / w), 0.1% (w / w) to 5% (w / w), 0.1% (w / w) to 2.5% (w / w), 0.1% (w / w) to 1% (w / w), and 0.25% (w / w) to 20%. (w / w), 0.25%(w / w)~15%(w / w), 0.25%(w / w)~10%(w / w), 0.25%(w / w)~5%, 0.25%~2.5(w / w), 0. 5%(w / w)~20%(w / w), 0.5%(w / w)~15%(w / w), 0.5%(w / w)~10%(w / w), 0.5%(w / w)~5%(w / w), 0.5% (w / w)~2.5%(w / w), 0.5%(w / w)~1%(w / w), 1%(w / w)~20%(w / w), 1%(w / w)~15%(w / w), 1%(w / w)~1 0%(w / w), 1%(w / w)~5%(w / w), 1%(w / w)~2.5%(w / w), 2.5%(w / w)~20%(w / w), 2.5%(w / w)~15%(w / Contains in amounts such as w), 2.5% (w / w) to 10% (w / w), 2.5% (w / w) to 5% (w / w), 5% (w / w) to 20% (w / w), 5% (w / w) to 15% (w / w), 5% (w / w) to 10% (w / w), 10% (w / w) to 20% (w / w), 10% (w / w) to 15% (w / w), or 15% (w / w) to 20% (w / w).

[0052] In a particular embodiment, the composition contains compound 1 in amounts such as 3% (w / w) to 20% (w / w), for example, 3% (w / w) to 15% (w / w), 3% (w / w) to 12% (w / w), 3% (w / w) to 10% (w / w), 3% (w / w) to 9% (w / w), or 3% (w / w) to 6% (w / w).

[0053] In certain embodiments, the composition comprises Compound 1 in an amount of 6% (w / w) to 20% (w / w), for example, 6% (w / w) to 15% (w / w), 6% (w / w) to 12% (w / w), or 6% (w / w) to 10% (w / w). In certain embodiments, the composition comprises Compound 1 in an amount of about 9% (w / w).

[0054] In certain embodiments, Compound 1 is present as Polymorph B. Polymorph B is described as "Polymorph 1" in U.S. Patent No. 9,056,833, the entire content of which is incorporated herein by reference. Polymorph B may be characterized by one or more of the following: (a) Characteristic reflections at 2θ angles [°] of 6.7±0.2, 13.2±0.2, 17.6±0.2, 19.1±0.2, 20.0±0.2, 21.4±0.2, and 22.5±0.2 in an X-ray powder diffractogram using CuKα1 radiation in transmission mode, (b) In an FT (Fourier transform) Raman spectrum using a near-infrared laser (λ=1064 nm), at 3050±2 cm -1 , 2929±2 cm -1 , 2887±2 cm -1 , 1605±2 cm -1 , 1293±2 cm -1 , and 1042±2 cm -1 characteristic signals, (c) A melting point with an onset temperature of 115.5±1° C. by DSC, (d) Crystal parameters determined by single crystal structure analysis, for example, the monoclinic space group P21 / c containing 1 molecule in the asymmetric unit (at room temperature, z=4, a=11.31±0.01 Å, b=8.44±0.01 Å, c=26.86±0.01 Å, β=101.80±0.01 Å, cell volume (V)=2510.0 Å 3 , ρ=1.269 Mgm -3 ).

[0055] In certain embodiments, compound 1 is prepared as a substantially pure polymorph B, i.e., at least 95% is polymorph B (the remainder being other polymorphs or amorphous forms), at least 96% is polymorph B, at least 97% is polymorph B, at least 98% is polymorph B, or at least 99% is polymorph B.

[0056] The compositions described herein also include one or more mucosal-adhering polymers. While we do not wish to be bound by theory, mucosal-adhering polymers are thought to improve the prevention or treatment of sleep disorders, such as OSA, by enabling the compositions to adhere to mucosal tissue and mucus.

[0057] Examples of mucosal-adhering polymers include, for example, polyacrylic acid derivatives, cellulose derivatives, natural polymers, polyvinylpyrrolidone (PVP) polymers, dextran polymers, polyethylene oxide (PEG) polymers, thermoreversible polymers, ion-responsive polymers, copolymers of polymethyl vinyl ether and maleic anhydride, polyvinyl alcohol polymers, salts of the aforementioned, derivatives of the aforementioned, and combinations thereof.

[0058] In certain embodiments, the mucosal adhesive polymer comprises or consists of polyacrylic acid, its salts (e.g., sodium salts), and / or derivatives thereof. Exemplary polyacrylic acid mucosal adhesive polymers include, for example, polyacrylic acid, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate), carbomers, salts thereof, derivatives thereof, and combinations thereof.

[0059] Examples of carbomers include, but are not limited to, carbomer homopolymer type A (allyl pentaerythritol crosslinked type), carbomer homopolymer type B (allyl pentaerythritol crosslinked type, allyl crose crosslinked type), carbomer homopolymer type C (allyl pentaerythritol crosslinked type), carbomer copolymer type B (allyl pentaerythritol crosslinked type), and carbomer copolymer type C (allyl pentaerythritol crosslinked type).

[0060] In certain embodiments, the mucosal adhesive polymer comprises or consists of a cellulose derivative. Exemplary cellulose derivatives include, for example, hydroxyalkylcellulose polymers, methylcellulose polymers, carboxymethylcellulose (CMC) polymers, salts of carboxymethylcellulose, and combinations thereof. In certain embodiments, the mucosal adhesive polymer comprises a hydroxyalkylcellulose polymer. In certain embodiments, the mucosal adhesive polymer comprises hydroxypropylmethylcellulose (HPMC). In certain embodiments, the mucosal adhesive polymer comprises hydroxypropylcellulose (HPC). In certain embodiments, the mucosal adhesive polymer comprises a hydroxyethylcellulose polymer. In certain embodiments, the mucosal adhesive polymer comprises a methylcellulose polymer.

[0061] In certain embodiments, the mucosal-adhering polymer includes or comprises natural polymers. Exemplary natural polymers include, for example, gum arabic, tragacanth gum, agar polymer, xanthan gum, guar gum, copolymers of alginic acid and sodium alginate, chitosan polymer, pectin, carrageenan, pullulan polymer, modified starch, gelatin, salts of the aforementioned, derivatives of the aforementioned, and combinations thereof.

[0062] In certain embodiments, the mucosal adhesive polymer includes or comprises polyvinylpyrrolidone (PVP) polymers, such as povidone, copovidone, and crospovidone.

[0063] In certain embodiments, the mucosal adhesive polymer comprises carrageenan. In certain embodiments, the carrageenan is selected from iotacarrageenan, kappacarrageenan, lambdacarrageenan, and combinations thereof. In certain embodiments, the carrageenan comprises lambdacarrageenan. In certain embodiments, the carrageenan is lambdacarrageenan. In certain embodiments, the carrageenan is non-gelling carrageenan. In certain embodiments, the carrageenan is Viscarin GP 109 or Viscarin GP 209NF.

[0064] In certain embodiments, the mucosal-adhering polymer includes or comprises a thermoreversible polymer. Exemplary thermoreversible polymers include, for example, poloxamers containing polyethylene-polypropylene glycol. Non-limiting examples include those commercially available as LUTROL F-127 (alpha-hydro-omega-hydroxypoly(oxyethylene)a poly(oxypropylene)b poly(oxyethylene)a block copolymer or polyethylene-polypropylene glycol) (poloxamer 407) and LUTROL F-68 (poloxamer 188), LUTROL F-108 (poloxamer 338) (commercially available from BASF), ethyl hydroxyethyl cellulose (EHEC), and combinations thereof.

[0065] In certain embodiments, the mucosal adhesive polymer includes or comprises copolymers of polymethyl vinyl ether and maleic anhydride, such as copolymers commercially available under the trade name GANTREZ, including GANTREZ S and GANTREZ MS type copolymers.

[0066] In certain embodiments, the mucosal adhesive polymer includes or comprises PEG3350, polycarbophil, polyquaternium-10, polyquaternium-7, Sepineo P600, tyroxapole, or a combination thereof.

[0067] By a specific mechanism, the mucosal adhesive polymer can be easily applied in concentrations of 0.1% (w / w) to 20% (w / w), for example, 0.1% (w / w) to 15% (w / w), 0.1% (w / w) to 10% (w / w), 0.1% (w / w) to 5% (w / w), 0.1% (w / w) to 2.5% (w / w), 0.1% (w / w) to 1% (w / w), 1% (w / w) to 20% (w / w), 1% (w / w) to 15% (w / w), 1% (w / w) to 10% (w / w), and 1% (w / w) to 5% (w / w). It contains in amounts such as 1%(w / w)~2.5%(w / w), 2.5%(w / w)~20%(w / w), 2.5%(w / w)~15%(w / w), 2.5%(w / w)~10%(w / w), 2.5%(w / w)~5%(w / w), 5%(w / w)~20%(w / w), 5%(w / w)~15%(w / w), 5%(w / w)~10%(w / w), 10%(w / w)~20%(w / w), 10%(w / w)~15%(w / w), or 15%(w / w)~20%(w / w).

[0068] In a particular embodiment, the composition contains a mucosal-adhering polymer in amounts such as 0.1% (w / w) to 1% (w / w), for example, 0.1% (w / w) to 0.6% (w / w), 0.1% (w / w) to 0.5% (w / w), 0.1% (w / w) to 0.4% (w / w), 0.1% (w / w) to 0.3% (w / w), 0.3% (w / w) to 1% (w / w), or 0.3% (w / w) to 0.6% (w / w).

[0069] In certain embodiments, the composition does not contain microcrystalline cellulose.

[0070] In certain embodiments, the composition further comprises one or more osmotic pressure modifiers, wetting agents, and / or preservatives.

[0071] In certain embodiments, the composition further comprises one or more osmotic regulators. Examples of osmotic regulators include, for example, dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, potassium chloride, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine, glycerin, sodium acetate, sodium sulfate, and combinations thereof. In certain embodiments, the osmotic regulator comprises sorbitol. In certain embodiments, the osmotic regulator comprises mannitol.

[0072] In a particular embodiment, the composition contains one or more osmotic regulators in amounts ranging from 0.1% (w / w) to 10% (w / w), for example, 0.1% (w / w) to 5% (w / w), 0.1% (w / w) to 2.5% (w / w), 0.1% (w / w) to 1% (w / w), 1% (w / w) to 10% (w / w), 1% (w / w) to 5% (w / w), 1% (w / w) to 2.5% (w / w), 2.5% (w / w) to 10% (w / w), 2.5% (w / w) to 5% (w / w), or 5% (w / w) to 10% (w / w). In a particular embodiment, the composition contains 0.1% (w / w) to 3% (w / w) of an osmotic regulator.

[0073] In certain embodiments, the composition further comprises one or more wetting agents. Examples of wetting agents include, for example, polysorbate, fatty acid glycerol polyethylene glycol ester, fatty acid polyethylene glycol ester, polyethylene glycol, glycerol ether, cyclodextrin (e.g., alpha, beta, or gamma-cyclodextrin, e.g., alkylated, hydroxyalkylated, carboxyalkylated, or alkyloxycarbonyl-alkylated derivatives, or mono or diglycosyl-alpha, beta, or gamma-cyclodextrin, mono or dimaltosyl-alpha, beta, or gamma-cyclodextrin, or panosyl-cyclodextrin), reaction products of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil or polyoxy 40 hydrogenated castor oil), castor oil, benzalkonium chloride, disodium edetate, N-dodecyl beta-D-maloside, potassium sorbate, sorbitan monolaurate, glycerin, silicon dioxide, magnesium stearate, PEG-8 laurate, Poloxamer 125, Poloxamer 182, Poloxamer 188, Poloxamer 407, Polypropylene Glycol 11 Stearyl Ether, Polypropylene Glycol 15 Stearyl Ether, Laureth-4, Glyceryl Oleate, Ceteth-20, Sodium Monooleate, Sodium Laureth-3 Sulfate, Sodium Laroyl Sarcosinate, Sodium Lauryl Sulfate, Tyloxapole, Trideceth-10, Ammonium Lauryl Sulfate, Ceteareth-12, Ceteareth-30, Diethanolamine Examples include diisopropanolamine, disodium laureth sulfosuccinate, disodium lauryl sulfosuccinate, sodium doxate, lauramine oxide, laureth sulfate, laureth-23, nonoxynol-9, nonoxynol-40, PEG-60 hydrogenated castor oil, polypropylene glycol, sodium laureth-2 sulfate, sodium laureth-5 sulfate, sodium cocoyl methyl taurate, steareth-20, steareth-21, steareth-40, and combinations thereof.

[0074] In certain embodiments, the wetting agent includes polysorbates, such as polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

[0075] In a particular embodiment, the composition contains one or more wetting agents in amounts of 0.1% (w / w) to 5% (w / w), for example, 0.1% (w / w) to 4% (w / w), 0.1% (w / w) to 3% (w / w), 0.1% (w / w) to 2% (w / w), or 0.1% (w / w) to 1% (w / w). In a particular embodiment, the composition contains one or more wetting agents in amounts of 0.3% (w / w) to 0.6% (w / w).

[0076] In certain embodiments, the composition further comprises one or more preservatives. Exemplary preservatives include, for example, chlorhexidine gluconate, phenylethyl alcohol, 1-phenoxyethanol, benzyl alcohol, sorbic acid, thimerosal, phenylmercury acetate, benzoates (e.g., sodium benzoate), parabens (e.g., methylparaben, propylparaben, and butylparaben), sorbates, benzalkonium chloride, chlorobutanol, sodium metabisulfate, trisodium citrate dihydrate, boric acid, calcium acetate, dehydroacetic acid, diazolidinyl urea, dichlorobenzyl alcohol, imidourea, methyl salicylates, methylchloroisothiazolinone, methylchloroisothiazolinone / methylchloroisothiazolinone mixtures, propionic acid, sodium sulfite, salts of the aforementioned, and combinations thereof. In certain embodiments, the preservative comprises potassium sorbate.

[0077] In a specific mechanism, a simple solution contains one or more preservatives in concentrations of 0.01% (w / w) to 2% (w / w), for example, 0.01% (w / w) to 1.5% (w / w), 0.01% to 1% (w / w), 0.01% (w / w) to 0.5% (w / w), 0.01% (w / w) to 0.25% (w / w), 0.01% (w / w) to 0.1% (w / w), 0.01% (w / w) to 0.05% (w / w). w), or 0.01%(w / w)~0.03%(w / w), 0.03%(w / w)~2%(w / w), 0.03%(w / w)~1.5%(w / w), 0.03%(w / w)~1%(w / w), 0.03%(w / w)~0.5%(w / w), 0.03%(w / w)~0.25%(w / w), 0.03%(w / w)~0.1%(w / w), 0.03%(w / w)~0.05%( w / w), 0.05%(w / w)~2%(w / w), 0.05%(w / w)~1.5%(w / w), 0.05%(w / w)~1%(w / w), 0.05%(w / w)~0.5%(w / w) , 0.05%(w / w)~0.25%(w / w), 0.05%(w / w)~0.1%(w / w), 0.01%(w / w)~2%(w / w), 0.01%(w / w)~1.5%(w / w), It contains amounts such as 0.01% (w / w) to 1% (w / w), 0.1% (w / w) to 0.5% (w / w), 0.1% (w / w) to 0.25% (w / w), 0.25% (w / w) to 2% (w / w), 0.25% (w / w) to 1.5% (w / w), 0.25% (w / w) to 1% (w / w), 0.25% (w / w) to 0.5% (w / w), or 0.5% (w / w) to 1% (w / w).

[0078] In a particular embodiment, the composition contains one or more preservatives in an amount of 0.01% (w / w) to 0.2% (w / w), for example, 0.05% (w / w) to 0.2% (w / w) or 0.05% (w / w) to 0.15% (w / w).

[0079] The compositions described herein further comprise an aqueous medium, i.e., a medium or carrier containing at least a minimum amount of water in which the above components are dissolved and / or suspended. Exemplary aqueous mediums include deionized water, saline solution, phosphate buffer, citrate buffer, malate buffer, tartaric acid buffer, equilibrium salt solutions, salts of organic acids, combinations of organic acids and salts of organic acids (e.g., tribasic sodium citrate and citric acid, malic acid and sodium malate, and potassium sodium tartrate and tartaric acid), acetic acid, hydrochloric acid, monobasic potassium phosphate, dibasic sodium phosphate (heptahydrate), monobasic sodium phosphate (anhydrous / monohydrate), sodium hydroxide, potassium hydroxide, sodium gluconolactone, lactic acid, nitric acid, sodium acetate, sodium lactate, tromethamine, ammonia, citric acid, calcium acetate, diethanolamine, diisopropanolamine, phosphoric acid, potassium citrate, potassium hydroxide, succinic acid, sulfuric acid, arginine hydrochloride, and combinations thereof. In certain embodiments, the aqueous medium comprises a citrate buffer. In certain embodiments, the aqueous medium comprises a phosphate buffer. In certain embodiments, the aqueous medium comprises a citrate phosphate buffer containing citric acid and dibasic sodium phosphate.

[0080] In a particular embodiment, the composition contains an aqueous medium in an amount of 85% (w / w) to 95% (w / w), for example, 85% (w / w) to 90% (w / w) or 90% (w / w) to 95% (w / w).

[0081] In certain embodiments, the composition further comprises a chelating agent. Exemplary chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, HEDTA trisodium, calcium disodium edetate, sodium edetate, trisodium edetate, edetate, pentasodium pentetate, sodium acetate, and combinations thereof. While not bound by theory, in certain cases, the presence of a chelating agent (e.g., EDTA) may prevent aggregation of compound 1 and / or the composition, thereby improving the stability of the composition.

[0082] In a specific mechanism, a simple solution is to use a chelating agent (e.g., EDTA) in concentrations of approximately 0.01% (w / w) to 2% (w / w), for example, 0.01% (w / w) to 1.5% (w / w), 0.01% (w / w) to 1% (w / w), 0.01% (w / w) to 0.5% (w / w), 0.01% (w / w) to 0.1% (w / w), 0.1% (w / w) to 2% (w / w), 0 It contains amounts such as 0.1% (w / w) to 1.5% (w / w), 0.1% (w / w) to 1% (w / w), 0.1% (w / w) to 0.5% (w / w), 0.5% (w / w) to 2% (w / w), 0.5% (w / w) to 1.5% (w / w), 0.5% (w / w) to 1% (w / w), 1% (w / w) to 2% (w / w), or 1.5% (w / w) to 2.0% (w / w).

[0083] In a particular embodiment, the composition contains a chelating agent (e.g., EDTA) in an amount of 0.1% (w / w) to 0.5% (w / w), for example, 0.1% (w / w) to 0.25% (w / w).

[0084] 4.2.1. Mixture composition In certain embodiments, the composition comprises compound 1 and a mucosal adhesive polymer. In certain embodiments, the composition comprises 0.1% (w / w) to 20% (w / w) of compound 1 (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)) and a mucosal adhesive polymer. In certain embodiments, the composition comprises 0.1% (w / w) to 20% (w / w) of compound 1 (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)) and a mucosal adhesive polymer.

[0085] In certain embodiments, the composition comprises compound 1 and a mucosal adhesive polymer, the mucosal adhesive polymer being a cellulose derivative (e.g., hydroxypropyl methylcellulose or methylcellulose). In certain embodiments, the composition comprises 0.1% (w / w) to 20% (w / w) (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)) of compound 1 and a mucosal adhesive polymer, the mucosal adhesive polymer being a cellulose derivative (e.g., hydroxypropyl methylcellulose or methylcellulose). In certain embodiments, the composition comprises 0.1% (w / w) to 20% (w / w) (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)) of compound 1 and a mucosal adhesive polymer, the mucosal adhesive polymer being a cellulose derivative (e.g., hydroxypropyl methylcellulose or methylcellulose).

[0086] In certain embodiments, the composition comprises compound 1 and a mucosal adhesive polymer, the mucosal adhesive polymer being a natural polymer (e.g., carrageenan). In certain embodiments, the composition comprises 0.1% (w / w) to 20% (w / w) (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)) of compound 1 and a mucosal adhesive polymer, the mucosal adhesive polymer being a natural polymer (e.g., carrageenan). In certain embodiments, the composition comprises 0.1% (w / w) to 20% (w / w) (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)) of compound 1 and a mucosal adhesive polymer being 0.1% (w / w) to 20% (w / w) of a mucosal adhesive polymer, the mucosal adhesive polymer being a natural polymer (e.g., carrageenan).

[0087] In certain embodiments, the composition comprises compound 1, a mucosal adhesive polymer, and a wetting agent. In certain embodiments, the composition comprises 0.1% (w / w) to 20% (w / w) (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)) of compound 1, a mucosal adhesive polymer, and a wetting agent. In certain embodiments, the composition comprises 0.1% (w / w) to 20% (w / w) (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)) of compound 1, 0.1% (w / w) to 20% (w / w) of a mucosal adhesive polymer, and 0.1% (w / w) to 5% (w / w) of a wetting agent.

[0088] In certain embodiments, the composition comprises compound 1, a mucosal adhesive polymer, and a wetting agent, wherein the mucosal adhesive polymer is a cellulose derivative (e.g., hydroxypropyl methylcellulose or methylcellulose), and the wetting agent is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil). In certain embodiments, the composition comprises compound 1 in 0.1% (w / w) to 20% (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)), a mucosal adhesive polymer which is a cellulose derivative (e.g., hydroxypropyl methylcellulose or methylcellulose), and a wetting agent which is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil). In certain embodiments, the composition comprises 0.1% (w / w) to 20% (w / w) of compound 1 (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)), 0.1% (w / w) to 20% (w / w) of a mucosal adhesive polymer, which is a cellulose derivative (e.g., hydroxypropyl methylcellulose or methylcellulose), and 0.1% (w / w) to 5% (w / w) of a wetting agent, which is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil).

[0089] In certain embodiments, the composition comprises compound 1, a mucosal adhesive polymer, and a wetting agent, wherein the mucosal adhesive polymer is a natural polymer (e.g., carrageenan), and the wetting agent is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil). In certain embodiments, the composition comprises compound 1 in 0.1% (w / w) to 20% (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)), a mucosal adhesive polymer which is a natural polymer (e.g., carrageenan), and a wetting agent which is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil). In a particular embodiment, the composition comprises 0.1% (w / w) to 20% (w / w) of compound 1 (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)), 0.1% (w / w) to 20% (w / w) of a mucosal adhesive polymer, which is a natural polymer (e.g., carrageenan), and 0.1% (w / w) to 5% (w / w) of a wetting agent, which is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil).

[0090] In certain embodiments, the composition comprises compound 1, a mucosal adhesive polymer, a wetting agent, and an osmotic pressure modifier. In certain embodiments, the composition comprises 0.1% (w / w) to 20% (w / w) (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)) of compound 1, a mucosal adhesive polymer, a wetting agent, and an osmotic pressure modifier. In certain embodiments, the composition comprises 0.1% (w / w) to 20% (w / w) (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)) of compound 1, 0.1% (w / w) to 20% (w / w) of a mucosal adhesive polymer, 0.1% (w / w) to 5% (w / w) of a wetting agent, and 0.1% (w / w) to 10% (w / w) of an osmotic pressure modifier.

[0091] In certain embodiments, the composition comprises compound 1, a mucosal adhesive polymer, a wetting agent, and an osmotic pressure modifier, wherein the mucosal adhesive polymer is a cellulose derivative (e.g., hydroxypropyl methylcellulose or methylcellulose), the wetting agent is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil), and the osmotic pressure modifier is selected from sorbitol and mannitol. In certain embodiments, the composition comprises 0.1% (w / w) to 20% (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)) of compound 1, a mucosal adhesive polymer which is a cellulose derivative (e.g., hydroxypropyl methylcellulose or methylcellulose), a wetting agent which is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil), and an osmotic pressure modifier selected from sorbitol and mannitol. In a particular embodiment, the composition comprises 0.1% (w / w) to 20% (w / w) of compound 1 (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)), 0.1% (w / w) to 20% (w / w) of a mucosal adhesive polymer, which is a cellulose derivative (e.g., hydroxypropyl methylcellulose or methylcellulose), 0.1% (w / w) to 5% (w / w) of a wetting agent, which is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil), and 0.1% (w / w) to 10% (w / w) of an osmotic pressure regulator, which is selected from sorbitol and mannitol.

[0092] In a particular embodiment, the composition comprises compound 1, a mucosal adhesive polymer, a wetting agent, and an osmotic pressure modifier, wherein the mucosal adhesive polymer is a natural polymer (e.g., carrageenan), the wetting agent is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil), and the osmotic pressure modifier is sorbitol. In a particular embodiment, the composition comprises compound 1 in 0.1% (w / w) to 20% (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)), a mucosal adhesive polymer which is a natural polymer (e.g., carrageenan), a wetting agent which is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil), and an osmotic pressure modifier which is sorbitol. In a particular embodiment, the composition comprises 0.1% (w / w) to 20% (w / w) of compound 1 (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)), 0.1% (w / w) to 20% (w / w) of a mucosal adhesive polymer, which is a natural polymer (e.g., carrageenan), 0.1% (w / w) to 5% (w / w) of a wetting agent, which is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil), and 0.1% (w / w) to 10% (w / w) of an osmotic pressure regulator, which is sorbitol.

