Method for treating sleep apnea using a combination of a cannabinoid and a carbonic anhydrase inhibitor

Abstract

A method for treating sleep apnea and snoring is described herein, which comprises the step of administering a combination of a cannabinoid and a carbonic anhydrase inhibitor (CAI), and optionally a muscarinic receptor antagonist (MRA). A pharmaceutical composition comprising a cannabinoid and a carbonic anhydrase inhibitor (CAI), and optionally an MRA is also described. In some embodiments, the cannabinoid is a non-THC cannabinoid. In some embodiments, the CAI is selected from the group consisting of dichlorphenamide, zonisamide, ethoxzolamide, topiramate and sulthiame or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit and priority of U.S. Provisional Application No. 63 / 353,903, filed on June 21, 2022, the entire content of which is incorporated herein by reference.

[0002] Technical Field The present invention provides a method for treating sleep apnea and snoring, which includes the step of administering a cannabinoid and a carbonic anhydrase inhibitor (CAI).

Background Art

[0003] Background Obstructive sleep apnea (OSA) is a common disorder caused by the collapse of the pharyngeal airway during sleep. OSA can have serious health consequences.

Summary of the Invention

[0004] Summary One aspect of the present invention provides a method for treating a subject having a condition related to pharyngeal airway collapse, the method comprising administering to a subject in need of treatment, in the absence of norepinephrine reuptake inhibitor (NRI) therapy, an effective amount of (i) a cannabinoid and (ii) a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorophenamide, zonisamide, ethoxzolamide, topiramate, and sulthiame or a pharmaceutically acceptable salt thereof.

[0005] Aspects of this aspect of the invention may include one or more of any of the following features. In some aspects, (i) the cannabinoid is selected from the group consisting of cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), and tetrahydrocannabivarinic acid (THCVA) or any combination thereof, or a pharmaceutically acceptable salt thereof. In some aspects, the cannabinoid is CBD. In some aspects, the cannabinoid is THC. In some aspects, (i) the cannabinoid is dronabinol. In some aspects, the CAI is sulthiame or a pharmaceutically acceptable salt thereof. In some aspects, sulthiame or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 to about 400 mg. In some aspects, CBD is administered at a dose of about 0.5 to about 300 mg. In some aspects, THC is administered at a dose of about 0.1 to about 30 mg. In some aspects, the method further comprises administering to the subject (iii) a muscarinic receptor antagonist (MRA). In some aspects, the MRA is selected from the group consisting of atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium, and oxybutynin or a pharmaceutically acceptable salt thereof.In some embodiments, the MRA is selected from the group consisting of anisotropine, benztropine, biperiden, clidinium, cycrimine, dicyclomine, diphemanil, diphenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixene, methscopolamine, oxyphencyclimine, oxyphenonium, procyclidine, scopolamine, tridihexethyl, and trihexyphenidyl or a pharmaceutically acceptable salt thereof. In some embodiments, the MRA is oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the MRA is (R)-oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 to about 15 mg. In some embodiments, oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 2 mg to about 10 mg. In some embodiments, (R)-oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 to about 10 mg. In some embodiments, (R)-oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 5 mg. In some embodiments, (i) a cannabinoid and (ii) a CAI are administered in a single composition. In some embodiments, (i) a cannabinoid, (ii) a CAI, and (iii) an MRA are administered in a single composition. In some embodiments, the single composition is in an oral dosage form. In some embodiments, the oral dosage form is a syrup, pill, tablet, troche, capsule, or patch.In some embodiments, the condition associated with pharyngeal airway collapse is sleep apnea. In some embodiments, the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA). In some embodiments, the condition associated with pharyngeal airway collapse is snoring. In some embodiments, the condition associated with pharyngeal airway collapse is simple snoring. In some embodiments, the subject is in a state of not being fully conscious. In some embodiments, the state of not being fully conscious is sleep.