[0093] In certain embodiments, the composition comprises compound 1, a mucosal adhesive polymer, a wetting agent, an osmotic pressure modifier, and a preservative. In certain embodiments, the composition comprises 0.1% (w / w) to 20% (w / w) (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)) of compound 1, a mucosal adhesive polymer, a wetting agent, an osmotic pressure modifier, and a preservative. In a particular embodiment, the composition comprises 0.1% (w / w) to 20% (w / w) of compound 1 (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)), 0.1% (w / w) to 20% (w / w) of a mucosal adhesive polymer, 0.1% (w / w) to 5% (w / w) of a wetting agent, 0.1% (w / w) to 10% (w / w) of an osmotic pressure regulator, and 0.01% (w / w) to 2% (w / w) of a preservative.

[0094] In certain embodiments, the composition comprises compound 1, a mucosal adhesive polymer, a humectant, an osmotic pressure modifier, and a preservative, wherein the mucosal adhesive polymer is a cellulose derivative (e.g., hydroxypropyl methylcellulose or methylcellulose), the humectant is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil), the osmotic pressure modifier is selected from sorbitol and mannitol, and the preservative is potassium sorbate. In certain embodiments, the composition comprises compound 1 in 0.1% (w / w) to 20% (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)) amounts, a mucosal adhesive polymer which is a cellulose derivative (e.g., hydroxypropyl methylcellulose or methylcellulose), a wetting agent which is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil), an osmotic pressure regulator selected from sorbitol and mannitol, and a preservative which is potassium sorbate. In a particular embodiment, the composition comprises 0.1% (w / w) to 20% (w / w) of compound 1 (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)), 0.1% (w / w) to 20% (w / w) of a mucosal adhesive polymer, which is a cellulose derivative (e.g., hydroxypropyl methylcellulose or methylcellulose), 0.1% (w / w) to 5% (w / w) of a wetting agent, which is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil), 0.1% (w / w) to 10% (w / w) of an osmotic pressure regulator, which is selected from sorbitol and mannitol, and 0.01% (w / w) to 2% (w / w) of a preservative, which is potassium sorbate.

[0095] In certain embodiments, the composition comprises compound 1, a mucosal adhesive polymer, a wetting agent, an osmotic pressure modifier, and a preservative, wherein the mucosal adhesive polymer is a natural polymer (e.g., carrageenan), the wetting agent is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil), the osmotic pressure modifier is sorbitol, and the preservative is potassium sorbate. In a particular embodiment, the composition comprises compound 1 in 0.1% (w / w) to 20% (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)) amounts, a mucosal adhesive polymer which is a natural polymer (e.g., carrageenan), a wetting agent which is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil), an osmotic pressure regulator which is sorbitol, and a preservative which is potassium sorbate. In a particular embodiment, the composition comprises 0.1% (w / w) to 20% (w / w) of compound 1 (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)), 0.1% (w / w) to 20% (w / w) of a mucosal adhesive polymer, which is a natural polymer (e.g., carrageenan), 0.1% (w / w) to 5% (w / w) of a wetting agent, which is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil), 0.1% (w / w) to 10% (w / w) of an osmotic pressure regulator, which is sorbitol, and 0.01% (w / w) to 2% (w / w) of a preservative, which is potassium sorbate.

[0096] In certain embodiments, the composition comprises compound 1, a mucosal adhesive polymer, a wetting agent, an osmotic pressure modifier, a preservative, and a chelating agent. In certain embodiments, the composition comprises 0.1% (w / w) to 20% (w / w) (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)) of compound 1, a mucosal adhesive polymer, a wetting agent, an osmotic pressure modifier, a preservative, and a chelating agent. In a particular embodiment, the simple comprises 0.1% (w / w) to 20% (w / w) of compound 1 (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)), 0.1% (w / w) to 20% (w / w) of a mucosal adhesive polymer, 0.1% (w / w) to 5% (w / w) of a wetting agent, 0.1% (w / w) to 10% (w / w) of an osmotic pressure regulator, 0.01% (w / w) to 2% (w / w) of a preservative, and 0.01% (w / w) to 2% (w / w) of a chelating agent.

[0097] In a particular embodiment, the composition comprises compound 1, a mucosal adhesive polymer, a wetting agent, an osmotic pressure modifier, a preservative, and a chelating agent, wherein the mucosal adhesive polymer is a natural polymer (e.g., carrageenan), the wetting agent is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil), the osmotic pressure modifier is sorbitol, the preservative is potassium sorbate, and the chelating agent is EDTA. In certain embodiments, the composition comprises 0.1% (w / w) to 20% (w / w) of compound 1 (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)), a mucosal adhesive polymer which is a natural polymer (e.g., carrageenan), a wetting agent which is a reaction product of castor oil and ethylene oxide (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil), an osmotic pressure regulator which is sorbitol, an osmotic pressure regulator which is potassium sorbate, and a chelating agent which is EDTA. In a particular embodiment, the composition comprises 0.1% (w / w) to 20% (e.g., 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w)) of compound 1, 0.1% (w / w) to 20% (w / w) of a mucosal adhesive polymer, which is a natural polymer (e.g., carrageenan), and 0.1% (w / w) to 5% (w / w) of a wetting agent, which is a reaction between castor oil and ethylene oxide. The product contains a wetting agent, which is a product of action (e.g., polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil); an osmotic pressure regulator in the form of 0.1% (w / w) to 10% (w / w) of sorbitol; a preservative in the form of 0.01% (w / w) to 2% (w / w) of potassium sorbate; and a chelating agent in the form of 0.01% (w / w) to 2% (w / w) of EDTA.

[0098] In a particular embodiment, the composition is a. Compound 1 in a concentration of 0.1% (w / w) to 20% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. A mucosal adhesive polymer in a concentration of 0.1% (w / w) to 20% (w / w), c. Osmotic pressure regulators in concentrations of 0.1% (w / w) to 10% (w / w), d. 0.1% (w / w) to 5% (w / w) of wetting agent, e. 0.01% (w / w) to 2% (w / w) of preservatives, f. Contains an aqueous medium of 85% (w / w) to 95% (w / w), g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0099] In a particular embodiment, the composition is a. Compound 1 in a concentration of 0.1% (w / w) to 20% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. A mucosal adhesive polymer comprising methylcellulose, HMPC, carrageenan, or a combination thereof, in a concentration of 0.1% (w / w) to 20% (w / w), c. A 0.1% (w / w) to 10% (w / w) osmotic pressure regulator containing mannitol, sorbitol, or a combination thereof, d. A humectant comprising 0.1% (w / w) to 5% (w / w) of polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, or a combination thereof, e. A preservative containing potassium sorbate, at a concentration of 0.01% (w / w) to 2% (w / w), f. A 85% (w / w) to 95% (w / w) aqueous medium containing citrate buffer, phosphate buffer, or a combination thereof, g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0100] In a particular embodiment, the composition is a. Compound 1 in a concentration of 0.1% (w / w) to 20% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. 0.1% (w / w) to 1% (w / w) of mucosal adhesive polymers, c. 0.1% (w / w) to 5% (w / w) of osmotic pressure adjusting agent, d. 0.1% (w / w) to 1% (w / w) of humectant, e. 0.01% (w / w) to 2% (w / w) of preservatives, f. Contains an aqueous medium of 85% (w / w) to 95% (w / w), g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0101] In a particular embodiment, the composition is a. Compound 1 in a concentration of 0.1% (w / w) to 20% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. A mucosal adhesive polymer comprising methylcellulose, HMPC, carrageenan, or a combination thereof, in a concentration of 0.1% (w / w) to 1% (w / w), c. A 0.1% (w / w) to 5% (w / w) osmotic pressure regulator containing mannitol, sorbitol, or a combination thereof, d. A humectant comprising 0.1% (w / w) to 1% (w / w) of polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, or a combination thereof, e. A preservative containing potassium sorbate, at a concentration of 0.01% (w / w) to 2% (w / w), f. A 85% (w / w) to 95% (w / w) aqueous medium containing citrate buffer, phosphate buffer, or a combination thereof, g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0102] In a particular embodiment, the composition is a. Compound 1 in a concentration of 0.1% (w / w) to 20% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. A mucosal adhesive polymer in a concentration of 0.3% (w / w) to 0.6% (w / w), c. 0.1% (w / w) to 3% (w / w) of osmotic pressure adjusting agent, d. A 0.3% (w / w) to 0.6% (w / w) humectant, e. Preservatives in a concentration of 0.01% (w / w) to 0.15% (w / w), f. Contains an aqueous medium of 85% (w / w) to 95% (w / w), g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0103] In a particular embodiment, the composition is a. Compound 1 in a concentration of 0.1% (w / w) to 20% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. A mucosal adhesive polymer containing methylcellulose, HMPC, carrageenan, or a combination thereof, in a concentration of 0.3% (w / w) to 0.6% (w / w), c. A 0.1% (w / w) to 3% (w / w) osmotic pressure regulator containing mannitol, sorbitol, or a combination thereof, d. A humectant comprising 0.3% (w / w) to 0.6% (w / w) of polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, or a combination thereof, e. A preservative containing potassium sorbate, in a concentration of 0.01% (w / w) to 0.15% (w / w), f. A 85% (w / w) to 95% (w / w) aqueous medium containing citrate buffer, phosphate buffer, or a combination thereof, g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0104] In a particular embodiment, the composition is a. Compound 1 in a concentration of 3% (w / w) to 20% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. A mucosal adhesive polymer in a concentration of 0.1% (w / w) to 20% (w / w), c. Osmotic pressure regulators in concentrations of 0.1% (w / w) to 10% (w / w), d. 0.1% (w / w) to 5% (w / w) of wetting agent, e. 0.01% (w / w) to 2% (w / w) of preservatives, f. Contains an aqueous medium of 85% (w / w) to 95% (w / w), g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0105] In a particular embodiment, the composition is a. Compound 1 in a concentration of 3% (w / w) to 20% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. A mucosal adhesive polymer comprising methylcellulose, HMPC, carrageenan, or a combination thereof, in a concentration of 0.1% (w / w) to 20% (w / w), c. A 0.1% (w / w) to 10% (w / w) osmotic pressure regulator containing mannitol, sorbitol, or a combination thereof, d. A humectant comprising 0.1% (w / w) to 5% (w / w) of polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, or a combination thereof, e. A preservative containing potassium sorbate, at a concentration of 0.01% (w / w) to 2% (w / w), f. A 85% (w / w) to 95% (w / w) aqueous medium containing citrate buffer, phosphate buffer, or a combination thereof, g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0106] In a particular embodiment, the composition is a. Compound 1 in a concentration of 3% (w / w) to 20% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. 0.1% (w / w) to 1% (w / w) of mucosal adhesive polymers, c. 0.1% (w / w) to 5% (w / w) of osmotic pressure adjusting agent, d. 0.1% (w / w) to 1% (w / w) of humectant, e. 0.01% (w / w) to 2% (w / w) of preservatives, f. Contains an aqueous medium of 85% (w / w) to 95% (w / w), g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0107] In a particular embodiment, the composition is a. Compound 1 in a concentration of 3% (w / w) to 20% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. A mucosal adhesive polymer comprising methylcellulose, HMPC, carrageenan, or a combination thereof, in a concentration of 0.1% (w / w) to 1% (w / w), c. A 0.1% (w / w) to 5% (w / w) osmotic pressure regulator containing mannitol, sorbitol, or a combination thereof, d. A humectant comprising 0.1% (w / w) to 1% (w / w) of polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, or a combination thereof, e. A preservative containing potassium sorbate, at a concentration of 0.01% (w / w) to 2% (w / w), f. A 85% (w / w) to 95% (w / w) aqueous medium containing citrate buffer, phosphate buffer, or a combination thereof, g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0108] In a particular embodiment, the composition is a. Compound 1 in a concentration of 3% (w / w) to 20% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. A mucosal adhesive polymer in a concentration of 0.3% (w / w) to 0.6% (w / w), c. 0.1% (w / w) to 3% (w / w) of osmotic pressure adjusting agent, d. A 0.3% (w / w) to 0.6% (w / w) humectant, e. Preservatives in a concentration of 0.01% (w / w) to 0.15% (w / w), f. Contains an aqueous medium of 85% (w / w) to 95% (w / w), g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0109] In a particular embodiment, the composition is a. Compound 1 in a concentration of 3% (w / w) to 20% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. A mucosal adhesive polymer containing methylcellulose, HMPC, carrageenan, or a combination thereof, in a concentration of 0.3% (w / w) to 0.6% (w / w), c. A 0.1% (w / w) to 3% (w / w) osmotic pressure regulator containing mannitol, sorbitol, or a combination thereof, d. A humectant comprising 0.3% (w / w) to 0.6% (w / w) of polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, or a combination thereof, e. A preservative containing potassium sorbate, in a concentration of 0.01% (w / w) to 0.15% (w / w), f. A 85% (w / w) to 95% (w / w) aqueous medium containing citrate buffer, phosphate buffer, or a combination thereof, g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0110] In a particular embodiment, the composition is a. Compound 1 in a concentration of 3% (w / w) to 10% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. A mucosal adhesive polymer in a concentration of 0.1% (w / w) to 20% (w / w), c. Osmotic pressure regulators in concentrations of 0.1% (w / w) to 10% (w / w), d. 0.1% (w / w) to 5% (w / w) of wetting agent, e. 0.01% (w / w) to 1% (w / w) of preservatives, f. Contains an aqueous medium of 85% (w / w) to 95% (w / w), g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0111] In a particular embodiment, the composition is a. Compound 1 in a concentration of 3% (w / w) to 10% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. A mucosal adhesive polymer comprising methylcellulose, HMPC, carrageenan, or a combination thereof, in a concentration of 0.1% (w / w) to 20% (w / w), c. A 0.1% (w / w) to 10% (w / w) osmotic pressure regulator containing mannitol, sorbitol, or a combination thereof, d. A humectant comprising 0.1% (w / w) to 5% (w / w) of polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, or a combination thereof, e. A preservative containing potassium sorbate, at a concentration of 0.01% (w / w) to 2% (w / w), f. A 85% (w / w) to 95% (w / w) aqueous medium containing citrate buffer, phosphate buffer, or a combination thereof, g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0112] In a particular embodiment, the composition is a. Compound 1 in a concentration of 3% (w / w) to 10% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. 0.1% (w / w) to 1% (w / w) of mucosal adhesive polymers, c. 0.1% (w / w) to 5% (w / w) of osmotic pressure adjusting agent, d. 0.1% (w / w) to 1% (w / w) of humectant, e. 0.01% (w / w) to 2% (w / w) of preservatives, f. Contains an aqueous medium of 85% (w / w) to 95% (w / w), g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0113] In a particular embodiment, the composition is a. Compound 1 in a concentration of 3% (w / w) to 10% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. A mucosal adhesive polymer comprising methylcellulose, HMPC, carrageenan, or a combination thereof, in a concentration of 0.1% (w / w) to 1% (w / w), c. A 0.1% (w / w) to 5% (w / w) osmotic pressure regulator containing mannitol, sorbitol, or a combination thereof, d. A humectant comprising 0.1% (w / w) to 1% (w / w) of polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, or a combination thereof, e. A preservative containing potassium sorbate, at a concentration of 0.01% (w / w) to 2% (w / w), f. A 85% (w / w) to 95% (w / w) aqueous medium containing citrate buffer, phosphate buffer, or a combination thereof, g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0114] In a particular embodiment, the composition is a. Compound 1 in a concentration of 3% (w / w) to 10% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. A mucosal adhesive polymer in a concentration of 0.3% (w / w) to 0.6% (w / w), c. 0.1% (w / w) to 3% (w / w) of osmotic pressure adjusting agent, d. A 0.3% (w / w) to 0.6% (w / w) humectant, e. Preservatives in a concentration of 0.01% (w / w) to 0.15% (w / w), f. Contains an aqueous medium of 85% (w / w) to 95% (w / w), g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0115] In a particular embodiment, the composition is a. Compound 1 in a concentration of 3% (w / w) to 10% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. A mucosal adhesive polymer containing methylcellulose, HMPC, carrageenan, or a combination thereof, in a concentration of 0.3% (w / w) to 0.6% (w / w), c. A 0.1% (w / w) to 3% (w / w) osmotic pressure regulator containing mannitol, sorbitol, or a combination thereof, d. A humectant comprising 0.3% (w / w) to 0.6% (w / w) of polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, or a combination thereof, e. A preservative containing potassium sorbate, in a concentration of 0.01% (w / w) to 0.15% (w / w), f. A 85% (w / w) to 95% (w / w) aqueous medium containing citrate buffer, phosphate buffer, or a combination thereof, g. It may contain 0.01% (w / w) to 2% (w / w) of a chelating agent (e.g., EDTA).

[0116] 4.2.2. Characteristics In certain embodiments, the pharmaceutical microparticle suspension composition contains dissolved compound 1 in an amount of less than 0.1% (w / w), for example, less than 0.05% (w / w), or less than 0.025% (w / w).

[0117] In a particular embodiment, the pharmaceutical microparticle suspension composition contains dissolved compound 1 in an amount of 0.001% (w / w) to 0.1% (w / w), for example, 0.001% (w / w) to 0.05% (w / w), 0.005% (w / w) to 0.05% (w / w), or 0.005% (w / w) to 0.025% (w / w).

[0118] In certain embodiments, the pharmaceutical composition has a molar osmotic pressure concentration of 200 mOsm / kg to 500 mOsm / kg, for example, 200 mOsm / kg to 450 mOsm / kg, 200 mOsm / kg to 400 mOsm / kg, 200 mOsm / kg to 350 mOsm / kg, 200 mOsm / kg to 300 mOsm / kg, 200 mOsm / kg to 250 mOsm / kg, 250 mOsm / kg to 500 mOsm / kg, 250 mOsm / kg to 450 mOsm / kg, 250 mOsm / kg to 400 mOsm / kg, and 250 mOsm / kg to 350 mOsm / kg. g, 250 mOsm / kg to 300 mOsm / kg, 300 mOsm / kg to 500 mOsm / kg, 300 mOsm / kg to 450 mOsm / kg, 300 mOsm / kg to 400 mOsm / kg, 300 mOsm / kg to 350 mOsm / kg, 350 mOsm / kg to 500 mOsm / kg, 350 mOsm / kg to 450 mOsm / kg, 350 mOsm / kg to 400 mOsm / kg, 400 mOsm / kg to 500 mOsm / kg, 400 mOsm / kg to 450 mOsm / kg, or 450 mOsm / kg to 500 mOsm / kg, etc. In certain embodiments, the pharmaceutical composition has a molar osmotic concentration of 250 mOsm / kg to 350 mOsm / kg. mOsm / kg means milliosmoles per kilogram. One milliosmol is one millimoles (i.e., one-thousandth of a mole) of an osmotically active compound, i.e., a compound that contributes to the osmotic pressure of a solution.

[0119] In certain embodiments, the pharmaceutical composition has an apparent pH of 5 to 7, for example, 5 to 6.5, 5 to 6, 5 to 5.5, 6 to 7, 6 to 6.5, or 6.5 to 7. In certain embodiments, the apparent pH of the pharmaceutical composition is 5.5 to 6.5 or 6 to 6.5.

[0120] In a particular embodiment, the particle size distribution of compound 1 in the pharmaceutical composition (D 10) is 0.1μm to 5μm, for example, 0.1μm to 4μm, 0.1μm to 3μm, 0.1μm to 2μm, 0.1μm to 1μm, 0.5μm to 5μm, 0.5μm to 4μm, 0.5μm to 3μm, 0.5μm to 2μm, 0.5μm to 1μm, 1μm to 5μm, 1μm to 4μm, 1μm to 3μm, 1μm to 2μm, 2μm to 5μm, 3μm to 5μm, or 4μm to 5. In a particular embodiment, the particle size distribution (D) of compound 1 in the pharmaceutical composition is 10 The particle size distribution (D) of compound 1 in the pharmaceutical composition is 0.1 μm to 1.5 μm. In a particular embodiment, the particle size distribution (D) of compound 1 in the pharmaceutical composition is 0.1 μm to 1.5 μm. 10 The size is between 0.1 μm and 3 μm.

[0121] In a particular embodiment, the particle size distribution of compound 1 in the pharmaceutical composition (D 50 The particle size distribution (D) of compound 1 in the pharmaceutical composition is 2 μm to 15 μm, for example, 2 μm to 10 μm, 2 μm to 5 μm, 5 μm to 15 μm, 5 μm to 10 μm, or 10 μm to 15 μm. In a particular embodiment, the particle size distribution (D) of compound 1 in the pharmaceutical composition is 2 μm to 15 μm, for example, 2 μm to 10 μm, 2 μm to 5 μm, 5 μm to 15 μm, 5 μm to 10 μm, or 10 μm to 15 μm. 50 The particle size distribution (D) of compound 1 in the pharmaceutical composition is 2 μm to 5 μm. In a particular embodiment, the particle size distribution (D) of compound 1 in the pharmaceutical composition is 2 μm to 5 μm. 50 The size is 5 μm to 15 μm.

[0122] In a particular embodiment, the particle size distribution of compound 1 in the pharmaceutical composition (D 90) refers to 4μm~50μm, for example, 4μm~45μm, 4μm~40μm, 4μm~35μm, 4μm~30μm, 4μm~25μm, 4~20μm, 4μm~10μm, 5μm~45μm, 5μm~40μm, 5μm~35μm, 5μm~30μm, 5μm~25μm, 5~20μm, 5μm~10μm, 10μm~50μm, 10μm~45μm, 10μm~40μm, 10μm~35μm, 10μm~30μm, 10μm~20μm, 20μm~ These include 50 μm, 20 μm~45 μm, 20 μm~40 μm, 20 μm~35 μm, 20 μm~30 μm, 20 μm~25 μm, 25 μm~50 μm, 25 μm~45 μm, 25 μm~40 μm, 25 μm~35 μm, 25 μm~30 μm, 30 μm~50 μm, 30 μm~45 μm, 30 μm~40 μm, 30 μm~35 μm, 35 μm~50 μm, 35 μm~45 μm, 35 μm~40 μm, 40 μm~50 μm, or 45 μm~50 μm. In a particular embodiment, the particle size distribution of compound 1 in the pharmaceutical composition (D 90 The particle size distribution (D) of compound 1 in the pharmaceutical composition is 4 μm to 15 μm. In a particular embodiment, the particle size distribution (D) of compound 1 in the pharmaceutical composition is 4 μm to 15 μm. 90 The size is between 10 μm and 35 μm.

[0123] In a particular embodiment, compound 1 is D 10 <3μm, D 50 <15μm, and D 90 It is <50 μm. In a particular embodiment, compound 1 is D 10 <3μm, D 50 <15μm, and D 90 It is <35 μm.

[0124] In a particular embodiment, compound 1 is D 10 <2μm, D 50 <5μm, and D 90 It is <10 μm. In a particular embodiment, compound 1 is D 10 is 0.1~1.5μm, D 50 is 2-5 μm, and D 90 The particle size is 5-10 μm.

[0125] In a particular embodiment, compound 1 is D10 0.1~3μm, D 50 is 5-15 μm, and D 90 The particle size is 10-50 μm. In a particular embodiment, compound 1 is D 10 0.1~3μm, D 50 is 5-15 μm, and D 90 The size is 10-35 μm.

[0126] In a particular embodiment, the particle size distribution of compound 1 in the pharmaceutical composition (D 90 ) is bimodal. In certain embodiments, 25% (w / w) to 75% (w / w) of compound 1 is D 90 The size is 20 μm to 30 μm, and the remainder of compound 1 is D 90 The size is between 5 μm and 15 μm.

[0127] In a particular embodiment, the pharmaceutical composition has a viscosity of 1 cP to 100 cP, for example, 20 cP to 100 cP, 20 cP to 50 cP, 20 cP to 40 cP, 20 cP to 30 cP, 25 cP to 50 cP, 25 cP to 40 cP, 25 cP to 30 cP, 30 cP to 50 cP, 30 cP to 40 cP, or 40 cP to 50 cP.

[0128] In certain embodiments, the pharmaceutical composition has shear-thickening rheology. In certain other embodiments, the pharmaceutical composition has shear-thickening rheology. In yet another embodiment, the pharmaceutical composition has Newtonian rheology.

[0129] In certain embodiments, the pharmaceutical composition exhibits storage-dominant behavior at low torque in vibration amplitude experiments (i.e., is more elastic / solid). In certain embodiments, the pharmaceutical composition exhibits loss-dominant behavior at low torque in vibration amplitude experiments (i.e., is more viscous / liquid).

[0130] In certain embodiments, the pharmaceutical composition has a surface tension of 40-50 mN / m, for example, 40-45 mN / m or 45-50 mN / m.

[0131] In certain embodiments, when the pharmaceutical composition is stored at 25°C and / or 40°C for at least two weeks ("storage conditions"), (i) recovery rate of compound 1, (ii) macroscopic appearance, (iii) microscopic appearance, (iv) apparent pH, (v) molar osmotic concentration, (vi) particle size distribution (D 90 (i) to (viii) is stable as determined by one or more of the following: (i), (vii) droplet size, and (viii) Raman analysis. In certain embodiments, the pharmaceutical composition is stable when stored at 25°C and / or 40°C for at least 4 weeks, 8 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months or longer. The definition of "stable" is further explained in the following sections for each of (i) to (viii).

[0132] The recovery rate of compound 1 can be determined, for example, by comparing the content of compound 1 in the pharmaceutical composition at an initial time (t=0) and at subsequent time points under storage conditions (e.g., 2 weeks, 4 weeks, 8 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months or more) (e.g., by HPLC). In certain embodiments, the recovery rate of compound 1 at subsequent time points is at least 90% of the content of compound 1 at t=0, for example, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In certain embodiments, the recovery rate of compound 1 at subsequent time points is 90% to 110% of the content of compound 1 at t=0.

[0133] The macroscopic appearance can be evaluated, for example, by comparing the visual appearance of the pharmaceutical composition at an initial time (t=0) and at subsequent time points under storage conditions (e.g., 2 weeks, 4 weeks, 8 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months or more). In certain embodiments, the macroscopic appearance of the pharmaceutical composition at subsequent time points shows no substantial change compared to the macroscopic appearance at t=0, for example, there is no discoloration, no aggregation, and no change in opacity.

[0134] The microscopic appearance can be evaluated, for example, by comparing microscopic images of the pharmaceutical composition (e.g., under 10x or 40x magnification) at an initial time point (t=0) and at subsequent time points under storage conditions (e.g., 2 weeks, 4 weeks, 8 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months or more). In certain embodiments, there is no substantial change in the microscopic appearance of the pharmaceutical composition at subsequent time points; for example, no aggregation is observed under magnification at subsequent time points compared to t=0. In certain embodiments, aggregation of less than 20% under magnification is observed, for example, less than 15%, less than 10%, or less than 5%.

[0135] The apparent pH of a pharmaceutical composition can be evaluated at an initial time (t=0) and at subsequent time points under storage conditions (e.g., 2 weeks, 4 weeks, 8 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months or more). In certain embodiments, the apparent pH is that of the extracted solution portion of the composition, i.e., not of the suspension composition. In certain embodiments, the apparent pH of the pharmaceutical composition changes by less than 1 pH unit at subsequent time points compared to the apparent pH at t=0, for example, by less than 0.5 pH units.

[0136] The molar osmotic pressure of a pharmaceutical composition can be evaluated at an initial time point (t=0) and at subsequent time points under storage conditions (e.g., 2 weeks, 4 weeks, 8 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months or more). In certain embodiments, the molar osmotic pressure of the pharmaceutical composition changes by less than 50 mOsm / kg at subsequent time points compared to the molar osmotic pressure at t=0, for example, by less than 25 mOsm / kg.

[0137] Particle size distribution of compound 1 in the pharmaceutical composition (D 90The particle size distribution of compound 1 in the pharmaceutical composition may be evaluated at an initial time (t=0) and at subsequent time points under storage conditions (e.g., 2 weeks, 4 weeks, 8 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months or more). In a particular embodiment, the particle size distribution of compound 1 in the pharmaceutical composition changes by less than 50% at subsequent time points compared to the particle size distribution at t=0, for example, by less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, or less than 5%.

[0138] Raman analysis of compound 1 in a pharmaceutical composition can be evaluated at an initial time point (t=0) and at subsequent time points under storage conditions (e.g., 2 weeks, 4 weeks, 8 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months or more). In certain embodiments, the polymorphism of compound 1 in the pharmaceutical composition remains unchanged after storage conditions.

[0139] 4.3. Method In one embodiment, the present disclosure provides a method for treating obstructive sleep apnea, comprising intranasal administration of a pharmaceutical composition described herein.

[0140] In one embodiment, the present disclosure provides a pharmaceutical composition described herein for use in a method for treating obstructive sleep apnea, the method comprising administering the pharmaceutical composition described herein to a subject.

[0141] In certain embodiments, the subject self-administers the pharmaceutical composition.

[0142] In certain embodiments, the pharmaceutical composition is administered daily, for example, before sleep at night. In certain embodiments, the pharmaceutical composition is administered once before sleep. In other embodiments, the composition is administered two or more times before sleep.

[0143] In certain embodiments, the pharmaceutical compositions described herein are administered to a subject while the subject is in an upright position, i.e., while the subject's head elevation angle is 60° to 90° relative to the horizontal, for example, 60° to 80°, 60° to 70°, 70° to 90°, 70° to 80°, or 80° to 90°.

[0144] In other embodiments, the pharmaceutical compositions described herein are administered to a subject while the subject's head is raised at an angle of 45° relative to the horizontal, for example, 10°–45°, 20°–45°, 30°–45°, 40°–45°, 20°–45°, 20°–40°, 20°–30°, 30°–45°, 30°–40°, or 40°–45°.

[0145] In certain embodiments, the pharmaceutical compositions described herein are administered to a subject while the subject is in a supine position (head elevation angle of 0° relative to the horizontal).

[0146] In certain embodiments, the subject assumes a supine position or a head elevation angle of 45° or less relative to the horizontal after administration of the pharmaceutical composition, for example, 10°~45°, 20°~45°, 30°~45°, 40°~45°, 20°~45°, 20°~40°, 20°~30°, 30°~45°, 30°~40°, or 40°~45°. In certain embodiments, the subject assumes a post-administration position within 20 minutes of administration of the pharmaceutical composition, for example, within 15 minutes, within 10 minutes, or within 5 minutes.

[0147] In certain embodiments, the pharmaceutical composition is administered to the subject while the subject is in an upright position, and after administration, the subject assumes a supine position or a head position of 45° or less.

[0148] In certain embodiments, the subject maintains a post-administration posture for at least 4 hours after administration of the pharmaceutical composition, for example, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, or at least 11 hours. In certain embodiments, "maintaining" the post-administration posture allows for brief (5-10 minute) deviations to a vertical position (e.g., for using the toilet).

[0149] In certain embodiments, the pharmaceutical composition is administered to the subject while the subject is in an upright position, and after administration, the subject assumes a supine position or a head position of 45° or less for 4 to 10 hours, for example, 8 hours.

[0150] In a specific mechanism, the pharmaceutical composition is administered 5 to 120 minutes before sleep, for example, 5 to 100 minutes before, 5 to 60 minutes before, 5 to 30 minutes before, 5 to 20 minutes before, 5 to 15 minutes before, 5 to 10 minutes before, 10 to 120 minutes before, 10 to 100 minutes before, 10 to 60 minutes before, 10 to 30 minutes before, 10 to 20 minutes before, 10 to 15 minutes before, 15 to 120 minutes before, 15 minutes to 1 The drug is administered to the subject at 00 minutes before, 15-60 minutes before, 15-30 minutes before, 15-20 minutes before, 20-120 minutes before, 20-100 minutes before, 20-60 minutes before, 20-30 minutes before, 30-120 minutes before, 30-100 minutes before, 30-60 minutes before, 60-120 minutes before, 60-100 minutes before, or 100-120 minutes before, etc. In a specific embodiment, the pharmaceutical composition is administered to the subject 10-30 minutes before sleep.

[0151] In a particular embodiment, intranasal administration of a pharmaceutical composition to a subject provides compound 1 in a total dose (i.e., the amount delivered to both nostrils) of 0.1 mg to 100 mg, for example, 0.1 mg to 75 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 10 mg, 5 mg to 100 mg, 5 mg to 75 mg, 5 mg to 50 mg, 5 mg to 25 mg, 25 mg to 100 mg, 25 mg to 75 mg, 25 mg to 50 mg, 50 mg to 100 mg, 50 mg to 75 mg, or 75 mg to 100 mg.

[0152] In a particular embodiment, intranasal administration of a pharmaceutical composition to a subject provides compound 1 in a total dose (i.e., the amount delivered to both nostrils) of 0.1 mg to 30 mg, for example, 0.1 mg to 20 mg, 0.1 mg to 10 mg, 5 mg to 30 mg, 5 mg to 25 mg, 5 mg to 20 mg, 5 mg to 10 mg, 10 mg to 30 mg, 10 mg to 25 mg, 10 mg to 20 mg, 10 mg to 15 mg, 15 mg to 30 mg, 15 mg to 25 mg, 15 mg to 20 mg, 20 mg to 30 mg, 20 mg to 25 mg, or 25 mg to 30 mg.

[0153] In certain embodiments, administration of the pharmaceutical composition alleviates upper airway (UA) collapse for at least 4 hours after administration and during sleep, for example, at least 4.5 hours, at least 5 hours, at least 5.5 hours, at least 6 hours, at least 6.5 hours, at least 7 hours, at least 7.5 hours, at least 8 hours, at least 8.5 hours, at least 9 hours, at least 9.5 hours, or at least 10 hours. In certain embodiments, administration of the pharmaceutical composition suppresses UA collapse for 4 to 10 hours after administration and during sleep, for example, 4 to 10 hours, 4 to 9 hours, 4 to 8 hours, 4 to 7 hours, 4 to 6 hours, 4 to 5 hours, 5 to 10 hours, 5 to 9 hours, 5 to 8 hours, 5 to 7 hours, 5 to 6 hours, 6 to 10 hours, 6 to 9 hours, 6 to 8 hours, 6 to 7 hours, 7 to 10 hours, 7 to 9 hours, 7 to 8 hours, 8 to 10 hours, 8 to 9 hours, or 9 to 10 hours.

[0154] In certain embodiments, suppression of UA collapse may be measured by a decrease in pharyngeal critical closure pressure (Pcrit) compared to the same subject not receiving the composition. Pcrit can be measured as described in Osman, et al., “Topical Potassium Channel Blockage Improves Pharyngeal Collapsibility,” 163 #4 CHEST April 2023. In such embodiments, a non-ventilated nasal mask equipped with a pressure transducer and respiratory flowmeter is fitted to the subject to quantify airflow and mask pressure. A modified CPAP machine can be used to temporarily reduce pressure and quantify UA collapse (pharyngeal critical closure pressure [Pcrit]) during sleep.

[0155] In certain embodiments, administration of the pharmaceutical composition to a subject results in a reduction of Pcrit of at least 2 cmH2O over at least 4 hours, for example, at least 2 cmH2O over at least 4 hours, at least 2 cmH2O over at least 6 hours, at least 3 cmH2O over at least 4 hours, at least 3 cmH2O over at least 6 hours, at least 4 cmH2O over at least 4 hours, at least 4 cmH2O over at least 6 hours, at least 5 cmH2O over at least 4 hours, at least 5 cmH2O over at least 6 hours, at least 6 cmH2O over at least 4 hours, at least 6 cmH2O over at least 6 hours, at least 7 cmH2O over at least 4 hours, at least 7 cmH2O over at least 6 hours, at least 8 cmH2O over at least 4 hours, at least 8 cmH2O over at least 6 hours, at least 9 cmH2O over at least 4 hours, at least 9 cmH2O over at least 6 hours, at least 10 cmH2O or more over at least 4 hours, or at least 10 cmH2O or more over at least 6 hours.

[0156] In certain embodiments, administration of the pharmaceutical composition to a subject results in a decrease in Pcrit of at least 2 cmH2O over at least 4 hours, for example, at least 3 cmH2O over at least 4 hours, at least 4 cmH2O over at least 4 hours, at least 5 cmH2O over at least 4 hours, at least 6 cmH2O over at least 4 hours, at least 7 cmH2O over at least 4 hours, at least 8 cmH2O over at least 4 hours, at least 9 cmH2O over at least 4 hours, or at least 10 cmH2O over at least 4 hours.

[0157] In certain embodiments, administration of the pharmaceutical composition to a subject results in a decrease in Pcrit of at least 2 cmH2O over at least 8 hours, for example, at least 3 cmH2O over at least 8 hours, at least 4 cmH2O over at least 8 hours, at least 5 cmH2O over at least 8 hours, at least 6 cmH2O over at least 8 hours, at least 7 cmH2O over at least 8 hours, at least 8 cmH2O over at least 8 hours, at least 9 cmH2O over at least 8 hours, or at least 10 cmH2O over at least 8 hours.

[0158] In certain embodiments, the subject does not exhibit signs of irritation, such as reverse sneezing, when the pharmaceutical composition is administered.

[0159] 4.3.1. Combinations of drugs and devices In one embodiment, the disclosure provides a nasal delivery device comprising a combination of a drug and a device, for example, (i) a pharmaceutical composition described herein and (ii) a device suitable for intranasal delivery of the pharmaceutical composition to a subject.

[0160] In certain embodiments, the device comprises a nosepiece for attachment to the nostrils of a subject and an operating mechanism. When the operating mechanism is activated (for example, by pressing or pushing), the device sprays a composition from a nozzle attached to the nosepiece, and if the device is present in the nostrils of a subject, delivers the pharmaceutical composition to the nasal airway of the subject.

[0161] In certain embodiments, the device comprises a fluid dispenser pump and reservoir, as described in EP2139605, which is incorporated herein by reference as a whole. In certain embodiments, the pump is an atmospheric pump. In certain embodiments, the reservoir contains a pharmaceutical composition as described herein. In certain embodiments, the fluid dispenser pump is positioned in contact with the neck of the reservoir. In certain embodiments, the fluid dispenser pump is attached to the neck of the reservoir via one or more fastening rings. In certain embodiments, the one or more fastening rings include a screw-in ring, a snap-on ring, a crimpable cap, or a combination thereof. In certain embodiments, the one or more fastening rings secure the pump to the neck of the reservoir. In certain embodiments, the one or more fastening rings include a compression region. In certain embodiments, the one or more fastening rings are attached to the neck of the reservoir and the pump by applying pressure to the compression region.

[0162] In certain embodiments, the pump includes a piston. In certain embodiments, the piston is located inside the pump. In certain embodiments, the piston moves between two positions: a resting position and a discharge position. In certain embodiments, the piston is in the resting position when no composition is being discharged from the device. In certain embodiments, the piston is in the discharge position when a composition is being discharged from the device. In certain embodiments, each time the device is used, the piston slides from the resting position to the discharge position within the pump to discharge the composition from the reservoir.

[0163] In certain embodiments, the piston is connected to the actuator. In certain embodiments, the actuator is a rod. In certain embodiments, the actuator moves between two positions: a resting position and a dispensing position. In certain embodiments, the actuator comprises a dispenser head. In certain embodiments, the actuator head is where the composition is dispensed. In certain embodiments, the actuator comprises a top and a bottom. In certain embodiments, the dispenser head is located on top of the actuator. In certain embodiments, the actuator further comprises a pusher. In certain embodiments, the pusher is located on bottom of the actuator. In certain embodiments, the user of the device applies pressure to the pusher directly or indirectly to cause the pump to dispense the composition. In certain embodiments, the user applies pressure to the pusher to move the actuator from the resting position to the dispensing position. In certain embodiments, the user applies pressure to the pusher to move the piston from the resting position to the dispensing position. In certain embodiments, the composition is dispensed when the actuator is in the dispensing position. In certain embodiments, the composition is dispensed when the piston is in the dispensing position. In certain embodiments, when the actuator moves to the discharge position, a certain amount of composition is transferred from the reservoir through the actuator to the actuator head. In certain embodiments, when this amount of composition is discharged from the reservoir, a corresponding amount of air is supplied to the reservoir from outside the device. In certain embodiments, the amount of composition discharged is a predetermined amount of the composition. In certain embodiments, the same amount of composition is discharged each time the device is used.

[0164] In certain embodiments, the pump further comprises a seal. In certain embodiments, the seal comprises a ferrule. In certain embodiments, when the actuator is in the rest position, the seal is in contact with the bottom of the actuator. In certain embodiments, when the actuator is in the rest position, the seal is not in contact with the top of the actuator. In certain embodiments, when the actuator is in the discharge position, the seal is not in contact with the bottom of the actuator. In certain embodiments, when the actuator is in the discharge position, the seal is in contact with the top of the actuator. In certain embodiments, the seal is attached to a fastener. In certain embodiments, the fastener is a snap fastener, a screw fastener, or both. In certain embodiments, the fastener is a fastening ring. In certain embodiments, the fastener attaches the seal to the neck of the reservoir. In certain embodiments, the seal prevents the composition from leaking out of the reservoir. In certain embodiments, the pump further comprises a gasket. In certain embodiments, the gasket is configured to attach the seal to the fastener. In certain embodiments, the air passage for air entering the pump may flow from the seal to the pump and then to the reservoir.

[0165] An exemplary device is shown in Figures 22 and 23. This device comprises a reservoir 1 with a neck 2, and a pump 10 is mounted to the neck 2 of the reservoir 1 by a retaining ring 5, preferably with a seal 9 called a seal of col interposed therebetween. The pump comprises a pump body 11 with an upper end edge 12. A piston 20 slides in a sealed manner inside the pump body 11 each time it is operated, discharging a certain amount of product from the tank 1. In conventional systems, the piston 20 is integrated with an operating rod 30, as shown in the drawings, and in particular forms a single part, with a discharge head or pusher (not shown) mounted on the operating rod, and the user operates the pump by directly or indirectly pushing the discharge head or pusher. A ferrule 40 is mounted inside the pump body 11 and works in cooperation with the piston 20 to define its resting position. The ferrule 40 supports a seal 50 adapted to achieve a seal between the ferrule 40 and the retaining ring 5. The retaining ring 5 may be any type, including a crimpable one as shown in the drawing, but may also be a snap-on, screw-in, or other suitable retaining ring.

[0166] The ferrule 40 cooperates with the actuating rod 30 in a sealed state when the actuating rod moves between the resting position and the intermediate position, but the ferrule 40 no longer cooperates with the actuating rod 30 in a sealed state between the intermediate position and the actuating position shown in Figure 23. Therefore, when the cooperation between the ferrule 40 and the actuating rod 30 is no longer sealed, the ventilation system is open in the conventional manner.

[0167] In a particular embodiment, an exemplary device comprises a reservoir 1 and a pump 10 for containing a pharmaceutical composition described herein, the pump 10 being assembled to the reservoir 1 by a fastening ring 5, the fluid pump 10 comprising a pump body 11, a piston 20 that slides leak-proof between a resting position and an operating position within the pump body 11, the piston 20 being fixed to an actuator rod 30 extending axially outward from the pump body 11, and a ferrule 40 mounted on the upper end edge 12 of the pump body 11, the piston The pump comprises a ferrule 40 defining the resting position of the piston 20, wherein the pump 10 is airtight, the ferrule 40 cooperates with the actuator rod 30 in a leak-proof manner while the actuator rod 30 is moving between the resting position and an intermediate position, and the ferrule 40 cooperates with the actuator rod 30 in a non-leak-proof manner while the actuator rod 30 is moving between the intermediate position and the operating position, and the piston 20 is not in contact with the ferrule 40 when it is in the resting position.

[0168] In a particular embodiment, the nasal device dispenses 50 μl to 150 μl of pharmaceutical composition with each operation of the device, for example, 50 μl to 125 μl, 50 μl to 100 μl, 50 μl to 75 μl, 75 μl to 150 μl, 75 μl to 125 μl, 75 μl to 100 μl, 100 μl to 150 μl, 100 μl to 125 μl, or 125 μl to 150 μl, etc.

[0169] In a particular embodiment, the nasal device delivers 85 mg to 130 mg of the pharmaceutical composition with each operation of the device, for example, 85 mg to 120 mg, 85 mg to 115 mg, 85 mg to 110 mg, 85 mg to 100 mg, 90 mg to 130 mg, 90 mg to 120 mg, 90 mg to 115 mg, 90 mg to 110 mg, 90 mg to 100 mg, 95 mg to 130 mg, 95 mg to 120 mg, 95 mg to 115 mg, 95 mg to 110 mg, 95 mg to 100 mg, 100 mg to 130 mg, 100 mg to 120 mg, 100 mg to 115 mg, 100 mg to 110 mg, 110 mg to 130 mg, 110 mg to 120 mg, or 120 mg to 130 mg. In certain embodiments, the nasal device delivers 100 mg to 120 mg or 105 mg to 120 mg of the pharmaceutical composition with each device operation.

[0170] In certain embodiments, the standard deviation of the amount of pharmaceutical composition between device operations is less than 10, for example, less than 8, less than 5, or less than 3.

[0171] Depending on the properties of the pharmaceutical composition and the nasal delivery device, the spray generated during operation may be a jet spray or a mist spray.

[0172] In certain embodiments, the device delivers a jet spray of a pharmaceutical composition when in operation. In certain embodiments, the jet spray contains droplets of a composition with droplet sizes ranging from 100 μm to 1,000 μm, for example, 100 μm to 750 μm, 100 μm to 500 μm, 100 μm to 250 μm, 250 μm to 1,000 μm, 250 μm to 750 μm, 250 μm to 500 μm, 500 μm to 1,000 μm, 500 μm to 750 μm, or 750 μm to 1,000 μm. In certain embodiments, the jet spray contains droplets of a pharmaceutical composition with a droplet size of approximately 300 μm to 500 μm. In certain embodiments, the jet spray contains droplets of a composition with a droplet size of 700 μm to 1,000 μm.

[0173] In certain embodiments, the device dispenses a mist spray of a pharmaceutical composition when in operation. In certain embodiments, the mist spray contains droplets of a pharmaceutical composition having a droplet size of 50 μm to 1,000 μm, for example, 50 μm to 750 μm, 50 μm to 500 μm, 50 μm to 250 μm, 100 μm to 1,000 μm, 100 μm to 750 μm, 100 μm to 500 μm, 100 μm to 250 μm, 250 μm to 1,000 μm, 250 μm to 750 μm, 250 μm to 500 μm, 500 μm to 1,000 μm, 500 μm to 750 μm, or 750 μm to 1,000 μm. In certain embodiments, the mist spray contains droplets of a pharmaceutical composition having droplet sizes of 70 μm to 150 μm, 80 μm to 150 μm, or 90 μm to 120 μm. In certain embodiments, the mist spray contains a pharmaceutical composition with droplet sizes of 80 μm to 100 μm, for example, 80 μm to 90 μm.

[0174] In certain embodiments, the device delivers, for example, 50 μl to 300 μl of a pharmaceutical composition, such as 50 μl to 250 μl, 50 μl to 200 μl, 50 μl to 150 μl, 50 μl to 100 μl, 100 μl to 300 μl, 100 μl to 250 μl, 100 μl to 200 μl, 100 μl to 150 μl, 150 μl to 300 μl, 150 μl to 250 μl, 150 μl to 200 μl, 200 μl to 300 μl, or 250 μl to 300 μl, etc., to the target nasal airway with each operation of the device.

[0175] The dose of compound 1 supplied to the patient (including all actions and administration into both nostrils) varies depending on the weight percentage of compound 1 in the pharmaceutical composition and the number of actions performed.

[0176] In certain embodiments, the nasal device delivers 9 mg to 11 mg of Compound 1 per 100 μl of the pharmaceutical composition ejected from the device, for example, 9 mg to 10.5 mg, 9 mg to 10 mg, 9 mg to 9.5 mg, 9.5 mg to 11 mg, 9.5 mg to 10.5 mg, 9.5 mg to 10 mg, 10 mg to 11 mg, 10 mg to 10.5 mg, or 10.5 mg to 11 mg. In certain embodiments, the nasal device delivers 9 to 10 mg or 10 to 11.5 mg of Compound 1 per 100 μl of the pharmaceutical composition ejected from the device.

[0177] In certain embodiments, the pharmaceutical composition is administered into one nostril by actuation of the nasal device to deliver the total dose of Compound 1 to the subject. In certain embodiments, the device can be actuated one or more times, for example, 2 times, 3 times, 4 times, or 5 or more times, to deliver the total dose of Compound 1 to the subject.

[0178] In certain embodiments, the pharmaceutical composition is administered into each nostril by actuation of the nasal device to deliver the total dose of Compound 1 to the subject. In certain embodiments, the device can be actuated one or more times, for example, 2 times, 3 times, 4 times, or 5 or more times, to deliver the total dose of Compound 1 to the subject.