[0006] Another aspect of the present invention provides a method of treating a subject having a condition associated with pharyngeal airway collapse, the method comprising administering to a subject in need of treatment, in the absence of norepinephrine reuptake inhibitor (NRI) therapy, an effective amount of (i) a non-tetrahydrocannabinol (non-THC) cannabinoid and (ii) a carbonic anhydrase inhibitor (CAI) or a pharmaceutically acceptable salt thereof.

[0007] Aspects of this aspect of the invention may include one or more of any of the following features. In some aspects, (i) the non-THC cannabinoid is selected from the group consisting of cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), and cannabicyclol (CBL) or any combination thereof or pharmaceutically acceptable salts thereof. In some aspects, the non-THC cannabinoid is CBD. In some aspects, (ii) the CAI is selected from the group consisting of acetazolamide, dichlorphenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide, topiramate, sulthiame or pharmaceutically acceptable salts thereof. In some aspects, the CAI is acetazolamide or a pharmaceutically acceptable salt thereof. In some aspects, the CAI, such as acetazolamide or a pharmaceutically acceptable salt thereof, is administered at a dose of about 250 mg to about 750 mg. In some aspects, the CAI, such as acetazolamide or a pharmaceutically acceptable salt thereof, is administered at a dose of about 500 mg. In some aspects, CBD is administered at a dose of about 0.5 to about 300 mg. In some aspects, the method further comprises administering to the subject (iii) a muscarinic receptor antagonist (MRA). In some aspects, the MRA is selected from the group consisting of atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium, and oxybutynin or pharmaceutically acceptable salts thereof. In some aspects, the MRA is selected from the group consisting of anisotropine, benztropine, biperiden, clidinium, cyclomine, dicyclomine, diphemanil, diphenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixene, methscopolamine, oxyfencyclimine, oxyfenonium, procyclidine, scopolamine, trihexyphenidyl, and tridihexethyl or pharmaceutically acceptable salts thereof.In some embodiments, the MRA is oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the MRA is (R)-oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dosage of about 1 to about 15 mg. In some embodiments, oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dosage of about 2 mg to about 10 mg. In some embodiments, (R)-oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dosage of about 0.5 to about 10 mg. In some embodiments, (R)-oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dosage of about 1 mg to about 5 mg. In some embodiments, (i) a non-THC cannabinoid and (ii) a CAI are administered in a single composition. In some embodiments, (i) a non-THC cannabinoid, (ii) a CAI, and (iii) an MRA are administered in a single composition. In some embodiments, the single composition is in an oral dosage form. In some embodiments, the oral dosage form is a syrup, pill, tablet, troche, capsule, or patch. In some embodiments, the condition associated with pharyngeal airway collapse is sleep apnea. In some embodiments, the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA). In some embodiments, the condition associated with pharyngeal airway collapse is snoring. In some embodiments, the condition associated with pharyngeal airway collapse is simple snoring. In some embodiments, the subject is in a state of not being fully conscious. In some embodiments, the state of not being fully conscious is sleep.

[0008] Another aspect of the present invention provides a pharmaceutical composition comprising (i) a cannabinoid and (ii) a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, ethoxzolamide, topiramate, and sulthiame, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, the composition not comprising a norepinephrine reuptake inhibitor (NRI).

[0009] Aspects of this aspect of the invention may include one or more of any of the following features. In some aspects, (i) the cannabinoid is selected from the group consisting of cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabinotriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV) and tetrahydrocannabivarinic acid (THCVA) or any combination thereof or a pharmaceutically acceptable salt thereof. In some aspects, the cannabinoid is CBD. In some aspects, the cannabinoid is THC. In some aspects, (i) the cannabinoid is dronabinol. In some aspects, the CAI is sulthiame or a pharmaceutically acceptable salt thereof. In some aspects, sulthiame or a pharmaceutically acceptable salt thereof is present in an amount of about 200 to about 400 mg. In some aspects, CBD is present in an amount of about 0.5 to about 300 mg. In some aspects, THC is present in an amount of about 0.1 to about 30 mg.