[0179] In certain embodiments, one or more priming sprays may be performed prior to administration. Since the initial actuation may contain a low weight of product, such priming sprays remove air from the tubes of the pump and actuator and replace it with a formulation ready for immediate administration. Such priming sprays are not ejected into the subject's nostrils and therefore do not deliver Compound 1 to the subject. In certain embodiments, 1, 2, 3, or 4 or more priming sprays are performed prior to administration of the composition to the subject's nostrils. 4.4. Enumeration of Embodiments 1. 2'-{[2-(4-methoxyphenyl)-acetylamino]-methyl}biphenyl-2-carboxylic acid (2-pyridine-3-yl-ethyl)-amide (compound 1) or a pharmaceutically acceptable salt thereof, Mucosal adhesive polymers, A pharmaceutical composition comprising, The pharmaceutical composition wherein compound 1 is present in an amount greater than 0.25% (w / w). 2. The composition according to Embodiment 1, wherein compound 1 is present in an amount greater than 0.25% (w / w) and up to 20% (w / w). 3. The composition according to Embodiment 1 or 2, wherein compound 1 is present in an amount of 3% (w / w) to 10% (w / w). 4. The composition according to Embodiment 3, wherein compound 1 is present in an amount of approximately 6% (w / w). 5. The composition according to Embodiment 3, wherein compound 1 is present in an amount of approximately 9% (w / w). 6. The composition according to any one of Embodiments 1 to 5, wherein the mucosal adhesive polymer includes a polyacrylic acid derivative, a cellulose derivative, a natural polymer, polyvinylpyrrolidone (PVP), a dextran polymer, a polyethylene oxide polymer, a thermoreversible polymer, an ion-responsive polymer, a copolymer of polymethyl vinyl ether and maleic anhydride, or a combination thereof. 7. The composition according to Embodiment 6, wherein the mucosal adhesive polymer comprises a cellulose derivative selected from hydroxyalkylcellulose polymer, methylcellulose polymer, carboxymethylcellulose (CMC) polymer, a salt of carboxymethylcellulose, or a combination thereof. 8. The composition according to Embodiment 7, wherein the mucosal adhesive polymer comprises a hydroxyalkylcellulose polymer selected from hydroxypropyl methylcellulose (HPMC) and hydroxypropylcellulose (HPC). 9. The composition according to Embodiment 8, wherein the mucosal adhesive polymer comprises HPMC. 10. The composition according to Embodiment 6, wherein the mucosal adhesive polymer is a cellulose derivative selected from hydroxyalkylcellulose polymer, methylcellulose polymer, carboxymethylcellulose (CMC) polymer, a salt of carboxymethylcellulose, or a combination thereof. 11. The composition according to Embodiment 10, wherein the mucosal adhesive polymer is a hydroxyalkylcellulose polymer selected from hydroxypropyl methylcellulose (HPMC) and hydroxypropylcellulose (HPC). 12. The composition according to Embodiment 11, wherein the mucosal adhesive polymer is HPMC. 13. The composition according to Embodiment 7, wherein the mucosal adhesive polymer comprises a methylcellulose polymer. 14. The composition according to Embodiment 7, wherein the mucosal adhesive polymer is a methylcellulose polymer. 15. The composition according to Embodiment 6, wherein the mucosal adhesive polymer comprises a natural polymer selected from gum arabic, tragacanth gum, agar polymer, xanthan gum, a copolymer of alginic acid and sodium alginate, chitosan polymer, pectin, carrageenan, pullulan polymer, modified starch, or a combination thereof. 16. The composition according to Embodiment 15, wherein the mucosal adhesive polymer comprises carrageenan. 17. The composition according to Embodiment 6, wherein the mucosal adhesive polymer is a natural polymer selected from gum arabic, tragacanth gum, agar polymer, xanthan gum, a copolymer of alginic acid and sodium alginate, chitosan polymer, pectin, carrageenan, pullulan polymer, modified starch, or a combination thereof. 18. The composition according to Embodiment 17, wherein the mucosal adhesive polymer is carrageenan. 19. The composition according to any one of Embodiments 1 to 18, wherein the mucosal adhesive polymer is present in an amount of 0.1% (w / w) to 20% (w / w). 20. The composition according to Embodiment 19, wherein the mucosal adhesive polymer is present in an amount of 0.3% (w / w) to 1% (w / w), preferably 0.3% (w / w) to 0.6% (w / w). twenty one. The composition described above is the composition according to any one of Embodiments 1 to 20, which does not contain microcrystalline cellulose. twenty two. The composition according to Embodiment 1, wherein the mucosal adhesive polymer does not contain microcrystalline cellulose. twenty three. A composition according to any one of Embodiments 1 to 23, further comprising an osmotic pressure regulator. twenty four. The composition according to Embodiment 23, wherein the osmotic pressure adjusting agent is selected from dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine, and combinations thereof. twenty five. The osmotic pressure adjusting agent is selected from sorbitol, mannitol, and combinations thereof, as described in Embodiment 24. 26. The composition according to any one of Embodiments 23 to 25, wherein the osmotic pressure adjusting agent is present in an amount of 0.1% (w / w) to 10% (w / w), preferably 0.1% (w / w) to 5% (w / w). 27. The composition according to Embodiment 26, wherein the osmotic pressure adjusting agent is present in an amount of 1% (w / w) to 3% (w / w). 28. A composition according to any one of Embodiments 1 to 27, further comprising a wetting agent. 29. The composition according to Embodiment 28, wherein the wetting agent is selected from polysorbates, fatty acid glycerol polyethylene glycol esters, fatty acid polyethylene glycol esters, polyethylene glycol, glycerol ethers, cyclodextrins (e.g., alpha, beta or gamma-cyclodextrin, such as alkylated, hydroxyalkylated, carboxyalkylated or alkyloxycarbonyl-alkylated derivatives, or mono- or diglycosyl-alpha, beta or gamma-cyclodextrin, mono- or dimaltosyl-alpha, beta or gamma-cyclodextrin, or panosyl-cyclodextrin), reaction products of castor oil and ethylene oxide, and combinations thereof. 30. The composition according to Embodiment 29, wherein the wetting agent is selected from polysorbates and reaction products of castor oil and ethylene oxide. 31. The composition according to Embodiment 30, wherein the wetting agent is a polysorbate, and the polysorbate is polysorbate 80. 32. The composition according to Embodiment 30, wherein the wetting agent is a reaction product of castor oil and ethylene oxide selected from polyoxyl 35 castor oil and polyoxyl 40 hydrogenated castor oil. 33. The composition according to any one of Embodiments 28 to 32, wherein the wetting agent is present in an amount of 0.1% (w / w) to 5.0% (w / w). 34. The composition according to Embodiment 33, wherein the wetting agent is present in an amount of 0.1% (w / w) to 1.0% (w / w), preferably 0.3% (w / w) to 0.6% (w / w). 35. The composition according to any one of Embodiments 1 to 34, further comprising an antibacterial preservative. 36. The composition according to Embodiment 35, wherein the antimicrobial preservative is selected from chlorhexidine gluconate, phenylethyl alcohol, 1-phenoxyethanol, benzyl alcohol, sorbic acid, thimerosal, phenylmercury acetate, benzoates, parabens, sorbates, and combinations thereof. 37. The composition according to Embodiment 36, wherein the antimicrobial preservative is potassium sorbate. 38. The composition according to any one of embodiments 35 to 37, wherein the antimicrobial preservative is present in an amount of 0.01% (w / w) to 1% (w / w). 39. The composition according to Embodiment 38, wherein the antimicrobial preservative is present in an amount of 0.05% (w / w) to 0.15% (w / w). 40. A composition according to any one of Embodiments 1 to 39, further comprising an aqueous medium. 41. The composition according to Embodiment 40, wherein the aqueous medium includes deionized water, saline solution, phosphate buffer, citrate buffer, malate buffer, tartaric acid buffer, equilibrium salt solution, salt of an organic acid, a combination of an organic acid and a salt of an organic acid (for example, sodium tribase citrate and citric acid, malate and sodium malate, and potassium sodium tartrate and tartaric acid), or a combination thereof. 42. The aqueous medium is the composition according to Embodiment 41, comprising a citrate buffer and a phosphate buffer. 43. The composition is the composition according to any one of Embodiments 40 to 42, comprising an aqueous medium in an amount of 85% (w / w) to 95% (w / w). 44. The composition is the composition according to Embodiment 43, comprising an aqueous medium in an amount of 85% (w / w) to 90% (w / w). 45. A composition according to any one of Embodiments 1 to 44, further comprising EDTA. 46. The composition is the composition according to Embodiment 45, comprising 0.01% (w / w) to 2% (w / w) of EDTA. 47. The composition described in Embodiment 1, Compound 1 at 0.25% (w / w) to 20% (w / w), 0.1% (w / w) to 20% (w / w) of mucosal adhesive polymers, Osmotic pressure regulators in concentrations of 0.1% (w / w) to 10% (w / w), 0.1% (w / w) to 5% (w / w) humectant, 0.01% (w / w) to 1% (w / w) of antimicrobial preservatives, 85% (w / w) to 95% (w / w) water-based media, The composition comprising the above. 48. The composition described in Embodiment 47, Compound 1 in 3% (w / w) to 10% (w / w) concentrations, A mucosal adhesive polymer in a concentration of 0.3% (w / w) to 0.6% (w / w), 1% (w / w) to 3% (w / w) osmotic pressure regulator, 0.3% (w / w) to 0.6% (w / w) (w / w) humectant, 0.05% (w / w) to 0.15% (w / w) of antimicrobial preservatives, 85% (w / w) to 90% (w / w) water-based media, The composition comprising the above. 49. The composition according to Embodiment 47 or 48, wherein the mucosal adhesive polymer is methylcellulose, the osmotic pressure regulator is mannitol, the wetting agent is polyoxyl 40 hydrogenated castor oil, the antimicrobial preservative is potassium sorbate, and the aqueous medium is a mixture of citrate buffer and phosphate buffer. 50. The composition according to Embodiment 47 or 48, wherein the mucosal adhesive polymer is HPMC, the osmotic pressure modifier is sorbitol, the wetting agent is polyoxyl 35 castor oil, the antimicrobial preservative is potassium sorbate, and the aqueous medium is a mixture of citrate buffer and phosphate buffer. 51. The composition according to Embodiment 47 or 48, wherein the mucosal adhesive polymer is carrageenan, the osmotic pressure regulator is sorbitol, the wetting agent is polyoxyl 35 castor oil, the antimicrobial preservative is potassium sorbate, and the aqueous medium is a mixture of citrate buffer and phosphate buffer. 52. The composition according to Embodiment 51, further comprising 0.01% (w / w) to 2% (w / w) of EDTA. 53. The composition according to any one of Embodiments 1 to 52, wherein the composition is in liquid form. 54. The composition according to embodiment 53, wherein the liquid is a suspension. 55. The composition according to any one of Embodiments 1 to 54, wherein the apparent pH is 4 to 9, preferably about 5 to 7, and more preferably about 6. 56. The composition is the composition according to any one of Embodiments 1 to 55, wherein the molar osmotic pressure concentration is 200 mOsm / kg to 500 mOsm / kg, more preferably 250 mOsm / kg to 350 mOsm / kg, and more preferably about 300 mOsm / kg. 57. The above composition has a particle size distribution D of compound 1. 90 The composition according to any one of Embodiments 1 to 56, wherein the particle size is 5 μm to 30 μm, preferably 5 μm to 15 μm. 58. The above composition has a bimodal particle size distribution D of compound 1. 90 The composition according to embodiment 57, having the following characteristics. 59. 25% (w / w) to 75% (w / w) of compound 1 is D 90 The size is 20 μm to 30 μm, and the remainder of compound 1 is D 90 The composition according to Embodiment 58, wherein the particle size is 5 μm to 15 μm. 60. A composition according to any one of Embodiments 1 to 59, wherein less than 0.1% (w / w) of compound 1 is dissolved. 61. When the composition is stored at 25°C for 2 weeks, (i) the recovery rate of compound 1, (ii) macroscopic appearance, (iii) microscopic appearance, (iv) apparent pH, (v) molar osmotic concentration, (vi) particle size distribution (D 90 A composition according to any one of Embodiments 1 to 60, which is stable as determined by one or more of the following: ) and Raman analysis. 62. When the composition is stored at 40°C for 2 weeks, (i) the recovery rate of compound 1, (ii) macroscopic appearance, (iii) microscopic appearance, (iv) apparent pH, (v) molar osmotic concentration, (vi) particle size distribution (D 90 (vii) A composition according to any one of Embodiments 1 to 61, which is stable as determined by one or more of the following: (vii) Raman analysis. 63. When the composition is stored at 25°C for 4 weeks, (i) recovery rate of compound 1, (ii) macroscopic appearance, (iii) microscopic appearance, (iv) apparent pH, (v) molar osmotic concentration, (vi) particle size distribution (D 90 A composition according to any one of Embodiments 1 to 62, which is stable as determined by one or more of the following: (vii) Raman analysis. 64. When the composition is stored at 40°C for 4 weeks, (i) the recovery rate of compound 1, (ii) macroscopic appearance, (iii) microscopic appearance, (iv) apparent pH, (v) molar osmotic concentration, (vi) particle size distribution (D 90 (vii) A composition according to any one of Embodiments 1 to 63, which is stable as determined by one or more of the following: (vii) Raman analysis. 65. The composition is administered intranasally to subjects suffering from obstructive sleep apnea before sleep onset, and the composition reduces upper airway collapse, as measured in the same subjects who did not receive the composition, by the pharyngeal critical closure pressure (P crit P compared with ) crit A composition according to any one of embodiments 1 to 64, which is measured by a decrease in and suppresses for at least 6 hours after administration and during sleep. 66. P critThe composition according to Embodiment 65, wherein the volume decreases by at least 2 cmH2O over at least 6 hours. 67. P crit The composition according to embodiment 65 or 66, wherein the concentration decreases by at least 2 to 10 cmH2O over a period of at least 6 hours. 68. P crit The composition according to any one of embodiments 65 to 67, wherein the concentration decreases over at least 8 hours. 69. A nasal delivery device comprising a pharmaceutical composition according to any one of Embodiments 1 to 68. 70. The transnasal supply device according to Embodiment 69, comprising a nosepiece for attachment to the nostrils of a target, and an operating mechanism, wherein the nosepiece includes a nozzle for supplying the composition as a spray into the nasal airway of the target when the operating mechanism is activated. 71. A nasal supply device according to embodiment 69 or 70, wherein a volume of 50 μl to 150 μl of the composition is supplied with each operation. 72. The nozzle is a nasal supply device according to embodiment 69 or 70, which supplies a jet spray of the composition when in operation. 73. The nasal delivery device according to Embodiment 72, wherein the jet spray contains droplets having a droplet size of 100 μm to 1,000 μm, preferably more than 400 μm. 74. The nozzle is a nasal supply device according to embodiment 69 or 70, which supplies a mist spray of the composition when in operation. 75. The nasal delivery device according to Embodiment 74, wherein the mist spray contains droplets having a droplet size of 50 μm to 1,000 μm, preferably about 80 μm to about 150 μm, and more preferably 90 μm to 120 μm. 76. A method for treating obstructive sleep apnea in a subject requiring treatment, comprising administering an effective amount of a pharmaceutical composition described in any one of Embodiments 1 to 68 to the subject before sleep. 77. The composition is administered intranasally according to the method of Embodiment 76. 78. The method according to Embodiment 77, wherein the composition is administered intranasally by a nasal delivery device described in any one of Embodiments 69 to 75. 79. The method according to Embodiment 77 or 78, wherein the composition is administered once (one activation per nostril) or twice (two activations per nostril) before sleep. 80. The method according to any one of embodiments 76 to 79, wherein the composition is administered 5 to 120 minutes, preferably 10 to 30 minutes, before sleep. 81. Upper airway collapse is measured in the same subject that has not received the composition, and the pharyngeal critical closure pressure (P crit P compared with ) crit The method according to any one of embodiments 76 to 80, which is measured by a decrease in and suppressed for at least 6 hours after administration and during sleep. 82. P crit The method according to Embodiment 81, wherein the volume decreases by at least 2 cmH2O over a period of at least 6 hours. 83. P crit The method according to embodiment 81 or 82, wherein the volume decreases by at least 2-10 cmH2O over a period of at least 6 hours. 84. P crit The method according to any one of embodiments 81 to 83, wherein the temperature decreases over a period of at least 8 hours. 85. The subject is the method according to any one of embodiments 76 to 84, wherein the subject does not experience reverse sneezing when the composition is administered. [Examples]

[0180] 4.5. Examples The following are examples of specific embodiments for carrying out the present invention. The examples are presented for illustrative purposes only and are not intended in any way to limit the scope of the present invention. Efforts have been made to ensure the accuracy of the numerical values ​​used (e.g., quantities, temperatures, etc.), but some experimental errors and deviations should naturally be accepted. 4.5.1. Example 1: In a Phase 2 clinical trial, no significant improvement in obstructive sleep apnea was observed after intranasal administration of compound 1. Based on early preclinical evidence (Wirth et al., SLEEP, 36(5):699-708 (2013)) that AVE-118 (compound 1) shifted the mechanoreceptor response threshold of the genioglossus muscle toward positive pressure in anesthetized pigs, thereby suppressing upper airway collapse in a dose-dependent manner, we prepared a formulation suitable for intranasal administration to human subjects and conducted a Phase 2 clinical trial.

[0181] 4.5.1.1 Test formulation The intranasal formulation ("Ph2 formulation") used in this study is listed in Table 1 below. This formulation is a suspension using micronized API with an average particle size of approximately 4 μm (corresponding to 30 mg / mL, 3% by weight of compound 1). Its composition was similar to commercially available suspensions for intranasal administration, such as Nasacort®. It included the following excipients. • Benzalkonium chloride (preservative) • Dispersible cellulose (microcrystalline cellulose (MCC) / carmellose sodium) (for stabilization, viscosity improvement, and aggregation prevention) • Mannitol (for isotonicity).

[0182] Benzalkonium chloride is a standard excipient for nasal medications and was used in the suspension at the usual concentrations required for preservation. [Table 1]

[0183] Tolerance studies of the formulation conducted by DSE in dogs confirmed sufficient tolerability, which is a prerequisite for initiating human clinical trials.

[0184] 4.5.1.2 Test Design This study was a multicenter, randomized, placebo-controlled, double-blind, two-period crossover trial involving a single intranasal dose in two treatment periods in male patients with obstructive sleep apnea-hypopnea syndrome (OSAHS).

[0185] After a screening phase of up to 21 days, patients received either a single dose of 18 mg of compound 1 administered as three 100 μL sprays of the test drug into each nostril (9 mg / nostril) at bedtime during each study period, or the same amount of placebo. This nasal single dose was administered in a seated position. A drug-free period of 2 days to 3 weeks was provided between the two study periods. The study period per patient ranged from 13 days to a maximum of 8 weeks.

[0186] Efficacy was blinded using centrally read overnight polysomnography (PSG) records. Central readers were blinded to the treatment sequence received by patients and to potential safety study outcomes. Additionally, the Maintenance of Wakefulness Test (MWT) and Stanford Sleepiness Score (SSS) were used to assess excessive daytime sleepiness (EDS), and plasma concentrations of compound 1 were assessed at baseline and approximately 10 hours after administration of the study drug (data not shown).

[0187] This study planned to randomize 38 patients (19 patients per sequence group) (accommodating a 10% dropout rate). Patients were randomized at a central institution using an interactive voice response system (IVRS) with a pre-prepared randomization list of randomly substituted blocks of size 4 to maintain a balance of allocation (1:1 ratio) between the two sequences, to one of two sequence groups (Sequence 1: placebo / compound 1, Sequence 2: compound 1 / placebo). Randomization was stratified by institution.

[0188] A schematic representation of this experimental design is shown in Figure 1.

[0189] 4.5.1.3 Primary Endpoint The primary efficacy endpoint was the change from baseline in the apnea-hypopnea index (AHI) (events / hour), defined as the number of apnea-hypopnea events divided by total sleep time (TST). Baseline was defined as the last available value before inhalation of the study drug in each period.

[0190] 4.5.1.4 Main Secondary Endpoints Since the objective was to investigate the potential initial effects of the drug, the primary secondary endpoint was the change from baseline in AHI (events / hour) during the first four hours of the night. AHI during the first four hours of the night was assessed by dividing the number of apnea-hypopnea events that occurred during the four hours following drug inhalation by the TST during that period.

[0191] 4.5.1.5 Definition of the analysis population Randomized patients

[0192] Randomized patients were defined as all patients who were assigned a treatment kit number through the randomization process and recorded in the IVRS database.

[0193] Intention to treat group

[0194] The intention-to-treat (ITT) population was defined as all randomized patients who inhaled the study drug at least once and underwent baseline AHI assessments and post-baseline AHI assessments for at least one treatment period. Patients were analyzed using the treatments actually received in each period, regardless of the randomized treatment sequence.

[0195] Protocol-compliant group

[0196] The protocol-fit (PP) population was defined as a subset of the intention-to-treat (ITT) population, consisting of all randomized patients who were evaluable for the primary efficacy criterion and did not have any significant protocol deviations related to efficacy. Patients were considered evaluable for the primary criterion if they underwent baseline AHI assessments and post-baseline AHI assessments for at least one treatment period, with a minimum TST of 4 hours for each assessment and a maximum baseline-to-post-baseline change in TST of 25%. In the PP analysis, only evaluable AHI measurements were considered (measurements with a minimum TST of 4 hours for each test during a period and a maximum baseline-to-post-baseline change in TST of 25%). For patient analysis, the treatments actually received by patients during each period were used.

[0197] Safety analysis target population

[0198] The safety analysis population was defined as all randomized patients exposed to the study drug, regardless of the amount of treatment administered. Patient analyses used the treatments actually received by patients during each period.

[0199] 4.5.1.6 Primary Efficacy Analysis Efficacy analyses were performed for the PP and ITT populations. The difference between treatment groups in the change in AHI from baseline to day 1 was evaluated using a linear mixed-effects model for a crossover design, with treatment, duration, sequence, and site as fixed effects, and patient (nested within the sequence) as a random effect, using baseline AHI as a covariate, and evaluated using SAS PROC MIXED.

[0200] The least squares (LS) mean of the difference between compound 1 and placebo in the change from baseline was obtained, along with its 95% confidence interval. The statistical test was a two-tailed test with a Type I error fixed at 5%.

[0201] 4.5.1.7 Results 4.5.1.7.1 Breakdown of patients All 38 randomized patients were included in the ITT population, the PK population, and the safety population.

[0202] Five patients were excluded from the PP analysis for the following reasons. Two patients had an AHI of over 72 at the time of enrollment (subjects 250001073 and 25002005). Three patients had less than 60% obstructive or mixed apnea-hypopnea (AH) events at the time of enrollment (subjects 250001051, 250002007, and 25002009).

[0203] Patient 250001034 was randomized to the treatment sequence "AVE0118 / placebo" but received the treatment sequence "placebo / AVE0118". Considering the early stages of the trial's development, this patient was analyzed using the treatments actually received at each time point in the ITT population, PP population, PK population, and safety analysis population.

[0204] Baseline demographic information is shown in Table 2. [Table 2]

[0205] 4.5.1.7.2 Exam Content All 38 randomized patients completed the trial as planned and received the planned total dose of compound 1, 18 mg.

[0206] 4.5.1.7.3 Effectiveness Figure 2 plots the mean change (±95% confidence interval) of AHI from baseline in the protocol-compliant (PP) population, with baseline defined as the last available value before drug inhalation in each period. Note that only evaluable measurements were considered (TST ≥ 4 hours and absolute change in TST during one period ≤ 25%). Figure 3 plots the individual values ​​of AHI in the protocol-compliant population. The results are summarized in Table 3 below. [Table 3]

[0207] In the protocol-fit population, a single dose of compound 1 tended to result in a greater reduction in AHI compared to placebo. However, this reduction was not statistically significant (p=0.0682). The observed difference between treatment groups was only 4.00 doses / hour (95% CI -8.31 to 0.31), favoring compound 1. This corresponded to a 14.75% change from baseline (95% CI 2.13 to 31.63), favoring compound 1, but fell significantly short of the 40% reduction targeted in the clinical trial protocol.

[0208] The results in the ITT population and the results from the sensitivity analysis based on square root transformation are consistent with these study findings, and the ITT population showed an even higher p-value (lower statistical significance) than the PP population.

[0209] 4.5.1.8 Safety Table 4 summarizes the adverse events (TEAEs) that occurred during treatment. [Table 4]

[0210] 4.5.2. Example 2: Evaluation of Phase 2 trial failure Despite promising animal model data, there are numerous possible reasons why the human Phase 2 trial was unsuccessful. Possible interpretations include the following, but these are not mutually exclusive or exhaustive. 1. Problems related to animal models a. The anesthetized pig OSA animal model used by Wirth in 2013 did not adequately reproduce the human disease and therefore did not predict its effectiveness in humans. i. In extreme cases, efficacy signals in this pig model may not predict efficacy in humans, and this drug may not work at all in humans. 2. Issues related to the design and / or implementation of clinical protocols a. Plasma PK in the human Phase 2 trial did not reflect the slow release profile observed in the porcine trial. b. Problems related to administration techniques i. Inconsistent angles ii. Inconsistent insertion depth c. The patient may not have had enough time to act before the clinical benefit was measured. It may be necessary to start the drug earlier, or to begin treatment a few days before the patient would experience clinical benefit. d. The apnea-hypopnea index (AHI) rate varied significantly from night to night in the same patient (depending on sleep quality, duration of REM sleep, and duration of supine and lateral positioning). This study may not have had sufficient power to account for this. e. The pathological characteristics of the test subject may have damaged the original drug target (if nerves are non-functional or their levels are reduced, the K+ channel blocking mechanism will have no effect). f. The efficacy of this mechanism of action may be lost in these patients due to their etiological characteristics (e.g., high loop gain, more prone to airway collapse). g. Poor adherence to clinical protocols 3. Inappropriate dosage a. The dosage cannot be applied from pigs to humans (doses exceeding 18 mg have not been tested in humans). b. Variation in patient response (for example, some patients may require 18 mg, while others may require 36 mg). 4. Drug Stability a. The drug was not physically or chemically stable in the formulation / device before application, and therefore the selected dose was not achieved. b. The drug lost its efficacy when applied to the nasal mucosa. 5. Supply of drugs a. For the following reasons, the device + formulation was suboptimal in terms of the dose delivered to the target site / site of action / pharyngeal nasal region (i.e., the drug was inhaled, ingested, or exhaled in excess): i. Particle size and droplet size were below the optimal level. ii. Too large a volume was sprayed into each nostril in too short a time. iii. Aggregation of the formulation particles resulted in expulsion (sneezing), or dissolution was below optimal. iv. Particle size increased mucociliary clearance. v. The device / formulation did not operate in the optimal position. vi. Drug particles adhere to the mucosal surface and cannot advance / dissolve further, and therefore are not absorbed. b. Amount of drug deposited in nasal tissue i. Too little drug was deposited. 1. The amount of medication administered was too low (18 mg was too little). 2. Inhaled in excess 3. Called out in excess 4. Swallowed in excess 5. The formulation failed to effectively deposit the drug: a. Aggregation of drug particles may have disrupted uniform dispersion on the tissue surface. b. Inappropriate adhesion to the epithelial surface i. Excessive adhesion in inappropriate locations may prevent the drug from reaching targets, which are presumably located primarily in the nasopharynx. c. The drug in the formulation failed to pass through the mucus layer and reach the epithelial surface. c. Location of drug deposition i. The spray device (plume shape) delivered the drug to an area where it was ineffective (or delivered to the lungs, or delivered too far back, resulting in ingestion). ii. The spray droplets were too large or too small to be properly transported to the correct location within the nasal passage by the airflow. 1. Small droplets may be inhaled, causing a rapid change in the plasma PK profile. max This also serves as an explanation. iii. The spray droplets, before depositing on the nasal mucosa, were either too large or too small to be transported to the nasopharyngeal target by epithelial mucus before the drug could be deposited (and immobilized) on the epithelial surface. iv. Particle size distribution and / or aggregation of the drug 1. Differences in deposition locations for different particle sizes. d. Duration of deposition i. Drug particles were removed by a "normal" mucus flow. ii. Drug particles were removed by a "clearance mechanism" (excess mucus production, sneezing, coughing) triggered by local irritation. iii. The drug particles dissolved too quickly (the average particle size was too small, or the proportion of small particles was too large, i.e., the particle size distribution was inappropriate). iv. Particle size distribution and / or aggregation of drugs - larger particles are removed more quickly by mucus. 6. Drug retention a. The drug dosage may have been sufficient for a short duration of action, but insufficient for an effect lasting several hours or even 8 hours. i. The drug may have been washed away by the mucus flow. ii. The drug may have dissolved too rapidly. iii. The drug may have entered the bloodstream too quickly. iv. For the reasons stated above, the retention at the site of action was below optimal, making it impossible to achieve continuous / controlled supply for 8 hours. 7. Tissue penetration a. The drug was unable to pass through the epithelial surface barrier. b. The drug did not remain in the target site. c. The drug could not diffuse laterally within the epithelial tissue and could not reach the nerve endings of pressure-sensing nerves (drug targets). i. There is sufficient dispersion / penetration to reach the nerves at a threshold percentage necessary to exert the desired pharmacological effect. d. Aggregation of drug particles may have hindered dissolution, potentially reducing the bioavailability of the dissolved drug in the tissue. e. The formulation may have been taken up systemically rather than locally, due to an excessively high flow rate. f. The drug in the formulation may have had insufficient flow rate into the tissue, and the flow rate may have been inconsistent. i. Failure to maintain appropriate buffering conditions to control drug release from particles (too much acidity may cause the drug to dissolve too rapidly). ii. The formulation is not optimized to match the saturation solubility of the active compound in order to maximize the thermodynamic driving force for penetration. g. Absorption through the mucosal epithelium was below optimal for the following reasons: i. The drug dissolution rate was insufficient. ii. Due to the inherent impermeability of the drug or suboptimal flow rate, the drug levels in the pressure-sensing nerves required to achieve the necessary tension elevation and collapse prevention over the duration necessary to achieve clinical benefit could not be reached. iii. The equilibrium between the suspended drug and the dissolved drug in the nasal mucus was below the optimal state for achieving the necessary dissolution and subsequent absorption. 8. The surface area of ​​the pressure-sensing nerve to which the drug bound was too small, resulting in no effect on the negative pressure reflex. a. The drugs clumped together. b. The device did not supply a uniform spray. c. There was no lateral diffusion of the drug within the organization. d. The supply did not adequately cover a sufficient proportion of the nasopharyngeal surface area. i. Binding / retention to mucosal epithelium, e.g., different mucosal layers and nasal cavity epithelium. In other words, the drug could not penetrate and act on pressure-sensing nerves, and the increase in tension and prevention of collapse did not occur. 9. Device a. The formulation and the device were not compatible. b. The supply of doses was inconsistent. c. The spray pattern lacked consistency.

[0211] 4.5.3. Example 3: Confirmation of the applicability of the porcine OSA model To rule out the possibility that the anesthetized pig model used by Wirth in 2013 yielded a false-positive result regarding the applicability of intranasal administration of compound 1 (Example 1), the following experiment was conducted.

[0212] Rosenberg et al. recently reported the success of a Phase 2 clinical trial using a combination of atomoxetine, a norepinephrine reuptake inhibitor, and alloxibutynin (an enantiomer of oxybutynin, the pure R isomer), an antimuscarinic agent, for the treatment of obstructive sleep apnea (Rosenberg et al., J. Clin. Sleep Med. 18(12):2837-2844, 2022). The treated subjects showed a statistically significant and clinically meaningful difference compared to placebo in terms of hypoxic load. Therefore, a trial was conducted to evaluate the efficacy of atomoxetine and oxybutynin in a porcine model.

[0213] 4.5.3.1 Method The principles of this study are detailed in Wirth et al., SLEEP, Vol.36, No.5, 2013. All animal studies were conducted in accordance with German animal protection laws. Castrated male German Landrace pigs (weight range 20-35 kg) were used.

[0214] Sedation To avoid stress responses during ear vein cannula insertion for induction of general anesthesia, pigs were sedated in the barn by intramuscular injection of a mixture of 3 ml of Rompun® 2% (xylazine HCl, 23.3 mg / mL; Bayer) and 7 ml of Zoletil® 100 (Virbac). The contents of the Zoletil® vial (250 mg tyletamine and 250 mg zolazepam) as a dry powder and 3 ml of Rompun were dissolved in 7 ml of medium. This solution was then administered intramuscularly at a dose of 0.1 ml / kg.

[0215] anesthesia The experiment was conducted under general anesthesia induced and maintained by a mixture of α-chloralose and urethane.

[0216] After sedating the pigs, cannulas were inserted into the ear veins. Before initiating general anesthesia, two vials of Novaminsulfone (Zentiva®, 2g metamisole sodium 1H2O) and two vials of atropine (Atropinsulfat B. Braun) to reduce saliva were administered intravenously at the start of the experiment and 3 hours later. Analgesia was supported throughout the experimental setup with intravenous administration of 0.04 mg / kg of Novaminsulfone.

[0217] Anesthesia was induced by intravenous administration of a 20 mL bolus of α-chloralose solution (25 g of α-chloralose (Sigma®) + 12.5 g of anhydrous borax, with a total volume of 600 ml of saline solution and Sigma®) into the ear vein (equivalent to a dose of 0.028 g / kg for a 30 kg pig), followed by administration of a 20 mL bolus of urethane solution (100 g / 500 mL of urethane, Sigma®; equivalent to a dose of 0.133 g / kg). The urethane was dissolved in saline solution (0.9%). The chloralose was dissolved in saline solution containing borax.

[0218] Before making the skin incision, bupivacaine 0.5% JENAPHARM®, which has a sustained anesthetic effect, was injected for further infiltration anesthesia. The incision was closed and sutured to prevent drying.

[0219] Next, anesthesia was maintained by inserting a cannula into the femoral vein using a percutaneous induction set, and continuously infusing 1 ml / kg / h of a mixture of urethane solution and α-chloralose solution (equivalent to a dose of 0.07 g / kg / h of chloralose and 4 g / kg / h of urethane) into the femoral vein using a 50 mL syringe filled with 40 mL of urethane solution and 10 mL of α-chloralose solution.

[0220] Anesthesia was monitored by heart rate, blood pressure, ventilation, electrocardiogram (ECG), blood gas quantification, pulse oximetry (tail), and standard pain reflex testing. Reflex testing was performed 15 minutes before each collapse test by corneal reflex sensitivity. If anesthesia was insufficient, the pigs would blink, in which case a bolus of 5 mL of maintenance anesthetic solution was administered, and this was repeated as needed until the reflex disappeared. Body temperature was monitored and maintained using an infrared lamp. If necessary to maintain oxygen saturation at nearly 95%, oxygen was applied via a tube placed directly in front of the outlet of a respiratory flow meter attached to a face mask. In this open system, an oxygen flow rate of 2 L / min was sufficient to maintain saturation at nearly 95%.

[0221] surgery A tracheostomy was performed 1-2 cm below the larynx. Care was taken to avoid damaging the laryngeal nerve. Two tracheal tubes (Mallinckrodt® 11.5 mm OD, 8.5 mm ID) were inserted into the trachea. One was inserted rostrally into the trachea and the other caudally, and they were secured with sutures around the trachea to seal the connection. A T-shaped connector was used to connect the tube to a negative pressure device and the rostral cannula to a distal tracheal cannula. The distal tracheal cannula was further connected via a T-shaped connector to a tube with an open end to the atmosphere, serving as an alternative to free breathing through the trachea bypassing the UA. Appropriate opening and closing of these tubes allowed breathing to be switched from nasal breathing to breathing through the caudal tracheal cannula bypassing the UA, and the (isolated) UA could be connected to a negative pressure device to generate an inspiratory airflow. To measure tracheal (sublaryngeal) pressure, a thin tube was inserted into the rostral tracheal tube system and connected to a pressure transducer element (MPX type 399 / 2 Hugo Sachs Electronic-Havard-Apparatus).

[0222] The nasal area, excluding the nostrils, was sealed with adhesive tape, and a silicone bag (the upper half of a 0.5L breathing bag) was placed over it. A respiratory flow meter (SN 370-1491 Hans Rudolph, Inc.) was attached to the free end of the bag. To measure nasal airflow, the respiratory flow meter was connected to a differential pressure transducer (Type 381, Hugo Sachs Electronic-Harvard Apparatus). The portion of the bag covering the pig's nose was hermetically sealed with an elastic ribbon.

[0223] The respiratory flowmeter was calibrated using the manufacturer's calibration coefficient and further calibrated using a rotameter with a specified airflow within the expected range. The differential pressure transducer was calibrated using a pressure calibration device (Gauer). Calibration settings were saved and checked monthly.

[0224] All biological signals were recorded using a Hugo Sachs Plugsys amplifier system and continuously stored on a computer hard disk using an online data acquisition and analysis system (Hem-evolution 4.3 Notocord Systems, Croissy-sur-Seine, France). Data backups were performed every 24 hours using a Langmeyer backup system.

[0225] Removal of mucus from the upper respiratory tract Mucus was removed from the upper airway using a human manual resuscitation device that applied mild negative pressure by introducing a suction tube from the distal end of the tracheal tube system, advancing it to the nostril, and slowly withdrawing it. This procedure was repeated as needed throughout the experiment, except for the first 30 minutes after administration of the test compound.

[0226] In cases of excessive mucus production, the mucous membranes of the upper airway were irrigated with isotonic saline. After switching from nasal to pulmonary respiration with the nose in a vertical position, 50 ml of isotonic (0.9%) saline heated to 37°C was slowly injected into the nostrils and allowed to drain out through the distal tracheal tube. This procedure was repeated until the nasal irrigation fluid became clear and no particles or visible mucus remained. All irrigation fluid was removed from the upper airway using a manual resuscitation device.

[0227] EMG measurement of the genioglossus muscle For bipolar recording of GG EMG, a steel needle was inserted through a small skin incision midway between the jaw and hyoid bone to a depth of 4-6 mm, passing through the mylohyoid muscle to reach the GG muscle. A Hugo Sachs EMG amplifier was used to amplify, filter (bandwidth 50 Hz to 10 kHz), rectify, and integrate the raw EMG signal (moving average with a time constant of 1 second).

[0228] Negative pressure application for collapse testing The negative pressure device consisted of a 50L negative pressure vessel equipped with a manometer, evacuated by a vacuum pump and actuated via a solenoid valve. This device was capable of generating negative pressure as low as -150 cmH2O. This pressure level was set and allowed to reach the desired level within the device before pressure loading. To induce UA collapse (collapse test), respiration was switched from nasal to tracheal breathing. Activation of the negative pressure device applied a pre-selected device pressure to the UA airway via a tube connecting the device to a cranial tracheal cannula. Since the UA dilator muscle was activated only during inspiration, both nostrils were closed with two fingers during expiration to increase nasal resistance, and then opened again during inspiration. After applying negative pressure for at least three breaths, UA collapse occurred under controlled conditions, as indicated by measurements of airflow (relative to the device) and sublaryngeal pressure. In pigs, such negative pressure loading was performed using negative pressures of -50, -100, and -150 cmH2O. The maximum pressure of -50 cmH2O was first applied and maintained for at least three breaths. After resting for at least 10 breaths, the next pressure load was applied with progressively lower negative pressure. Complete collapse tests were performed at the three pressure levels described above before administration of the test compound and at regular intervals after administration (up to 420 minutes after administration of the test compound).

[0229] Without treatment, the ulnar artery (UA) would remain collapsed during inspiration. If the investigational drug effectively stimulates the activity of the UA dilating muscle, the UA will Intake It opens during exhalation and closes again during exhalation, similar to under controlled conditions (physiologically, Exhalation There is no activity of the UA dilater muscle at that time (because the UA is continuously exposed to negative pressure) (and will open again during the next inspiration). The opening of the UA during inspiration is indicated by the sublaryngeal pressure rising during inspiration and approaching atmospheric pressure, and the resumption of airflow in the isolated UA region during inspiration.

[0230] To distinguish actual collapse from paradoxical collapse (occlusion of the surrounding tissue of the UA due to aspiration or mucus), collapse is indicated by a negative pressure increase (ΔP) of 90% from baseline of the adjusted device pressure and a decrease in peak inspiratory flow rate to approximately 0 ml / sec.

[0231] Intravenous administration of the test compound Atomoxetine and oxybutynin were dissolved in a medium of the following composition. 10% ethanol 40% polyethylene glycol 50% Auqua dest.

[0232] The bolus dose was 0.1 ml / kg, and the subsequent infusion rate was 1 ml / kg / h.

[0233] Two anesthetized pigs were used in this study. At zero, the pigs were given an intravenous bolus of atomoxetine 1 mg / kg over 1 minute, followed immediately by a continuous infusion of 0.275 mg / kg / h. Ten minutes later, oxybutynin 20 μg / kg was administered as a bolus, followed immediately by a continuous infusion of 12.5 μg / kg / h for 4 hours.

[0234] Euthanasia: At the end of the experiment, the pigs were euthanized by intravenous bolus of T61 without being allowed to recover from anesthesia.

[0235] 4.5.3.2 Results The drug combination completely suppressed upper airway collapse after a 60-minute delay following bolus injection. At 30 minutes, suppression of collapse was still incomplete. The drug combination was continuously infused for 4 hours, and its effectiveness lasted until 120 minutes at a pressure level of -150 cmH2O, 150 minutes at a pressure level of -100 cmH2O, and 180 minutes at a pressure level of -50 cmH2O (Figure 4, n=2). Differences in PK and metabolism resulting from the need for the formation of oxybutynin's active metabolite, interspecies differences in metabolism, and differences in administration mode (intravenous administration in pigs versus oral administration in humans) may have influenced the time profile of effectiveness in this study.

[0236] Following administration of the combination, a significant increase in heart rate and a moderate increase in blood pressure and respiratory rate were observed. The pigs became temporarily restless (moving their hind limbs) after administration of the atomoxetine and oxybutynin combination. No changes were observed in genioglossus muscle EMG measurements after drug administration.

[0237] 4.5.3.3 Conclusion In this pig upper airway collapse study, the combination of atomoxetine and racemic oxybutynin, which has demonstrated clinical efficacy in OSA patients (Rosenberg et al., 2022), showed complete suppression of upper airway collapse. The time to onset and full efficacy was delayed by 60 minutes under strong negative pressure conditions of -100 cm and -150 cmH2O. Loss of efficacy occurred during a 4-hour continuous infusion of the drug combination. Three hours after the start of bolus administration (and during subsequent maintenance infusion), collapse recurred at all pressures tested despite continuous infusion.

[0238] In conclusion, the combination of atomoxetine and oxybutynin, which has demonstrated clinical efficacy in the human clinical OSA trial (Rosenberg et al., 2022), showed complete suppression of upper airway collapse in this porcine model. However, efficacy was lost during continuous infusion, strongly suggesting that the infusion dose used in this study was too low to maintain efficacy. Similar to the AD109 clinical trial reported by Rosenberg, systemic side effects on heart rate and blood pressure limited the applicability of this study, providing further evidence that this porcine model is meaningful for application.

[0239] These data demonstrate the applicability of the porcine model to predict efficacy in human OSA, however, these results were obtained using intravenously administered drugs, not locally administered via nasal infusion.

[0240] 4.5.4. Example 4: Solution formulations have a longer duration of effectiveness than suspension formulations. 4.5.4.1 Overview To determine whether the failure of the Phase 2 trial in Example 1 was attributable to the use of the suspension formulation of Compound 1, the efficacy of the Phase 2 suspension formulation and the efficacy of the solution formulation were compared in a porcine OSA model.

[0241] 4.5.4.2 Method The method used was essentially the same as that described in Example 3, with only certain modifications.

[0242] 4.5.4.3 Formulation, preparation, and storage of test compounds Preparation of compound 1 solutionCompound 1 was dissolved in a medium containing 5% DMSO and 95% PEG 400. 18.75 mg of Compound 1 was dissolved in 5 ml of the medium to prepare a stock solution of 3.75 mg / ml. The milky white solution was stirred with a magnetic stirrer at room temperature until completely dissolved, and stored at 4°C in a light-protected brown glass vial. A diluted solution of the stock solution was prepared immediately before administration of the test compound. The solution was diluted 10-fold with the medium to obtain a dose of 0.3 mg / pig. Applying 400 μl of this solution to each nostril resulted in a dose of 0.3 mg per pig. Applying 400 μl of the stock solution to each nostril resulted in a dose of 3 mg per pig.

[0243] Preparation of Compound 1 Suspension Compound 1 was received either as a ready-to-use formulation at a concentration of 3% w / w or as a diluent. The diluent was used to prepare the suspension on the day of use by adding finely ground Compound 1 to bring the concentration of Compound 1 to 2.25% w / w (Table 5). 67.5 mg of Compound 1 was suspended in 3 ml of medium on the first day of administration. The suspension was stored at room temperature in a brown glass vial protected from light in a box (for 50 days). The suspension prepared from the solid material was prepared only at the time of administration.

[0244] In the laboratory where the pig experiments were conducted, all suspension formulations were stirred at 1000 rpm with a magnetic stirrer (Heidolph®) for 1 hour, followed by ultrasonic treatment (HBM®) for 10 minutes, and then immediately shaken manually until administration. Homogeneity of the suspension was visually confirmed immediately before nasal administration. The compound was then delivered to each nostril using an Eppendorf pipette in volumes of 200 μl or 400 μl, depending on the experiment, to a dose of 12 mg / head or 24 mg / head. The 18 mg dose was administered in volumes of 400 μl per nostril. The nose was held vertical to allow the test compound to flow throughout the pharynx. [Table 5]

[0245] 4.5.4.4 Results In vertically positioned pigs, a total of 0.3 mg (400 μl / nostril) of compound 1 solution applied to the nasal cavity showed complete suppression of UA collapse at all collapse levels from 10 minutes to 270 minutes, but the suppression continued beyond the end of the observation period, which was terminated at 300 minutes, at the -50 and -100 cmH2O collapse levels (Table 6, Figure 5, n=2). [Table 6]

[0246] The compound 1 suspension formulation (12 mg, 200 μl / nostril) applied to the nasal cavity showed complete suppression of UA collapse at all collapse levels from 30 minutes to 150 minutes, but at the -50 cmH2O collapse level, the suppression persisted until 180 minutes (Table 7, Figure 6, n=2). [Table 7]

[0247] These results demonstrate that the solution formulation of Compound 1 has a longer duration of efficacy than the suspension formulation used in the unsuccessful Phase 2 trial of Example 1.

[0248] 4.5.5. Example 5: However, only the suspension formulation maintains upper airway collapse after nasal irrigation. 4.5.5.1 Overview The results of Example 4 suggested that the failure of the Phase 2 trial could be attributed, at least in part, to the use of a suspension of compound 1 rather than a solution formulation. To better model the duration of efficacy in post-administration mucus flow during lateral recumbent and sleep in human patients, the following experiments were conducted.

[0249] In a porcine collapsed airway model (OSA model) for suppressing upper airway collapse, compound 1, formulated as either a solution or suspension as described in Example 4, was administered intranasally. Subsequently, nasal irrigation was performed to model post-administration mucus flow, and tolerance to upper airway collapse after nasal irrigation was investigated.

[0250] 4.5.5.2 Method The method used was a modified version of the method described in Example 4.

[0251] To investigate whether the collapse-inducing effects of various formulations of test compounds could be eliminated by nasal irrigation, isotonic saline heated to 37°C was applied to the upper airway. This fluid was slowly injected through the nostrils and drained out through the distal tracheal tube. A manual resuscitation device was used to remove the remaining lavage fluid from the upper airway.

[0252] Nasal irrigation was performed at various time points after nasal medication administration and using various volumes of saline solution, as shown in Table 8. [Table 8]

[0253] 4.5.5.3 Results Solution formulations:

[0254] One pig was administered a 0.3 mg solution of compound 1 intranasally (400 μl / nostril), and a second pig was administered a 3 mg solution of compound 1 intranasally (400 μl / nostril). In both pigs, complete efficacy of both doses was demonstrated at 30 and 60 minutes at all collapse levels, after which nasal irrigation was performed with 50 ml of saline per nostril. At 10 and 30 minutes after nasal irrigation, and at 70 and 90 minutes after drug administration, the efficacy of compound 1 was completely lost at both doses (Tables 9, 10, Figures 7 and 8). [Table 9] [Table 10]

[0255] Suspension formulations:

[0256] Compound 1 was administered intranasally at a 3% w / w suspension of 24 mg (400 μl / nostril). After demonstrating complete efficacy at all collapse levels 30 and 60 minutes after administration, nasal irrigation was performed with 10 ml of saline solution 60 minutes after administration. 30 minutes after irrigation (90 minutes after administration), compound 1 still showed sustained efficacy against UA collapse at all collapse levels. When irrigation with 10 ml of saline solution was performed again after 90 minutes after administration, complete efficacy was still demonstrated at 120 minutes. Increasing the volume of saline solution to 20 ml / nostril did not negate the efficacy at 150 minutes after administration (Table 11, Figure 9, n=1). In the second pig, 24 mg of compound 1 was administered intranasally (400 μl / nostril), the volume of saline solution irrigation was increased to 50 ml / nostril, and nasal irrigation was performed 30 minutes after administration and repeated at 90 and 120 minutes after administration. Indeed, the effectiveness against UA collapse was maintained after nasal irrigation at all levels of collapse (Table 12, Figure 10, n=1). Therefore, none of the irrigation methods could negate the upper airway collapse inhibitory effect. [Table 11] [Table 12]

[0257] 2.25% w / w suspension formulation: 18 mg of compound 1 was administered intranasally (400 μl / nostril), and nasal irrigation with 50 ml of saline was performed just 1 minute after the 18 mg intranasal administration (400 μl / nostril) and before suppression of UA collapse was achieved. In this case as well, complete suppression of collapse at all pressure levels was achieved from 40 minutes to 120 minutes (Table 13, Figure 11, n=1). [Table 13]

[0258] These results demonstrate that a specific compound 1 suspension formulation is resistant to the deactivation of its inhibitory effect on upper airway collapse after nasal irrigation. Inhibition of upper airway collapse was maintained for a considerable time after irrigation with the compound 1 suspension formulation at all doses and irrigation methods tested. In contrast, the inhibitory effect of compound 1 solution formulation on upper airway collapse was completely lost by nasal irrigation at all doses and irrigation methods tested.

[0259] Therefore, the failure of the Phase 2 trial in Example 1 is not necessarily attributable to the use of the suspension formulation of Compound 1, and no clear reason for the failure of the Phase 2 trial has been obtained.

[0260] 4.5.6. Example 6: Local intranasal administration of a mucosal adhesive formulation of Compound 1 is effective in reducing upper airway collapse in anesthetized pigs. 4.5.6.1 Overview Several nasal suspension formulations of compound 1 were investigated for their ability to suppress upper airway collapse in a vertically positioned anesthetized pig obstructive sleep apnea model. The in vivo performance of the formulations was evaluated by comparing them to the suspension formulation used in the unsuccessful Phase 2 clinical trial (Example 1).