[0010] Another aspect of the invention provides a pharmaceutical composition comprising (i) a non-tetrahydrocannabinol (non-THC) cannabinoid and (ii) a carbonic anhydrase inhibitor (CAI) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, wherein the composition does not contain a norepinephrine reuptake inhibitor (NRI).

[0011] Aspects of this aspect of the invention may include one or more of any of the following features. In some aspects, (i) the non-THC cannabinoid is selected from the group consisting of cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV) and cannabicyclol (CBL) or any combination thereof or pharmaceutically acceptable salts thereof. In some aspects, the non-THC cannabinoid is CBD. In some aspects, (ii) the CAI is selected from the group consisting of acetazolamide, dichlorphenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide, topiramate, sulthiame or pharmaceutically acceptable salts thereof. In some aspects, the CAI is acetazolamide or a pharmaceutically acceptable salt thereof. In some aspects, the CAI, such as acetazolamide or a pharmaceutically acceptable salt thereof, is present in an amount of about 250 mg to about 750 mg. In some aspects, the CAI, such as acetazolamide or a pharmaceutically acceptable salt thereof, is present in an amount of about 500 mg. In some aspects, CBD is present in an amount of about 0.5 to about 300 mg. In some aspects, the composition further comprises (iii) a muscarinic receptor antagonist (MRA). In some aspects, the MRA is selected from the group consisting of atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium and oxybutynin or pharmaceutically acceptable salts thereof. In some aspects, the MRA is selected from the group consisting of anisotropine, benzotropine, biperiden, clidinium, cyclimin, dicyclomine, diphemanil, diphenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixene, methscopolamine, oxyfenclimine, oxyfenonium, procyclidine, scopolamine, tridihexethyl and trihexyphenidyl or pharmaceutically acceptable salts thereof.In some embodiments, the MRA is oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the MRA is (R)-oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, oxybutynin or a pharmaceutically acceptable salt thereof is present in an amount of about 1 to about 15 mg. In some embodiments, oxybutynin or a pharmaceutically acceptable salt thereof is present in an amount of about 2 mg to about 10 mg. In some embodiments, (R)-oxybutynin or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5 to about 10 mg. In some embodiments, (R)-oxybutynin or a pharmaceutically acceptable salt thereof is present in an amount of about 1 mg to about 5 mg. In some embodiments, (i) a cannabinoid, (ii) a CAI and optionally (iii) an MRA are formulated in a single composition. In some embodiments, (i) a non-THC cannabinoid, (ii) a CAI and optionally (iii) an MRA are formulated in a single composition. In some embodiments, the single composition is in an oral dosage form. In some embodiments, the oral dosage form is a syrup, a pill, a tablet, a troche, a capsule or a patch.

[0012] In some embodiments, the pharmaceutical composition is for use in the treatment of a subject having a condition associated with pharyngeal airway collapse. In some embodiments, the condition associated with pharyngeal airway collapse is sleep apnea. In some embodiments, the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA). In some embodiments, the condition associated with pharyngeal airway collapse is snoring. In some embodiments, the condition associated with pharyngeal airway collapse is simple snoring. In some embodiments, the subject is in a state of not being fully conscious. In some embodiments, the state of not being fully conscious is sleep.

[0013] Another aspect of the invention provides a kit comprising (i) a cannabinoid and (ii) a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, ethoxzolamide, topiramate and sulthiame or a pharmaceutically acceptable salt thereof, and optionally (iii) a muscarinic receptor antagonist (MRA), wherein the kit does not include a norepinephrine reuptake inhibitor (NRI).

[0014] Another aspect of the invention provides a kit comprising (i) a non-THC cannabinoid and (ii) a selected carbonic anhydrase inhibitor (CAI) or a pharmaceutically acceptable salt thereof, and optionally (iii) a muscarinic receptor antagonist (MRA), wherein the kit does not include a norepinephrine reuptake inhibitor (NRI). In some embodiments, the kit is for use in the treatment of a subject having a condition associated with pharyngeal airway collapse.