[0261] All three formulations tested at 2 mg (SU41, SU45, and SU28) were superior to the original 2 mg Ph2 formulation in terms of duration of action and onset of action. The duration of action of the new formulations exceeded the 480-minute observation period. The onset of action for SU41 and SU45 was observed as early as 15 minutes after administration, while the onset of action for SU28 was 30 minutes and 60 minutes in the two pigs tested. The Ph2 formulation showed efficacy 30 minutes after administration and completely lost its efficacy 120 minutes after administration.

[0262] 4.5.6.2 Method The method used was essentially the same as described in Example 4, with only certain modifications.

[0263] 4.5.6.3 Formulation, preparation, and storage of test compounds The novel formulation of Compound 1 was provided to the laboratory as a ready-to-use formulation, and the Ph2 placebo and active formulations were prepared at the laboratory. The compositions are shown in Table 14 below. [Table 14]

[0264] The ready-to-use formulations were stored at room temperature in brown glass vials, protected from light. On each experimental day, the formulations were stirred for 1 hour at 1000 rpm using a magnetic stirrer (Heidolph®), followed by 10 minutes of sonic treatment (HBM®), and then manually shaken immediately before administration.

[0265] The Ph2 active drug formulation (see Table 1 and Example 1 above) was prepared on each day of the experiment: 7.5 mg of the finely powdered compound 1 active ingredient was suspended in 3 ml of the diluted formulation, stirred for 1 hour at 1000 rpm with a magnetic stirrer (Heidolph®), followed by ultrasonic treatment (HBM®) for 10 minutes, and then manually shaken immediately before administration.

[0266] The homogeneity of the suspension was visually confirmed immediately before intranasal administration. The suspension was then delivered to each nostril using an Eppendorf pipette in volumes of 100 μl, 200 μl, or 400 μl, depending on the experiment. The nose was held vertically to ensure the test compound flowed throughout the pharynx.

[0267] 4.5.6.4 Results Novel nasal suspension formulations of compound 1 were tested in a porcine model of upper respiratory tract (UA) collapse. These compositions are listed in Table 14 above. A comparative Phase 2 formulation is listed in Table 1. All formulations completely suppressed UA collapse over a certain period, but differed in the dose required to demonstrate complete efficacy, duration of action, and time to onset of action.

[0268] The suspension formulation used in the unsuccessful Phase 2a trial described in Example 1, referred to as the first Ph2 formulation, was used as the reference formulation. A new suspension formulation was tested and compared with the Ph2 reference formulation.

[0269] Table 15 lists the results for duration of action and time to onset of action for the different formulations and dosages tested. [Table 15-1] [Table 15-2]

[0270] Figure 12 shows the average time to onset of action for each formulation at the three negative pressure levels tested: -50 cm, -100 cm, and -150 cmH2O. Figure 13 shows the average duration of action for each formulation at the three negative pressure levels tested: -50 cm, -100 cm, and -150 cmH2O. Observation was completed after 480 minutes (8.0 hours).

[0271] Figures 14-21 show data for individual pigs.

[0272] Particularly high levels of efficacy were observed for 2 mg suspension formulations SU41 (n=1) and SU45 (n=2), administered at the same dose as the original Ph2 formulation, with 400 μl given to each nostril. The duration of action exceeded the 480-minute observation period at all pressure levels tested. The onset of action occurred at the first measurement 15 minutes after administration of the formulation.

[0273] SU41 was also tested at 1 mg using 200 μl per nostril (n=1), but the response was only slightly weaker compared to the 2 mg dose. The duration of action at -150 cmH2O was 420 minutes, but at -50 and -100 cmH2O, the duration exceeded 480 minutes. When 100 μl of 9% (w / w) SU41 was administered per nostril, at a dose of 18 mg, equivalent to the clinical dose used in the standard Ph2 formulation in the unsuccessful Phase 2 trial of Example 1, complete inhibition was observed at all measurement points and was indistinguishable from the 2 mg dose.

[0274] The SU28 formulation was administered at a dose of 2 mg, 400 μl per nostril (n=2). The duration of action obtained exceeded the 480-minute observation period at all pressure levels. However, the onset of action was delayed compared to the SU41 and SU45 formulations, occurring at 30, 30, and 30 minutes, respectively, at -50, -100, and -150 cmH2O.

[0275] When 400 μl of the SU40 formulation was administered to each nostril at a dose of 2 mg (n=4 animals), complete suppression of collapse was observed, but the duration of action was shortened at -50, -100, and -150 cmH2O. Regarding the SU40 formulation, the micronized active pharmaceutical ingredient (D) used in all other novel formulations and the Ph2 standard formulation was also used. 90 (approximately 4.9 μm) is not the case, but rather the compound 1 of the non-micronized batch was obtained after sieving with a 32 μm mesh (therefore D 90 The effect of particle size distribution was evaluated by preparing an additional SU40 formulation (batch 5099 / 77A) using the active pharmaceutical ingredient (API) whose particle size was approximately 28 μm. When the alternative SU40 formulation (batch 5099 / 77A) was administered at 400 μl per nostril and tested at 2 mg (n=1 animal), complete suppression of collapse was observed. However, the duration of action at -50, -100, and -150 cmH2O was extended to 270, 240, and 210 minutes, respectively, compared to the SU40 formulation obtained from the micronized API, while the onset of action was shortened to 15 minutes.

[0276] In conclusion, the three novel mucosal adhesive suspension formulations (SU41, SU45, and SU28) tested at 2 mg doses were significantly superior in terms of duration of action and onset of action compared to the 2 mg primary Ph2 suspension formulation used in the unsuccessful Phase 2a OSA patient study (Example 1). The duration of action of the novel suspension formulations (SU45, SU41, and SU28) exceeded the 480-minute observation period, and the onset of action was observed either 15 minutes or more after administration (for SU41 and SU45) or 30 minutes or more after administration (for SU28). Experimental data obtained for two SU40 formulations obtained from either micronized or sieved active pharmaceutical ingredients suggest that the particle size distribution of the suspended active pharmaceutical ingredient may be related to the duration of action of the formulation.

[0277] These formulations, when administered intranasally, may be effective in reducing the severity of obstructive sleep apnea in human patients.

[0278] 4.5.7. Example 7: Characteristics of the formulation containing compound 1 The SU28 and SU40 formulations were evaluated at 2 and 4 weeks during a short-term stability program under storage conditions of 25°C and 40°C. The formulations were evaluated using an Aptar VP7 pump with a glass bottle and an AeroPump pump with a polyethylene bottle. The following tests were performed: • Total content and solubility of compound 1 • Compound 1 related substances • Visual appearance • Microscopic appearance Appearance • Molar osmotic pressure • Particle size determined by laser diffraction • Droplet size determined by laser diffraction • NGI data • Raman evaluation

[0279] 4.5.7.1 Recovery rate of compound 1 and related substances The content (total content and dissolved content) and purity (% area) of compound 1 were evaluated at t=0 and after 4 weeks of storage at 25°C and 40°C. The analytical method for quantifying compound 1 is shown in Table 16. The results are shown in Table 17 (total recovery rate), Table 18 (purity), and Table 19 (dissolved content). [Table 16] [Table 17] [Table 18] [Table 19]

[0280] 4.5.7.2 Visual Appearance The macroscopic characteristics of the developed formulations (i.e., color, transparency, and apparent viscosity) were evaluated at t=0 and after storage at 25°C and 40°C for up to 4 weeks. The results are shown in Tables 20 and 21. Representative images are shown in Figure 25. At t=0, all formulations were low-viscosity, white, opaque suspensions.

[0281] After storage at 25°C and 40°C for 4 weeks, there was no change in the macroscopic appearance of the formulations. In particular, the Phase II formulation (3% by weight of compound 1) showed aggregation at 100x and 400x at t=0 (Figure 24). [Table 20] [Table 21]

[0282] 4.5.7.3 Apparent pH The apparent pH of the prepared formulations was evaluated at t=0 and after storage at 25°C and 40°C for up to 4 weeks. The results are shown in Table 22. Because the suspended drug interfered with the pH meter, giving variable results, the apparent pH of the formulations was measured after centrifugation of the samples to obtain more consistent pH readings during the extraction of dissolved content. The pH remained stable throughout the 4-week test period (change from t=0 was less than 1 pH unit). [Table 22]

[0283] 4.5.7.4 Molar Osmotic Concentration The molar osmotic pressure of the manufactured formulations was evaluated at t=0 and after storage at 25°C and 40°C for up to 4 weeks. The results are shown in Table 23. [Table 23]

[0284] The molar osmotic pressure (MOO) values ​​of all formulations were within the isotonic range (270-310 mOsm / kg). No significant changes in MOO were observed after storage at 25°C and 40°C for 4 weeks.

[0285] 4.5.7.5 Particle size determined by laser diffraction Particle size of the manufactured formulation (D 90 The particle size (μm) was evaluated at t=0 and after storage at 25°C and 40°C for up to 4 weeks. The particle size of compound 1 was evaluated using a SympaTEC particle size analyzer equipped with a cuvette module, with 0.5% Tween® 20 as the dispersion medium. The results are shown in Table 24. [Table 24]

[0286] Overall, all formulations showed good performance, particle size was within the expected range (5-15 μm), and did not change over time.

[0287] 4.5.7.6 Droplet side by laser diffraction Droplet size of the manufactured formulation (D 90 The size (μm) was evaluated by laser diffraction using a SympaTec nasal sprayer after storage at t=0 and at 25°C and 40°C for up to 4 weeks. The results are shown in Table 25. [Table 25]

[0288] Droplet size (D) at t=0 90The droplet size (μm) was either close to 100 μm or ≥ 706.57 μm. These values ​​corresponded to the visual appearance of the formulation after spraying. For formulations with a droplet size of approximately 100 μm, the spray was conical and "mist-like." For formulations with larger droplet sizes, these formulations were sprayed more "jet-like," and a single flow of the formulation was observed. All "mist" formulations (e.g., SU28) contained methylcellulose as a gelling agent, while the "jet" formulations (e.g., SU41 and SU43) contained either carrageenan or HPMC. Using the same package for different formulations resulted in a wide range of droplet sizes and spray types ("mist" vs. "jet"), demonstrating that the formulation components influence droplet size / spray plume shape.

[0289] The SympaTec droplet size measuring instrument used was designed based on the manufacturer's recommendations for nasal products. However, for "jet" sprays, this instrument could not accurately capture droplet size, only a portion of the normal distribution was obtained. Therefore, not all of these values ​​truly reflect the droplet size of the formulations.

[0290] After 4 weeks of storage, there was no significant trend in changes in droplet size. Overall, the droplet size data demonstrated that for formulations with measurable droplet sizes (i.e., "mist" form; SU28 (both content)), the droplet size remained stable throughout the test period.

[0291] 4.5.7.7 Raman Analysis Raman analysis of compound 1 in the developed nasal formulation was evaluated at t=0 and after 4 weeks of storage at 40°C to confirm whether or not changes in polymorphism occurred over time (data not shown). This was done because compound 1 has other known polymorphs (e.g., polymorph A). Polymorph A was not observed at t=0 or after 4 weeks of storage at 40°C, and the only form observed corresponded to the spectrum of starting material polymorph B.

[0292] 4.5.7.8 SU45 Formulation stability experiments showed that SU40 (compound 1 at 6% w / w) appeared to aggregate. A modified formulation containing 9% (w / w) compound 1 and EDTA (0.2% w / w) was also prepared (SU45). The composition is detailed in Table 26. [Table 26]

[0293] SU45 was stored at 25°C and 40°C for stability testing. Table 27 shows the particle size results obtained by laser diffraction, and Figure 26 shows representative microscopic images of SU40 and SU45 containing 9% w / w of compound 1 at t=0 and after 4 weeks of storage at 25°C and 40°C. [Table 27]

[0294] In general, the particle sizes of SU40 and SU45 appeared similar during the test period. The particle size data at t=4 weeks is consistent with microscopic observations, which showed some aggregation of SU45 at 40°C but not at 25°C, while aggregation was observed for SU40 at both temperatures. Microscopic images show that SU45 did not aggregate as much as SU40 after 4 weeks of storage at 25°C and 40°C, although the difference in particle size was observed only at 25°C. Overall, it is thought that including EDTA in this composition reduces aggregation.

[0295] SU45 containing 9% (w / w) of compound 1 was evaluated using the same characterization tests performed on SU28 and SU41 (Table 28). [Table 28]

[0296] 4.5.7.9 Viscosity The viscosity of three lead formulations, SU28, SU41, and SU45, was evaluated. The viscometer was formulated using SU41, as its viscosity appeared to be between SU28 (lowest viscosity) and SU45 (highest viscosity). This method was formulated using a Brookfield viscometer with an S18 spindle and a small sample adapter. Spindle 18 was selected because it was able to evaluate the lowest viscosity using the available instrument. When formulating the viscometer, the torque value should be between 10% and 100% to obtain accurate readings, and furthermore, the torque should generally be less than 90% when formulating the method so that it can be used even if the composition increases in viscosity over time.

[0297] The developed method involved using spindle 18 at 60 RPM (the maximum speed of the instrument), and after its development, all formulations were evaluated using this method. The results are shown in Table 29. [Table 29]

[0298] The developed viscosity method was found to be suitable for SU41 and SU45 (torque readings of 46.6-90.6%), but the torque reading for SU28 was too low for accurate reading (approximately 9%). The viscosity of the Phase 2 formulation (3 wt% compound 1) was evaluated visually and determined to be low.

[0299] 4.5.7.10 Sedimentation The precipitation rate of compound 1 in three lead formulations, SU28, SU41, and SU45, as well as SU40 (EDTA-free SU45), was evaluated using a LUMiSizer. The LUMiSizer functions as a centrifuge that accurately measures when a sample begins to precipitate by measuring transmitted light through the sample. These four formulations were evaluated at 200 RPM at 25°C. The results are shown in Figure 27. The precipitation rate is given as a percentage between 0 and 1, where 1 represents the fastest precipitation and 0 represents no precipitation. It should be noted that this test evaluates precipitation due to rotational force and is dependent on the selected rate and temperature. Therefore, this test does not apply the precipitation rate of a stationary sample to the real world, but is typically used as a ranking tool. In this case, the work was performed to perform a relative ranking of formulation precipitation rates and to deepen insights into rheological research results. Due to the high drug load (9% w / w), the precipitation rates were relatively low in all formulations (due to the specific test methodology, which measures light transmission rather than physical laws). However, differences between formulations were still observed. The precipitation rate was highest for SU28 and lowest for SU41. The precipitation rates for SU40 and SU45 were similar, suggesting that EDTA did not affect the precipitation rate.

[0300] Initially, it was assumed that SU40 / SU45, being the most viscous formulation, would have a lower precipitation rate than SU41. However, after rheological evaluation of the formulations, it was found that SU40 / 45 had more polymer interactions (and therefore higher viscosity), but SU41 had stronger polymer interactions. Therefore, drug-polymer interactions may have a greater impact on precipitation rate than viscosity.

[0301] 4.5.7.11 Rheology The rheological properties of three lead formulations, SU28, SU41, and SU45, as well as SU40 (SU45 without EDTA), were evaluated. All tests were performed using a TA Instruments Discovery Rheometer equipped with a double-walled concentric cylinder. First, formulations were prepared by mixing with a steel ball in a Turbula mixer for 20 minutes to ensure thorough dispersion of the suspended drug. Then, approximately 11 g of the formulation was added to the concentric cylinder using a 20 mL syringe.

[0302] The following formulations were subjected to rheological evaluation. Due to the rheological properties of SU28 (Newtonian fluid-like), only a flow sweep was performed. • Flow Sweep: This test was chosen to investigate the viscosity of different formulations to which gradually increasing energy (using vibrational shear rate) was applied, and to determine whether the formulations were shear-deviscating (viscosity decreases tangentially with increasing energy), shear-thickening (viscosity increases tangentially with increasing energy), or Newtonian (viscosity does not change with energy). An example of a shear-deviscating material / product is ketchup, an example of a shear-thickening material is sand in water, and an example of a Newtonian fluid is water. The viscosity (Pa·s) of the formulation samples was measured under gradually increasing shear rate (s -1 ) was measured against. • Vibration amplitude: This test was selected to obtain an indicator of molecular interactions in the suspension. Furthermore, the yield stress can be derived from this test, which gives the stress at which the material begins to flow, i.e., the ease of spraying the formulation. The storage modulus and loss modulus (Pa) were measured against a gradually increasing vibration torque (μN·m). • Vibration time: This test was performed to simulate the formulation in a stationary state before shaking, during spraying, and after returning to the stationary state. The storage modulus and loss modulus (Pa) of the samples were measured over time after increasing the torque from 1 μN.m to 16 μN.m and then returning to 1 μN.m.

[0303] Flow Sweep The viscosity and rheological behavior of the SU28 medium were found to match the profile of a Newtonian fluid. Newtonian fluids (such as water) are characterized by viscosity that is independent of shear rate. This was confirmed by a linear flow sweep graph (not shown) that differed from that of the other three mediums. The other three mediums all exhibited pseudoplastic (shear-deviscated) behavior, meaning that their viscosity decreased with increasing shear rate.

[0304] The active ingredients SU41, SU45, and SU40 were all found to exhibit shear-thinning properties, and no significant precipitation was observed during the test period. These results were consistent with other physical property evaluation tests (including precipitation analysis). The precipitation analysis showed that SU41 precipitated the slowest, followed by SU45, and SU28 precipitated the fastest. This viscosity test also confirmed that SU45 / SU40 had the highest viscosity, followed by SU41, and finally SU28 had the lowest viscosity.

[0305] Vibration amplitude SU40 and SU45 exhibited similar behavior in vibration amplitude, and there was no significant difference (or lack thereof) caused by the presence of EDTA. This is consistent with the evaluation of viscosity and droplet size, which were similar between the two formulations. Therefore, in the following description, they will be treated as a single formulation.

[0306] SU40 / SU45 exhibited storage-dominant behavior (i.e., more elastic / solid behavior) at low torque, while SU41 (not exhibiting this behavior) showed loss-dominant behavior (i.e., more viscous / liquid behavior), which was consistent with the viscosity readings of these formulations. Storage-dominant behavior was higher for SU40 / 45 than for SU41, suggesting that SU40 / 45 has more molecular interactions than SU41.

[0307] The linear viscoelastic region (LVR) of SU40 / 45 was shorter than that observed in SU41. This suggests that SU40 / 45 had more polymer interactions at low torque than SU41, but these polymer interactions were weaker and more fragile than those observed in SU41. This should mean that SU41 requires more energy to begin flowing despite having a lower viscosity than SU40 / 45. While it is possible that LVR is related to the amount of aggregation (particle size distribution), with a shorter LVR indicating more aggregation, no significant difference was expected as these were prepared immediately before use.

[0308] Stronger polymer interactions (drug-polymer or polymer-polymer) may be the reason why SU41 was observed to precipitate the slowest among these formulations.

[0309] Oscillation time sweep Similar to the flow sweep and vibration amplitude tests, SU40 and SU45 (not shown) exhibited similar behavior in the vibration time sweep, and there was no significant difference caused by the presence of EDTA.

[0310] Similar to the vibration amplitude test, SU40 / SU45 exhibited storage-dominant behavior (i.e., more elastic behavior) at low torque, while SU41 (did not exhibit this behavior) showed loss-dominant behavior (i.e., more viscous behavior).

[0311] SU40 / 45 was observed to rapidly recover its structure after stress application (representing action), and its storage modulus (elastic behavior) appeared to increase to a greater value than before stress application. This may indicate that the stress mixes the sample, and therefore the drug disperses better, leading to more interactions. This could mean that the formulation rapidly recovers its structure after spraying, resulting in increased adhesion and reduced runoff.

[0312] SU41 begins to recover its structure after stress is applied, but then the effect of continuous low shear appears to further disrupt polymer interactions, as indicated by a continuous decrease. This could mean that viscosity decreases after spraying SU41, resulting in the formulation becoming less adhering to tissues and more prone to flowing off. However, it should be noted that compound 1 precipitates the slowest with SU41, which is thought to be a result of the strength of the interactions in this formulation (characterized by a longer LVR). Since the stress applied to SU41 during reconstitution (Turbula mixing) is much higher than the stress applied during the vibration time sweep, it appears that not only the stress itself, but also sustained low shear after the stress is required to further disrupt polymer interactions (polymer-polymer or polymer-drug).

[0313] 4.5.7.12 Surface tension The surface tension of three lead formulations, SU28, SU41, and SU45, was evaluated by measuring their surface tension using the suspension drop method with the Kruess Drop Shape Analyzer-DSA25E and its associated Advance Software. The results are shown in Table 30. Surface tension was investigated because it can affect how a spray formulation disperses and, consequently, how it is sprayed during operation (i.e., plume shape / droplet size). [Table 30]

[0314] The surface tension evaluation results showed that all three formulations exhibited similar surface tension (approximately 44 mN / m).

[0315] 4.5.8. Example 8: An open-label crossover pharmacoscintigraphy study testing a single dose of compound 1 nasal spray in four different formulations in healthy male and female volunteers. 4.5.8.1 Overview The safety, tolerability, and PK profile of a nasal suspension formulation containing 9% (w / w) of technetium-99-labeled compound 1 will be evaluated in healthy volunteers using scintigraphy imaging and pharmacokinetic studies. The three nasal dilutions described above (SU28, SU41, and SU45) will be mixed with the technetium-99 radiolabeled drug substance in a clinical setting by adding a diluent to compound 1 in a device, closing the device, and then mixing. The PK performance of these three formulations will be evaluated in a scintigraphy study, where both deposition and retention will be monitored using camera images to assess pharmacokinetics in the blood. Furthermore, to evaluate the effect of particle size distribution on deposition and retention time in the nasal cavity, the SU45 formulation will be tested in combination with two types of micronized drug substance with different drug particle size distributions (d90 < 10 μm and d90 < 35 μm).

[0316] The radioactive preparation is manufactured on the day of use and administered within a 12-hour time frame.

[0317] In preparation for clinical trials, a nasal suspension formulation containing 9% (w / w) of technetium-99-labeled compound 1 was prepared and evaluated, delivered in 100 μL doses using a multi-dose spray pump.

[0318] 4.5.8.2 Analysis of the batch of compound 1 The following batch of compound 1 was prepared (Table 31). [Table 31]

[0319] Table 32 summarizes the test results to date. [Table 32-1] [Table 32-2] [Table 32-3]

[0320] Identification of Compound 1: Compound 1 was identified and its content and related substances were quantified using high-performance liquid chromatography (HPLC) according to Ph.Eur.2.29 (Tables 33, 34, and 35). This test was performed using a concentration gradient elution. An appropriate amount of Compound 1 was pre-dissolved in a solvent. The sample solution was then injected into a Waters Symmetry C18 column (or equivalent) and eluted with a mixture of purified water and acetonitrile containing 0.1% trifluoroacetic acid, respectively. The operating wavelength was set to 262 nm. [Table 33] [Table 34] [Table 35]

[0321] The active pharmaceutical ingredient (API) of compound 1 was identified by comparing the retention time of the main peak and the UV spectrum in the sample solution with the retention time of compound 1 in the standard solution. The retention time of the main peak of compound 1 was 14-16 minutes, and the maximum UV values ​​were approximately 205 nm and 262 nm.

[0322] The active pharmaceutical ingredient of compound 1 was quantified by external calibration using a 100% standard solution at the working concentration. The content of compound 1 was calculated using the following formula. Compound 1(%)=[(A sample ×DF sample ) / (RF mean ×Xs ample )] × 100 A Sample Area (AU) of compound 1 in the sample solution DF Sample : Dilution factor of sample solution (L) X Sample : Sample weight (mg) RF mean : The average value of the response coefficient (RF) calculated from the first 6 STD-1 injections. (AU*L / mg)

[0323] Related substances: Impurities were quantified by external calibration using a 1.0% standard solution at the working concentration. Impurities are calculated using the following formula. Impurity content (%)=[(A sample ×DF sample ) / (RRF mean ×X sample )] × 100 A Sample Area (AU) of impurities in the sample solution DF Sample : Dilution factor of sample solution (L) X Sample : Sample weight (mg) RRF: Relative response coefficient of impurities RF mean : The average value of the response coefficient (RF) calculated from the first 6 STD-1 injections. (AU*L / mg)

[0324] The response coefficient is calculated using the following formula (applicable to both content and related substances): RF[AU×(L / mg)]=(A standard / Conc standard ) A Standard : Area (AU) of the compound in standard solution Conc Standard :Concentration of the compound in the standard solution (mg / L)

[0325] Container closure system: Compound 1 was packed into a double-layer low-density polyethylene (LDPE) bag and placed in a high-density polyethylene (HDPE) drum.

[0326] 4.5.8.3 Stability analysis of compound 1 Stability testing was initiated for compound batch 1 H (non-micronized, GMP) according to the ICH storage conditions described in Table 36.

[0327] Currently, results from storage at 25±2℃ / 60±5%RH, 30±2℃ / 65±5%RH, and 40±2℃ / 75±5%RH for one month are available.