[0015] Another aspect of the invention provides a cannabinoid and a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, ethoxzolamide, topiramate and sulthiame or a pharmaceutically acceptable salt thereof, and optionally a muscarinic receptor antagonist (MRA) for use in the treatment of a subject having a condition associated with pharyngeal airway collapse in the absence of norepinephrine reuptake inhibitor (NRI) therapy.

[0016] Another aspect of the present invention provides a non-THC cannabinoid and a carbonic anhydrase inhibitor (CAI) or a pharmaceutically acceptable salt thereof, and optionally a muscarinic receptor antagonist (MRA) for use in the treatment of a subject having a condition associated with pharyngeal airway collapse in the absence of norepinephrine reuptake inhibitor (NRI) therapy. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention, and other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0017] Other features and advantages of the present invention will be apparent from the following detailed description, drawings, and claims.

Brief Description of the Drawings

[0018] Brief Description of the Drawings The following drawings are provided by way of example and are not intended to limit the scope of the claimed invention.

Figure 1

Modes for Carrying Out the Invention

[0019] Detailed Description In humans, the pharyngeal airway region has no bony or cartilaginous support and is held open by muscles. When these muscles relax during sleep, the pharynx collapses, which can cause airflow cessation. As shown in Figure 1, ventilatory effort continues and increases the attempt to overcome the obstruction indicated by the increased esophageal pressure change. The movements of the thorax and abdomen are in opposite directions, and as a result of the diaphragm contracting against the obstructed airway, the abdominal wall expands outward and the chest wall caves inward.

[0020] Increasing the effort to breathe results in arousal from sleep that can be visualized on the EEG (Figure 1), and airway opening and resumption of normal breathing occur. The absence of airflow during apnea also causes hypoxia, indicated by a decrease in oxyhemoglobin saturation (Figure 1). Severity is generally measured using the apnea-hypopnea index (AHI), which is the combined average number of apneas (cessation of breathing for at least 10 seconds) and hypopneas (decrease in airflow and oxygen saturation) that occur per hour of sleep (Ruehland et al., The new AASM criteria for scoring hypopneas: Impact on the apnea hypopnea index. SLEEP 2009;32(2):150-157).

[0021] Figure 1 is a graphical representation of obstructive apnea. The top channel shows the electroencephalogram (EEG) pattern of sleep. The next channel shows airflow. The next three channels show ventilatory effort by the movements of the thorax and abdomen and the change in esophageal pressure, all of which reflect the respiratory effort against the obstructed upper airway. The last channel shows oxyhemoglobin saturation.

[0022] When a strict definition of OSA is used (AHI > 15 events per hour or AHI > 5 events per hour with daytime sleepiness), the estimated prevalence is approximately 15% in men and 5% in women. An estimated 30 million individuals in the United States have OSA, of which approximately 6 million are diagnosed. The prevalence of OSA in the United States appears to be increasing due to the increasing rates of aging and obesity. OSA is associated with major comorbidities and economic costs, such as: hypertension, diabetes, cardiovascular disease, motor vehicle accidents, workplace accidents, and fatigue / productivity loss. (Young et al., WMJ 2009; 108:246; Peppard et al., Am J Epidemiol 2013; 177:1006.)

[0023] The current main treatment is continuous positive airway pressure (CPAP). CPAP is effective in virtually all patients, and approximately 85% of diagnosed patients are prescribed CPAP, but compliance is low. Patients find that CPAP is uncomfortable and sometimes intolerable, and at least 30% (up to 80%) of patients are not regularly adherent, and thus untreated (Weaver, Proc Am Thorac Soc. 2008 Feb 15; 5(2): 173-178). Other treatment modalities with variable success rates include oral appliances (10%) and surgery (5%), but neither may be effective in all of the general population.

[0024] Research for a medicine for activating pharyngeal muscles in humans during sleep is disappointing, and drugs such as serotonin reuptake inhibitors, tricyclic antidepressants, and sedatives have all been tested in humans and shown to be ineffective in reducing OSA severity. See, for example, Proia and Hudgel, Chest. 1991 Aug;100(2):416-21; Brownell et al., N Engl J Med 1982, 307:1037-1042; Sangal et al., Sleep Med. 2008 Jul;9(5):506-10. Epub 2007 Sep 27; Marshall et al. p. 2008 Jun;31(6):824-31; Eckert et al., Clin Sci (Lond). 2011 Jun;120(12);505-14; Taranto-Montemurro et al., Sleep. 2017 Feb 1;40(2).