[0328] Stability testing of compound batches L and M (GMP-planned sublots of compound batch H, pulverized to d90 < 10 μm and d90 < 35 μm, respectively) is scheduled to begin in accordance with the ICH standard storage conditions described in Tables 37 and 38.

[0329] Furthermore, the stability of the active pharmaceutical ingredient (API) was evaluated by reviewing supplemental stability batch data for Compound 1 obtained from past API manufacturing campaigns. [Table 36] [Table 37] [Table 38]

[0330] Currently, available data for Compound 1 APIs are limited for both non-micronized and micronized forms. Stability data for past lots (manufactured in 2004) of Compound 1 non-micronized polymorph B material showed stability under both long-term conditions of up to 36 months at 25±2℃ / 60±5% and accelerated conditions of up to 6 months at 40±2℃ / 75±5%RH (data not shown). Stability data for Compound 1 micronized polymorph B material (from the same 2004 lot) showed stability under both long-term conditions of up to 12 months at 25±2℃ / 60±5% and accelerated conditions of up to 6 months at 40±2℃ / 75±5%RH (data not shown).

[0331] 4.5.8.4 Diluent The diluents are used as a medium for the immediate reconstitution of the final product (nasal suspension) formulation. In a Phase 1 scintigraphy study, three diluents, SU28, SU41, and SU45, are used to reconstitute three nasal spray suspensions containing 9% (w / w) compound 1 (Table 39). Each diluent is a clear, colorless, particulate, homogeneous solution. The diluents are filled into clear borosilicate glass bottles and sealed with screw caps. [Table 39]

[0332] The manufacturing process for diluents is simple and conventional, consisting of mixing the components in a buffer solution and then filling it into vials / bottles, and involves several established steps: Step 1: Preparation of buffer (citrate phosphate buffer pH 6.0) Step 2: Preparation of diluent by adding excipients Step 3: Filling into vials / bottles Step 4: Quality Control

[0333] Step 1: Prepare citrate-phosphate buffer (pH 6.0). The scale and manufacturing vessel may be adjusted to match the final batch scale. 1. Weighing and dissolution - Preparation of 0.1M citric acid solution: Weigh the required amount of citric acid, transfer it to a 3L volumetric flask, then add half of the required amount of sterile water for injection and stir the solution. Once no more particles are visible in the solution, add the remaining water to obtain a 0.1M citric acid solution. - Preparation of 0.2M dibasic sodium phosphate solution: Weigh the required amount of sodium phosphate salt (dibular sodium phosphate heptahydrate), transfer it to a 5L volumetric flask, then add half of the required amount of sterile water for injection, and stir the solution. Once no granular material is visible in the solution, add the remaining water to obtain a 0.2M dibasic sodium phosphate solution. 2.Mixing - Add approximately 2196 mL of 0.1 M citric acid solution and approximately 3804 mL of 0.2 M sodium dibasic phosphate solution to a 15 L container and stir to ensure a homogeneous mixture. 3. Final buffer - Monitor the initial pH; add the required buffer to achieve the target pH of 6.0; then bring the volume of the container to approximately 85% with water. Monitor the pH, and if the pH is outside the target range (pH 6.00±0.05), adjust the pH up or down using sodium phosphate solution or citric acid solution, respectively. Next, add water to the container to make a total of 12 L, mix for 30 seconds, and then take the final pH reading.

[0334] Step 2: Preparation of Diluent 4. Weighing and Dissolution - Weigh the required amount of buffer for each diluted formulation into a container, then add all remaining excipients (excluding the polymer) in sequence. Perform a visual inspection to ensure complete dissolution before adding the next excipient. - Stir the resulting solution until it is clear and free of particulate matter. 5. Polymer Addition - Once all excipients are dissolved, increase the stirring speed, add the polymer slowly, and stir until the diluent is clear and visually homogeneous.

[0335] Step 3: Filling into Vials / Bottles

[0336] Step 4: Quality Control

[0337] 4.5.8.5 Description and Composition of Pharmaceutical Product 99m The pharmaceutical product containing the Tc radiolabeled drug substance Compound 1 is a white to off-white homogeneous suspension intended for nasal administration.

[0338] This nasal suspension uses the Compound 1 drug substance 99 radiolabeled with Tc tracer, suspended in the diluent, and immediately manufactured by filling into a 3 mL amber glass bottle assembled with an Aptar V7 pump spray. Each bottle contains 5 mm stainless steel beads to facilitate dispersion during manufacture and prior to administration of the nasal spray suspension.

[0339] Each bottle contains 2.5g of the radiolabeled product, which is equivalent to 25 sprays at 4MBq / 100μL per device, or a total of 100MBq / device. One dose (per nostril) is: 99 Tc compound 1 is present at a concentration of 9 mg per 100 μL of the radiolabeled product.

[0340] For Phase 1 scintigraphy studies, three diluted formulations, namely SU28, SU41, and SU45, have been developed and all three will be used to prepare the nasal suspension. In addition, two different compound particle sizes will be tested. These are referred to as small particle size (SPS) and large particle size (LPS), respectively.

[0341] Table 40 lists the investigational drugs to be evaluated in planned scintigraphy clinical trials, along with their reference names. [Table 40]

[0342] The detailed compositions of all four investigational drugs are shown in Tables 41-44. [Table 41] [Table 42] [Table 43] [Table 44]

[0343] 99A nasal spray suspension containing 9% of Compound 1 radiolabeled with technetium was developed for limited clinical evaluation. It is intended for use only in a planned Phase I clinical pharmacoscintigraphy study that aims to demonstrate that Compound 1 can be delivered in a nasal spray form using the spray pump (Aptar VP7). The Aptar VP7 spray pump is a high-efficiency pre-compression nasal spray pump that ensures consistent spray performance over a wide range of administration volumes (25 μl to 130 μl), and is suitable for solutions, suspensions, and viscous drug formulations. The Aptar VP7 spray pump consists of (1) a spray pump (VP7AE / 100; 18 / 415 thread), (2) an actuator (232 NA / B / R actuator ASM), and (3) a PP clip. Schematic diagrams of the VP7 spray pump are shown in Figure 22 and Figure 23.

[0344] For the nasal spray suspension containing 9% of the investigational drug 99Tech Compound 1, the target administration volume is 100 μl.

[0345] Radiolabeling of the drug substance Compound 1 with technetium gas was selected as the preferred radiolabeling method, as it exhibits high binding affinity for the drug substance and suggests a high likelihood of obtaining tracking information for the Compound 1 drug substance after patient administration (including the deposition position of spray particles in the nasopharynx) during gamma scintigraphy.

[0346] 99m Tc SU28 SPS , 99m Tc SU41 SPS , 99m Tc SU45 SPS and 99m Tc SU45 LPS A validation test was conducted to confirm that the radiolabeling of does not significantly affect performance.

[0347] Radioisotope 99m Due to the short half-life of Tc (approximately 6 hours), the formulation 99m Tc SU28 SPS , 99m Tc SU41 SPS ,99mTc SU45 SPS and 99m Tc SU45 LPS It is manufactured within 12 hours prior to administration.

[0348] Radiolabeling procedure for compound 1 (API): The radiolabeling process involves the physical association of techne gas particles with the dried API powder. The radionuclides required for use in a techne gas generator include sodium pertechnetate (Na). + TcO4 - ) is used. This is received in liquid form and processed in a techne gas generator. 99m Tc-labeled carbon nanoparticles are produced. These particles are encased in multiple carbon layers. 99m Because it contains hexagonal flat crystals of Tc, 99m Tc metal is protected from the environment, and therefore oxidation and the formation of pertechnetium salts are prevented. 99m Sodium Tc pertechnetinate is placed in a carbon crucible and then in a techne gas generator to produce radioactive aerosolized particles at high temperatures. These particles are then drawn into a chamber containing API dried powder using a vacuum pump. A 6% ethylenediaminetetraacetic acid (EDTA) solution is used as a trap to capture unabsorbed techne gas particles by chelation.

[0349] Three aliquots of API are radiolabeled to produce up to four devices as needed each test day. All three radiolabeled API aliquots are combined by manually mixing them for 5 minutes while rotating them in a sealed miniature container (bijou) placed behind a lead shield. The total radioactivity is recorded using a Capintec dose calibrator.

[0350] The API (radioactive label) and diluent are combined in a nasal spray pump / device along with 5mm stainless steel beads to aid in the dispersion of the insoluble API. The products are mixed for 20 minutes using a Turbula mixer at speed setting 3.

[0351] The actual and predicted (at the time of planned administration) radiolabeled dose for each radiolabeled nasal spray pump / device will be quantified at the time of manufacture using a dose calibrator. Each radiolabeled product (2500 mg in a spray pump) will be prepared for each study participant during use in the study under the direct control of an authorized person and will require a final QP release.

[0352] During clinical trials, radiolabeled samples are manufactured and administered within a 12-hour timeframe; therefore, extended QC testing cannot be performed on the products manufactured for administration. Accordingly, validation work was performed to ensure that the planned radiolabeling method would satisfy the objectives of the clinical trial and that the samples could be manufactured reproducibly.

[0353] Process validation. In the validation test, four small-scale formulations of the radiolabeled pharmaceutical product were prepared manually. Simultaneously, four small-scale non-radiolabeled formulations of the pharmaceutical product were manually reconstituted in the same facility as the radiolabeled formulations, using the same manufacturing process as described above, except that the radiolabeling process portion was excluded.

[0354] During validation, the radiolabeled pharmaceutical product, process parameters considered critical to the radiolabeled manufacturing process, and pharmaceutical quality were documented, as summarized in Table 45, to confirm the levels of radioactive material as appropriate markers for tracking the location of substances in the nasal cavity using gamma machinography for up to 12 hours. [Table 45]

[0355] Furthermore, to demonstrate that radioactive labeling does not alter the performance of the product or the quality of the pharmaceutical, Table 46 summarizes the tests conducted during validation studies for both the non-radioactively labeled and "cooled" formulations. [Table 46]

[0356] Radioactivity uptake by compound 1 API. Table 47 shows the total amount of radioactive label uptake by a 350 mg aliquot of compound 1 API. [Table 47]

[0357] The results indicate that the total amount of radiolabeling incorporated by the active pharmaceutical ingredient ranges from 37.1 to 190.6 MBq per compound aliquot (350 mg) of the active pharmaceutical ingredient.

[0358] Evaluation of radioactive labeling dose uniformity. The results of the uniformity of radioactive labeling in the sprayed product at time of delivery (TOD) (average supply dose after priming, per 100 μl) are summarized in Table 48. [Table 48]

[0359] The results indicate that an average radiation dose of approximately 0.9–3.1 MBq was observed. The observed difference in average radiolabeled dose may be due to differences in the active pharmaceutical ingredient (PSD) or the density of the diluent. Therefore, a specification of 0.8–4 MBq per 100 μl spray was recommended for TOD.

[0360] Table 49 summarizes the average radiolabeled dose within the device (2.5g of product in a 3mL spray bottle) in TOD. [Table 49]

[0361] The total radiation dose per device in TOD is observed to be in the range of 18–65 MBq. Therefore, this specification is set to 10–100 MBq per device in TOD.

[0362] Priming spray. The number of priming sprays was confirmed by recording the weight dispensed with each spray and identifying when the value was within the predicted range. Priming was necessary to remove air from the pump and actuator tubing and replace it with the formulation ready for administration. The initial spray is unsuitable for administration because it dispenses a low weight of product outside of 75-125% (depending on product density) of the nominal spray weight containing 9 mg of compound 1 active ingredient. The number of priming sprays and associated dispensed weights of the product are shown in Table 50. [Table 50]

[0363] Therefore, the required number of priming weights was determined to be ≥ 4.

[0364] Evaluation of average supply dose weight. Dose testing and data for radioactive and non-radioactively labeled products performed after priming spraying are shown in Table 51. [Table 51]

[0365] Average discharge / supply weight is radiolabeled 99m Tc SU45SPS is better. 99m Tc SU28SPS, 99m Tc SU41SPS and 99m Compared to Tc SU45LPS, the values ​​were lower and showed greater variability, but the results were within the expected range. This corresponds to 96.50% of the expected average discharge weight of the SU45 diluent (103.30 mg). The data for non-radioactively labeled SU45SPS were within the trend range.

[0366] Evaluation of the average dose-to-dose (content uniformity) after priming. The dose-to-dose is the amount of drug released from the drug device that is available to the user when the device is functioning correctly. Dose-to-dose uniformity (DDU) was measured by firing the test device into a dose-to-sampling device (DUSA) containing a filter. The active drug captured on the filter was then dissolved in a solvent and analyzed using the same HPLC analysis method used to identify compound 1. The average dose-to-dose (after priming) for radiolabeled and non-radiolabeled products is shown in Table 52 (n=10). [Table 52]

[0367] The average supply dose after priming is radiolabeled 99m Tc SU45 SPS That would be better, 99m Tc SU28 SPS , 99m Tc SU41 SPS and 99m Tc SU45 LPS Although slightly lower than the theoretical dose, the result was within the expected range. This corresponds to 96.33% of the theoretical dose of 9 mg / 100 μL.

[0368] To demonstrate that radioactive labeling does not alter the quality and properties of the product, a comparison of the characteristics of non-radioactively labeled products and "cooled" products was conducted and summarized in Table 53. [Table 53-1] [Table 53-2] [Table 53-3]

[0369] 4.5.8.1 Test Protocol This study is a single-center, open-label, four-group crossover trial to evaluate single doses of four formulations of compound 1 delivered intranasally in eight healthy male and female volunteers. Participants will visit the center six times, including screening and follow-up visits. The first treatment dose will be administered within 28 days of screening. A drug-free period of at least three days will be provided between each administration opportunity. Follow-up visits will be conducted at least seven days after the participant's last treatment visit and within 14 days. The study design is shown in Figure 28. Each therapeutic agent will be administered via technetium-99( 99m The compound is radiolabeled with Tc) and its post-administration behavior is tracked using a gamma camera. Gamma scintigraphy is a valuable tool for evaluating the in vivo performance of pharmaceutical dosage forms. Scintigraphy is a non-invasive method that provides information on the deposition and migration of the formulation. The radioactive load is minimal, and all procedures are well-established. Scintigraphy analysis is used to visualize the deposition of the radiolabeled product in the nasal cavity and to monitor its residence time. In this study, nasal scintigraphy imaging is combined with blood sampling for PK analysis to evaluate the behavior of a novel intranasal formulation of compound 1.

[0370] 4.5.8.2 Purpose and Endpoints Primary objective: To evaluate the safety and tolerability of four different formulations of compound 1 administered as a single 18 mg dose via nasal administration in healthy adult male and female participants.

[0371] Primary endpoint: • Incidence, type, timing, severity, and association of adverse events (including SAEs) that occurred during treatment. • Blood samples for safety assessment at baseline, 24 hours after each dose, and at follow-up visits. • Urinalysis at baseline and during follow-up visits • Baseline, predetermined time points after administration, and 12-lead ECG (HR, QRS, and QTc interval) at follow-up visits. • Vital signs at baseline, specified time points after administration, and at follow-up visits. • Clinically significant changes in physical examination results assessed at screening, treatment visits, and follow-up visits.

[0372] Secondary purpose: • Evaluate the behavior of four different formulations of compound 1 after a single 18 mg intranasal administration using scintigraphy. • Confirm the plasma pharmacokinetics of four different formulations of compound 1 after a single 18 mg intranasal administration.

[0373] Secondary endpoint: • Location of radioactive markers in the nasal cavity over time • The relative amount of radioactive labeling in the nasal cavity over time (the amount at time 0 is expressed as 100%). • Total residence period of radioactive markers in the nasal cavity • For the following PK parameters, the sample collected for in vivo analysis at the specified time: highest concentration (C max ), maximum concentration time (T max ), lag time (T lag ), Area under the curve (AUC) from time 0 to 24 hours last ), Area under the curve (AUC) from time 0 to infinity 0-inf ), terminal phase first-order rate constant (K), and terminal phase disappearance half-life (T 1 / 2 ).

[0374] 4.5.8.3 Study population This proof-of-concept trial aims to recruit a total of eight healthy male and female volunteers, with the goal of obtaining at least six evaluable participants (evaluable participants are those who receive all four doses). It is important to ensure that subjects do not have any significant acute or chronic nasal disorders that could affect the validity of scintigraphy deposition and retention data. This will be assessed at each treatment visit. BMI of 32 kg / m² is required. 2 Participants exceeding a certain age will be excluded because shielding from bones, muscles, other organs, and soft tissues will attenuate gamma rays.

[0375] Eligibility Criteria. Participants are eligible for inclusion in the study only if they meet all of the following criteria. 1. Age: 18-65 years old (including both extremes). 2. Weight and Body Mass Index (BMI): BMI between 18 and 32 kg / m² 2 (Including both endpoints). 3. Compliance: I understand, am willing to abide by, am able to abide by, and am highly likely to abide by, all examination procedures and restrictions. 4. Consent: Demonstrates an understanding of and willingness to participate in the examination, as evidenced by a voluntarily informed consent form (signed and dated) obtained prior to any examination-related activities. 5. Overall health status: Healthy (as determined by the principal investigator) based on medical history, physical examination (including nasal examination), vital signs, 12-lead ECG, and clinical safety test results. 6. Nasal spray tolerability: At the screening visit, the participant will demonstrate their ability to tolerate the administration of nasal spray into each nostril, as assessed by the principal investigator. The principal investigator or a designated person with appropriate skills may administer up to three doses of 0.9% saline (1 dose = 100 μL per nostril). Whether or not this is tolerable will be determined and documented by the principal investigator. Tolerance for at least one spray in each nostril must be achieved. 7. Family planning / contraception i. Male participant: Male participants are eligible to participate if they agree to the following during the trial intervention period and for at least 90 days after the last dose of the intervention drug: • Refrain from donating sperm, and one of the following: • To refrain from heterosexual intercourse as a desirable and normal lifestyle (to practice long-term and sustained abstinence), and to agree to continue abstinence, or • When having sexual intercourse with a woman of childbearing age who is not currently pregnant, the female partner must agree to the use of a condom in addition to using an additional highly effective method of contraception with a failure rate of less than 1% per year. ii. Female participants: Female participants are eligible to participate if they are not pregnant or breastfeeding and meet one of the following conditions: • Being a woman who is unable to conceive (WONCBP), or • The patient must be a WOCBP (Wound-On-the-Crew Blood Pressure) patient and use a low-user-dependency, highly effective (less than 1% failure rate per year) contraceptive during the trial intervention period and at least until the trial follow-up visit. The principal investigator must assess the likelihood of contraceptive failure (e.g., non-compliance, recent initiation) in relation to the first dose of the trial intervention drug.

[0376] Exclusion Criteria. Participants who meet any of the following criteria during eligibility assessment will be excluded from the study: a. Medical history i. Any current or recurrent disease / condition (including, but not limited to, a history of hay fever, rhinitis, asthma, syncope, or hypertension) that the Principal Investigator believes could potentially affect the conduct of the study, affect the participant's safety as a result of participation, and / or affect the participant's ability to complete the study or clinical laboratory evaluation. ii. A current, serious, or unstable mental illness, or a history thereof, that may require treatment, reduce the likelihood of the participant completing the study, or present an excessive risk from the study drug or procedure. iii. The patient has a clinically significant condition (e.g., active allergy, fever, hypersensitivity reaction) within three months prior to the first dose. iv. Hematological or biochemical blood tests at screening are outside the normal range and are deemed clinically significant by a PI or a medically qualified designated person. v. The principal investigator determines, based on the results of a clinically significant physical examination or clinically significant investigation (including those conducted at screening and during the treatment group), that the volunteer is unsuitable for the study. vi. Body temperature (measured during screening or at the time of administration visit) is above 38°C vii. Rhinitis (whether or not being treated) and / or nasal congestion during the two weeks prior to the first dose. viii. A positive serological reaction suggestive of acute or chronic infection with HIV, Hep.B (HBsAg positive), or HCV. ix. A history of hepatitis of any cause, excluding hepatitis A, that has resolved within three months prior to the first dose. x. Positive result on COVID-19 lateral flow screening at the time of screening or treatment visit. xi. Extension of the corrected QT interval in the 12-lead ECG (calculated using the Fridericia and Framingham formulas) (defined as QTc > 460 msec (female) and 450 msec (male) based on either calculation). b. Drug use i. Use of nasal sprays, rinses, or irrigators in the two weeks prior to the initial dose and / or subsequent doses. This excludes saline nasal sprays administered for tolerability testing at screening and nasal sprays administered according to the protocol. ii. The participant plans to use a prescription drug within 14 days prior to the first dose of compound 1 (or within 5 half-lives, whichever is longer), and the principal investigator believes this will interfere with the study procedure or compromise safety. Acceptable prescription drugs are oral / IM / implantable contraceptives. iii. The participant plans to use over-the-counter (OTC) medications, including vitamins, probiotics and prebiotics, and naturopathic or herbal remedies, within 48 hours prior to the first dose (unless approved by the principal investigator). c. Alcohol / substance abuse i. A recent history of alcohol or other substance abuse (within the past year). ii. History of regular / habitual use of inhaled recreational drugs iii. Participants' average weekly alcohol intake exceeds 14 units. iv. The participant's urine test for abused drugs is positive at the time of screening or prior to the evaluation of administration. v. The participant's breath alcohol test is positive at the time of screening or before administration evaluation (the breath test may be repeated once within 5 minutes of the initial test, at the discretion of the principal investigator). d. Smoking i. The participant has recently (less than 3 months) stopped smoking or using e-cigarettes. ii. The participant is currently a smoker, e-cigarette user, or user of nicotine-containing products. iii. The participant's urinary cotinine test is positive at the time of screening or prior to administration evaluation.

[0377] 4.5.8.4 Trial intervention. The following treatments will be administered to the participants (Table 54): a. Treatment 1: SU28 containing 9 mg of compound 1 in 100 μL 10 Administer twice (one spray into each nostril = total dose 18 mg). b. Treatment 1: SU45 containing 9 mg of compound 1 in 100 μL 10 Administer twice (one spray into each nostril = total dose 18 mg). c. Treatment 1: SU41 containing 9 mg of compound 1 in 100 μL 10 Administer twice (one spray into each nostril = total dose 18 mg). d. Treatment 1: SU45 containing 9 mg of compound 1 in 100 μL 10 Administer twice (one spray into each nostril = total dose 18 mg).

[0378] This study does not include a reference product. The product contains a maximum of 2 MBq per spray at the time of administration. 99m The nasal spray will be radiolabeled to contain Tc (maximum total 4 MBq). The radiolabeled nasal spray will be administered by an authorized laboratory staff member, with a second clinical staff member present during administration. The PI or a designated medical professional will be on-site during administration and for 4 hours afterward. The PI or designated medical professional will be on call for the remainder of each treatment visit.

[0379] Participants must receive the drug in an upright position and immediately lie down after administration. Participants may maintain a supine position or elevate their back at a 45-degree angle to the horizontal for 18 hours after administration. Toilet breaks and meals are permitted as exceptions. [Table 54]

[0380] The testing procedures, their timing, and acceptable timeframes are outlined in the Activity Schedule (SOA; Table 55). Compliance with the test design requirements, including those specified in the SoA, is essential for conducting the tests. [Table 55-1] [Table 55-2] [Table 55-3] [Table 55-4] [Table 55-5] [Table 55-6] [Table 55-7]

[0381] 4.5.8.5 Test Evaluation Screening visit. All screening evaluations must be completed and reviewed to confirm that the candidate participant meets all eligibility criteria. The PI shall record details of all screened participants and maintain a screening log to confirm eligibility or record the reasons for screening failure, as appropriate. If clinical laboratory results are outside the normal range and deemed CS, or if there are technical problems with the sample, the PI or a medically qualified designated person may repeat the tests at their discretion.

[0382] Treatment visits. At each treatment visit, the PI or a medically qualified designated person will assess whether the participant remains eligible for the trial by confirming that the participant still meets the above entry criteria. At each treatment visit, a urine drug abuse test, breath alcohol test, urine cotinine test, urine pregnancy test (in the case of WOCBP), COVID-19 lateral flow test, and vital signs measurement (blood pressure, temperature, and heart rate) will also be performed to confirm continued eligibility. The results of all assessments will be reviewed by the PI or a medically qualified designated person.

[0383] During treatment visits, participants are not permitted to consume any food or beverages other than those provided by the study site staff from the time of arrival until departure. Blood samples for safety evaluation will be collected before discharge at each treatment visit (approximately 24 hours after administration). After each visit, repeated or unscheduled samples may be collected for safety reasons or due to technical problems with the samples.

[0384] Participants will enter the facility approximately two hours before administration at each treatment visit. Administration will be administered in the early afternoon of each treatment visit. Participants must remain lying down from immediately after administration until 18 hours afterward. Lunch and dinner will be provided on the first day of each treatment visit, and breakfast and dinner on the second day. Water, decaffeinated tea, and decaffeinated coffee may be consumed freely during the visit, except for 30 minutes before the scheduled ECG.

[0385] All scintigraphy images will be taken with the participant in a supine position. Dynamic imaging will be performed for 10 minutes immediately after administration, followed by static imaging up to 10 hours after administration. Imaging will be performed at the time specified in the State of Action (SoA). Blood samples for PK analysis will be collected up to 24 hours after administration at the time specified in the SoA. Blood samples for safety evaluation for clinical testing will be collected before departure for treatment.

[0386] ECG and vital signs measurements should be performed at specific points during the treatment visit, according to the State of Action (SoA). The acceptable timeframe for ECG and vital signs is ±15 minutes from the time specified in the protocol. Except during screening, any abnormal findings that the PI or a designated medically qualified person considers clinically significant should be recorded as an AE or SAE.

[0387] Participants will be discharged from the study facility once they have completed all study procedures and any adverse events observed during their visit have resolved or been recorded for follow-up. The maximum period a participant is present at the study facility during each treatment visit is approximately 26 hours.

[0388] Follow-up visit. The follow-up visit after the trial will take place 7 to 14 days after the last admission to the trial facility. This follow-up visit will consist of a repeated physical examination, assessment of vital signs, collection of blood and urine samples (the tests performed on these samples will be the same as those performed at the screening visit, except for COVID-19 lateral flow testing, cotinine testing, and drug abuse testing, which will not be performed), and ECG. Participants will also be asked whether they have experienced any adverse events (AEs) or made any changes to their concomitant medications since their last treatment visit. After the follow-up visit, repeated or unscheduled samples may be collected for safety reasons or due to technical issues with the samples.

[0389] Scintigraphy imaging. Upon arrival for treatment, each participant will have a maximum of 0.02 MBq of scintigraphy performed on their left temple and left mastoid process. 99m External anatomical markers, including Tc, are taped in place to allow for precise alignment of sequential images. Imaging is performed at the following time points after administration: dynamic imaging for 0–10 minutes, followed by static imaging for 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, and 10 hours. If deemed appropriate by the study staff, imaging may be stopped early, for example, if there is no evidence of residual radiolabeling in the nasal cavity in two or more sequential images.

[0390] For safety reasons, due to inadequate image quality, or due to technical issues with the camera, additional images may be acquired at the discretion of the PI. This must be adequately documented in the appropriate source document / eCRF(s). The timing of imaging may be changed during the course of the test based on newly available data.

[0391] The actual imaging time, along with the scheduled time, should be recorded in the source document. The actual time should be recorded in 24-hour format. For images acquired between 0 and 60 minutes, if any images are acquired more than ±2 minutes outside the scheduled time, an explanation must be added. For images acquired between 1 and 10 hours, if any images are acquired more than ±5 minutes outside the scheduled time, an explanation must be added.

[0392] Scintigraphy images are analyzed using the WebLink image analysis program. Images are evaluated by two trained analysts. The following parameters are recorded, where applicable. • Location of radioactive markers in the nasal cavity at each point in time • Relative amount of radioactive labeling in the nasal cavity over time

[0393] Time is recorded as the midpoint between the image in which the endpoint was first observed and the previous image.

[0394] Pharmacokinetic measurement. Samples are used to evaluate the PK of compound 1. Each plasma sample is divided into two aliquots (one for PK and one for backup). The characteristics of the PK to be evaluated are C max , T max , T lag AUC last AUC 0-inf , K, and T 1 / 2 That is the case.

[0395] At each treatment visit, a blood sample will be collected at the appropriate time using an indwelling cannula or by venipuncture by appropriately trained facility staff so that the concentration of compound 1 in the plasma can be evaluated as prescribed by SoA. The total blood volume collected at each time point will be described in the study-specific laboratory manual.

[0396] A blood sample should be taken within one hour prior to administration. Thereafter, blood samples should be taken at the following specified intervals after administration: 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 18 hours, and 24 hours.

[0397] The actual sample time (the time the sample was collected) shall be recorded in the source document along with the scheduled time and entered at the time of sampling or as soon as possible after sampling. The actual time must be recorded in 24-hour format. If any blood samples were collected outside the set sampling time, an explanation must be added. The permissible blood sampling time is ±5 minutes of the target time. The timing of sampling may be changed during the course of the study based on newly available data to ensure appropriate monitoring (for example, to obtain data closer to the time of peak plasma concentration).

[0398] This study will demonstrate the safety and tolerability of formulations containing compound 1 via intranasal administration to healthy adult participants. The study will also show the location of radiolabeling within the nasal cavity over time.

[0399] 5. Incorporation by equivalents and references While the provided disclosures are specifically illustrated and described with reference to preferred embodiments and various alternative embodiments, it will be understood by those skilled in the art that various modifications can be made to their form and details without departing from the spirit and scope of the provided disclosures.

[0400] All references, granted patents, and patent applications cited herein are incorporated herein by reference in their entirety, regardless of their purpose. In particular, U.S. Provisional Patent Application No. 63 / 586,254 (filed September 28, 2023), UK Application No. 2315863.7 (filed October 17, 2023), and U.S. Provisional Patent Application No. 63 / 599,900 (filed November 16, 2023) are incorporated herein by reference in their entirety.

Claims

1. 2'-{[2-(4-methoxyphenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid (2-pyridine-3-yl-ethyl)-amide (compound 1) or a pharmaceutically acceptable salt thereof, and Mucosal adhesive polymers A pharmaceutical composition containing the following:

2. The pharmaceutical composition according to claim 1, wherein the composition is in the form of a liquid such as a suspension.

3. The pharmaceutical composition according to claim 1 or claim 2, wherein the composition is in the form of a fine particle suspension.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein compound 1 is present in the pharmaceutical composition in an amount of 0.1% (w / w) to 20% (w / w).

5. The pharmaceutical composition according to claim 4, wherein compound 1 is present in the pharmaceutical composition in an amount of 3% (w / w) to 10% (w / w), for example, 6% (w / w) to 15% (w / w) or 6% (w / w) to 10% (w / w).

6. The pharmaceutical composition according to claim 4, wherein compound 1 is present in the pharmaceutical composition in an amount of about 9% (w / w).

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the mucosal adhesive polymer is selected from polyacrylic acid derivatives, cellulose derivatives, natural polymers, polyvinylpyrrolidone (PVP) polymers, dextran polymers, polyethylene oxide (PEG) polymers, thermoreversible polymers, ion-responsive polymers, copolymers of polymethyl vinyl ether and maleic anhydride, polyvinyl alcohol polymers, salts of the foregoing, derivatives of the foregoing, and combinations thereof.

8. The pharmaceutical composition according to claim 7, wherein the mucosal adhesive polymer is a cellulose derivative selected from hydroxyalkylcellulose polymer, methylcellulose polymer, carboxymethylcellulose (CMC) polymer, a salt of carboxymethylcellulose, and combinations thereof.

9. The pharmaceutical composition according to claim 8, wherein the mucosal adhesive polymer is a hydroxyalkylcellulose polymer selected from hydroxypropyl methylcellulose (HPMC) and hydroxypropylcellulose (HPC).

10. The pharmaceutical composition according to claim 9, wherein the mucosal adhesive polymer is a methylcellulose polymer.

11. The pharmaceutical composition according to claim 7, wherein the mucosal adhesive polymer is selected from gum arabic, tragacanth gum, agar polymer, xanthan gum, guar gum, a copolymer of alginic acid and sodium alginate, chitosan polymer, pectin, carrageenan, pullulan polymer, modified starch, gelatin, salts of the foregoing, derivatives of the foregoing, and combinations thereof.

12. The pharmaceutical composition according to claim 11, wherein the mucosal adhesive polymer is carrageenan.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the mucosal adhesive polymer is present in the pharmaceutical composition in an amount of 0.1% (w / w) to 20% (w / w).

14. The pharmaceutical composition according to claim 13, wherein the mucosal adhesive polymer is present in the pharmaceutical composition in an amount of 0.3% (w / w) to 1% (w / w), for example, 0.3% (w / w) to 0.6% (w / w).

15. The pharmaceutical composition described above is the pharmaceutical composition according to any one of claims 1 to 14, wherein the pharmaceutical composition does not contain microcrystalline cellulose.

16. A pharmaceutical composition according to any one of claims 1 to 15, further comprising a wetting agent.

17. The aforementioned wetting agents include polysorbate, fatty acid glycerol polyethylene glycol ester, fatty acid polyethylene glycol ester, polyethylene glycol, glycerol ether, cyclodextrin (including alkylated, hydroxyalkylated, carboxyalkylated or alkyloxycarbonyl-alkylated derivatives, or mono or diglycosyl-alpha, beta or gamma-cyclodextrin, mono or dimaltosyl-alpha, beta or gamma-cyclodextrin, or panosyl-cyclodextrin, such as alpha, beta or gamma-cyclodextrin), reaction products of castor oil and ethylene oxide (such as polyoxyl 35 castor oil or polyoxy 40 hydrogenated castor oil), castor oil, benzalkonium chloride, disodium edetate, N-dodecyl beta-D-maloside, potassium sorbate, sorbitan monolaurate, glycerin, silicon dioxide, magnesium stearate, PEG-8 laurate, poloxamer 125, poloxamer -182, Poloxamer 188, Poloxamer 407, Polypropylene glycol 11 stearyl ether, Polypropylene glycol 15 stearyl ether, Laureth-4, Glyceryl oleate, Ceteth-20, Sodium monooleate, Sodium laureth-3 sulfate, Sodium laroyl sarcosinate, Sodium lauryl sulfate, Tyloxapol, Trideceth-10, Ammonium lauryl sulfate, Ceteareth-12, Ceteareth-30, Diethanolamine, Diisopropanolamine, La A pharmaceutical composition according to claim 16, selected from disodium ureth sulfosuccinate, disodium lauryl sulfosuccinate, sodium doxate, lauramine oxide, laureth sulfate, laureth-23, nonoxynol-9, nonoxynol-40, PEG-60 hydrogenated castor oil, polypropylene glycol, sodium laureth-2 sulfate, sodium laureth-5 sulfate, sodium cocoyl methyl taurate, steareth-20, steareth-21, steareth-40, and combinations thereof.

18. The pharmaceutical composition according to claim 17, wherein the wetting agent is selected from polysorbate, a reaction product of castor oil and ethylene oxide, and a combination thereof.

19. The pharmaceutical composition according to claim 18, wherein the wetting agent is polysorbate, and the polysorbate is polysorbate 80.

20. The pharmaceutical composition according to claim 18, wherein the wetting agent is a reaction product of castor oil and ethylene oxide, for example, polyoxyl 35 castor oil or polyoxyl 40 hydrogenated castor oil.

21. The pharmaceutical composition according to any one of claims 16 to 20, wherein the wetting agent is present in the pharmaceutical composition in an amount of 0.1% (w / w) to 5.0% (w / w).

22. The pharmaceutical composition according to claim 21, wherein the wetting agent is present in the pharmaceutical composition in an amount of 0.1% (w / w) to 1.0% (w / w), for example, 0.3% (w / w) to 0.6% (w / w).

23. A pharmaceutical composition according to any one of claims 1 to 22, further comprising an osmotic pressure adjusting agent.

24. The pharmaceutical composition according to claim 16, wherein the osmotic pressure adjusting agent is selected from dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, potassium chloride, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine, glycerin, sodium acetate, sodium sulfate, and combinations thereof.

25. The pharmaceutical composition according to claim 24, wherein the osmotic pressure adjusting agent is selected from sorbitol, mannitol, and combinations thereof.

26. The pharmaceutical composition according to any one of claims 16 to 25, wherein the osmotic pressure adjusting agent is present in the pharmaceutical composition in an amount of 0.1% (w / w) to 10% (w / w), for example, 0.1% (w / w) to 5% (w / w).

27. The pharmaceutical composition according to claim 26, wherein the osmotic pressure adjusting agent is present in the pharmaceutical composition in an amount of 1% (w / w) to 3% (w / w).

28. A pharmaceutical composition according to any one of claims 1 to 27, further comprising a preservative.

29. The pharmaceutical composition according to claim 28, wherein the preservative is selected from chlorhexidine gluconate, phenylethyl alcohol, 1-phenoxyethanol, benzyl alcohol, sorbic acid, thimerosal, phenylmercury acetate, benzoates (such as sodium benzoate), parabens (such as methylparaben, propylparaben, and butylparaben), sorbate, benzalkonium chloride, chlorobutanol, sodium metabisulfate, trisodium citrate dihydrate, boric acid, calcium acetate, dehydroacetic acid, diazolidinyl urea, dichlorobenzyl alcohol, imidourea, methyl salicylate, methylchloroisothiazolinone, methylchloroisothiazolinone / methylchloroisothiazolinone mixture, propionic acid, sodium sulfite, salts of the above, and combinations thereof.

30. The pharmaceutical composition according to claim 29, wherein the preservative is potassium sorbate.

31. The pharmaceutical composition according to any one of claims 28 to 30, wherein the preservative is present in the pharmaceutical composition in an amount of 0.01% (w / w) to 2% (w / w).

32. The pharmaceutical composition according to claim 31, wherein the preservative is present in the pharmaceutical composition in an amount of 0.05% (w / w) to 0.15% (w / w).

33. A pharmaceutical composition according to any one of claims 1 to 32, further comprising an aqueous medium.

34. The pharmaceutical composition according to claim 33, wherein the aqueous medium comprises deionized water, saline solution, phosphate buffer, citrate buffer, malate buffer, tartaric acid buffer, equilibrium salt solution, salt of an organic acid, combination of an organic acid and a salt of an organic acid (such as tribasic sodium citrate and citric acid, malic acid and sodium malate, and potassium sodium tartrate and tartaric acid), acetic acid, hydrochloric acid, monobasic potassium phosphate, dibasic sodium phosphate (heptahydrate), monobasic sodium phosphate (anhydrous / monohydrate), sodium hydroxide, potassium hydroxide, sodium gluconolactone, lactic acid, nitric acid, sodium acetate, sodium lactate, tromethamine, ammonia, citric acid, calcium acetate, diethanolamine, diisopropanolamine, phosphoric acid, potassium citrate, potassium hydroxide, succinic acid, sulfuric acid, arginine hydrochloride, or a combination thereof.

35. The pharmaceutical composition according to claim 34, wherein the aqueous medium comprises a citrate phosphate buffer.

36. The pharmaceutical composition according to any one of claims 33 to 35, wherein the pharmaceutical composition comprises an aqueous medium in an amount of 85% (w / w) to 95% (w / w).

37. The pharmaceutical composition according to claim 36, wherein the pharmaceutical composition contains an aqueous medium in an amount of 85% (w / w) to 90% (w / w).

38. A pharmaceutical composition according to any one of claims 1 to 37, further comprising a chelating agent.

39. The pharmaceutical composition according to claim 38, wherein the chelating agent is selected from ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, HEDTA trisodium, calcium disodium edetate, sodium edetate, trisodium edetate, edetate, pentasodium pentetate, sodium acetate, and combinations thereof.

40. The pharmaceutical composition according to claim 39, wherein the chelating agent is EDTA.

41. The pharmaceutical composition according to any one of claims 38 to 40, comprising 0.01% (w / w) to 2% (w / w) of the chelating agent.

42. A pharmaceutical composition according to any one of claims 1 to 37, a. Compound 1 in a concentration of 0.1% (w / w) to 20% (w / w), for example, 6% (w / w) to 20% (w / w) or 6% (w / w) to 12% (w / w), b. A mucosal adhesive polymer in a concentration of 0.1% (w / w) to 20% (w / w), c. 0.1% (w / w) to 10% (w / w) osmotic pressure regulator, d. 0.1% (w / w) to 5% (w / w) humectant, e. 0.01% (w / w) to 2% (w / w) of preservatives, f. Aqueous media of 85% (w / w) to 95% (w / w), The pharmaceutical composition comprising the above.

43. A pharmaceutical composition according to claim 42, a. A mucosal adhesive polymer in a concentration of 0.3% (w / w) to 0.6% (w / w), b. 1% (w / w) to 3% (w / w) osmotic pressure regulator, c. A 0.3% (w / w) to 0.6% (w / w) (w / w) humectant, d. Preservatives in a concentration of 0.05% (w / w) to 0.15% (w / w), e. Aqueous media of 85% (w / w) to 90% (w / w), The pharmaceutical composition comprising the above.

44. The pharmaceutical composition according to claim 42 or 43, wherein the mucosal adhesive polymer is methylcellulose, the osmotic pressure regulator is mannitol, the wetting agent is polyoxyl 40 hydrogenated castor oil, the preservative is potassium sorbate, and the aqueous medium is citrate phosphate buffer.

45. The pharmaceutical composition according to claim 42 or 43, wherein the mucosal adhesive polymer is HPMC, the osmotic pressure regulator is sorbitol, the wetting agent is polyoxyl 35 castor oil, the antimicrobial preservative is potassium sorbate, and the aqueous medium is citrate phosphate buffer.

46. The pharmaceutical composition according to claim 42 or 43, wherein the mucosal adhesive polymer is carrageenan, the osmotic pressure regulator is sorbitol, the wetting agent is polyoxyl 35 castor oil, the antimicrobial preservative is potassium sorbate, and the aqueous medium is citrate phosphate buffer.

47. The pharmaceutical composition according to claim 46, further comprising EDTA in an amount of 0.01% (w / w) to 2% (w / w).

48. The pharmaceutical composition according to any one of claims 1 to 47, wherein the pharmaceutical composition is in the form of a fine particle suspension and contains less than 0.1% (w / w) of dissolved compound 1, for example, 0.001% (w / w) to 0.1% (w / w) of dissolved compound 1.

49. The pharmaceutical composition according to any one of claims 1 to 48, wherein the molal osmotic pressure concentration is 200 mOsm / kg to 500 mOsm / kg, for example, 250 mOsm / kg to 350 mOsm / kg.

50. The pharmaceutical composition according to any one of claims 1 to 49, wherein the apparent pH is 4 to 9, for example, 5.5 to 6.5 or 6 to 6.

5.

51. Particle size distribution of compound 1 (D １０ The pharmaceutical composition according to any one of claims 1 to 50, wherein the particle size is 0.1 μm to 5 μm, for example, 0.1 μm to 1.5 μm or 0.1 μm to 3 μm.

52. Pharmaceutical particle size distribution of compound 1 (D ５０ The pharmaceutical composition according to any one of claims 1 to 51, wherein the particle size is 2 μm to 15 μm, for example, 2 μm to 5 μm or 5 μm to 15 μm.

53. Particle size distribution of compound 1 (D ９０ The pharmaceutical composition according to any one of claims 1 to 52, wherein the particle size is 4 μm to 50 μm, for example, 5 μm to 35 μm, 5 μm to 15 μm, or 10 μm to 35 μm.

54. The particle size distribution of compound 1 is (a) D 0.1 to 1.5 μm １０ , D 2-5 μm ５０ , and D 5-10 μm ９０ ,or (b) D of 0.1 to 3 μm １０ , D of 5 to 15 μm ５０ , and D of 10 to 35 μm ９０ , A pharmaceutical composition according to any one of claims 1 to 49.

55. The pharmaceutical composition according to any one of claims 1 to 54, wherein the pharmaceutical composition has a viscosity of 1 cP to 100 cP, for example, 30 cP to 50 cP.

56. The pharmaceutical composition according to any one of claims 1 to 55, wherein the pharmaceutical exhibits shear reduction or Newtonian rheology.

57. The pharmaceutical composition according to any one of claims 1 to 56, wherein the pharmaceutical composition has a surface tension of 40 mN / m to 50 mN / m.

58. When the pharmaceutical composition is stored at 25°C or 40°C for at least two weeks, (i) recovery rate of compound 1, (ii) macroscopic appearance, (iii) microscopic appearance, (iv) apparent pH, (v) molar osmotic concentration, (vi) particle size distribution (D ９０ The pharmaceutical composition according to any one of claims 1 to 57, wherein it is determined to be stable by one or more of (vii) droplet size and (viiii) Raman analysis.

59. When the composition is stored at 25°C or 40°C for at least 4 weeks, (i) recovery rate of compound 1, (ii) macroscopic appearance, (iii) microscopic appearance, (iv) apparent pH, (v) molar osmotic concentration, (vi) particle size distribution (D ９０ The composition according to any one of claims 58, wherein it is determined to be stable by one or more of the following: (vii) Raman analysis.

60. A transnasal delivery device comprising a pharmaceutical composition according to any one of claims 1 to 59, and a device suitable for intranasal delivery of the pharmaceutical composition to a target.

61. The nasal supply device according to claim 60, comprising a nosepiece for attachment to the nostrils of the target, and an operating mechanism, wherein the nosepiece includes a nozzle for supplying the composition as a spray into the nasal airway of the target when the operating mechanism is activated.

62. The device comprises a reservoir 1 for containing the pharmaceutical composition and a pump 10, the pump 10 being assembled to the reservoir 1 by a fastening ring 5, the fluid pump 10 comprising a pump body 11, a piston 20 that slides leak-proof between a resting position and an operating position within the pump body 11, the piston 20 being fixed to an actuator rod 30 extending axially outward from the pump body 11, and a ferrule 40 mounted on the upper end edge 12 of the pump body 11, the ferrule defining the resting position of the piston 20 The nasal feeding device according to claim 60 or 61, comprising a 40, wherein the pump is characterized in that the ferrule 40 cooperates with the actuator rod 30 in a leak-proof manner while the actuator rod 30 is moving between the resting position and the intermediate position, and the ferrule 40 cooperates with the actuator rod 30 in a non-leak-proof manner while the actuator rod 30 is moving between the intermediate position and the operating position, and the piston 20 is not in contact with the ferrule 40 when in the resting position.

63. The nasal supply device according to claim 61 or 62, wherein a volume of 50 μl to 150 μl of the pharmaceutical composition is supplied intranasally to the target each time the device is operated.

64. The nasal supply device according to claim 63, wherein the device supplies a jet spray of the pharmaceutical composition when the device is in operation.

65. The nasal delivery device according to claim 64, wherein the jet spray includes droplets having a droplet size of 100 μm to 1,000 μm, for example, 700 μm to 1,000 μm.

66. The nasal supply device according to claim 63, wherein the device supplies a mist spray of the pharmaceutical composition when the device is in operation.

67. The nasal supply device according to claim 66, wherein the mist spray includes droplets having a droplet size of 50 μm to 1,000 μm, for example, about 80 μm to about 100 μm, or 80 μm to 90 μm.

68. The nasal delivery device according to any one of claims 60 to 67, wherein the device delivers 85 mg to 130 mg, for example, 100 mg to 120 mg or 105 mg to 120 mg of the pharmaceutical composition each time the device is operated.

69. The nasal supply device according to any one of claims 60 to 68, wherein the device supplies 50 μl to 300 μl, for example, 150 μl to 250 μl, of the pharmaceutical composition each time the device is operated.

70. A method for treating obstructive sleep apnea in a subject requiring treatment, comprising administering an effective amount of a pharmaceutical composition according to any one of claims 1 to 59 to the subject intranasally.

71. The method according to claim 70, wherein the pharmaceutical composition is administered before sleep, for example, 5 to 120 minutes before sleep or 10 to 30 minutes before sleep.

72. The method according to claim 70 or 71, wherein the pharmaceutical composition is administered when the subject is in an upright position or when the subject's head is raised at a maximum angle of 45° relative to the horizontal.

73. The method according to claim 72, wherein the subject assumes a post-administration posture that is supine or a post-administration posture in which the head elevation angle with respect to the horizontal is 45° or less after administration of the pharmaceutical composition.

74. The method according to claim 73, wherein the subject assumes the post-administration posture within 20 minutes, for example, 10 minutes, after administering the pharmaceutical composition.

75. The method according to claim 73 or 74, wherein the subject maintains the post-administration posture for at least four hours, for example, four to ten hours or at least eight hours, after administration of the pharmaceutical composition.

76. The method according to any one of claims 70 to 75, wherein a total dose of compound 1, such as 0.1 mg to 100 mg, for example, 0.1 mg to 30 mg or 10 mg to 20 mg, is administered to the subject.

77. The upper airway collapse in the subject was measured against the pharyngeal critical closure pressure (P) measured in the same subject that had not received the composition. ｃｒｉｔ P compared to ) ｃｒｉｔ The method according to any one of claims 70 to 76, wherein the suppression is measured by a decrease in and lasts for at least four hours after administration and during sleep, for example, four to ten hours.

78. P ｃｒｉｔ However, for at least 4 hours, at least 2 cmH ２ O, for example, 2-10 cmH ２ The method according to claim 77, which reduces O.

79. P ｃｒｉｔ The method according to claim 77 or 78, wherein the temperature decreases over a period of at least eight hours.

80. The method according to any one of claims 70 to 79, wherein the subject does not experience reverse sneezing.

81. The method according to any one of claims 70 to 79, wherein the pharmaceutical composition is administered via a nasal delivery device according to any one of claims 60 to 69.

82. The method according to claim 81, wherein one or more priming sprays, for example four priming sprays, are performed on the nasal delivery device before administration to the subject.

83. The method according to claim 81 or 82, wherein the pharmaceutical composition is administered into one nostril by the operation of the nasal delivery device in order to deliver the total dose of compound 1 to the target.

84. The method according to claim 81 or 82, wherein the pharmaceutical composition is administered into each nostril by the operation of the nasal supply device in order to deliver the total dose of compound 1 to the target.

Images