[0025] In recent trials, a combination of atomoxetine and oxybutynin, referred to as "ato-oxy" and administered before bedtime, has been shown to reduce OSA in patients with a wide range of severities. The ato-oxy combination administered overnight reduced the number of obstructive events, improved overnight oxygen desaturation, and increased genioglossus muscle activity in a non-selective group of patients with OSA. Data collected in a proof-of-concept trial showed that it is possible to improve or abolish OSA using drugs with a specific neurotransmitter profile administered systemically. See Taranto-Montemurro, L. et al., The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover Trial. Am J Respir Crit Care Med 2019 May 15;199(10):1267-1276.

[0026] There remains a need for additional therapies for treating conditions associated with pharyngeal airway collapse, such as sleep apnea.

[0027] Treatment methods Methods described herein include methods for treating disorders associated with pharyngeal airway muscle collapse during sleep. In some embodiments, the disorder is sleep apnea (e.g., obstructive sleep apnea (OSA)) or snoring (e.g., simple snoring). Generally, the method includes administering to a subject in need of or determined to be in need of such treatment, in the absence of norepinephrine reuptake inhibitor (NRI) therapy, (i) a cannabinoid and (ii) an effective amount of a carbonic anhydrase inhibitor (CAI). In other embodiments, the method further comprises administering a muscarinic receptor antagonist (MRA).

[0028] As used in this context, "treating" means ameliorating at least one symptom of a disorder associated with pharyngeal airway collapse. Often, pharyngeal airway collapse during sleep results in snoring and / or breathing interruptions (apnea or hypopnea), awakenings from sleep, and a decrease in oxygen enrichment (hypoxemia), so treatment can result in a reduction in snoring, apnea / hypopnea, sleep fragmentation, and hypoxemia. Administration of a therapeutically effective amount of a compound described herein for the treatment of a subject with OSA can result in a reduction in AHI. Measurement of OSA disease and symptoms can be, for example, by polysomnography (PSG).

[0029] Generally, an "effective amount" of a compound refers to an amount sufficient to exhibit a desired biological response, e.g., for treating a condition associated with pharyngeal airway collapse, e.g., for treating sleep apnea or snoring. As will be understood by those skilled in the art, the effective amount of a compound of the invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the dosage form, and the age, weight, health status, and condition of the subject. Effective amounts include therapeutic and prophylactic treatments.

[0030] An effective amount can be administered at a dosage, application, or dose of 1 or greater. The composition can be administered one or more times per day to one or more times per week; for example, it can be administered once every other day. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily before bedtime, for example, immediately before bedtime or 15 to 60 minutes before bedtime. Those skilled in the art will understand that certain factors, including but not limited to the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present, can affect the dosage and timing required to effectively treat the subject. Further, the treatment of a subject with a therapeutically effective amount of a therapeutic compound described herein can include a single treatment or a series of treatments.

[0031] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means the amount of a therapeutic agent that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0032] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to an animal (e.g., a bird such as a chicken, quail, or turkey, or a mammal), specifically a "mammal" such as a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee, and human), and more specifically a human. In one embodiment, the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In a preferred embodiment, the subject is a human.

[0033] As used herein, "norepinephrine reuptake inhibitor (NRI) therapy" refers to the administration of a norepinephrine reuptake inhibitor (NRI). Norepinephrine reuptake inhibitors (NRIs) include, but are not limited to, selective NRIs such as amedalin (UK-3540-1), atomoxetine (Strattera), CP-39,332, daledalin (UK-3557-15), edivoxetine (LY-2216684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY-94,939), reboxetine (Edronax, Vestra), talopram (Lu 3-010), talsupram (Lu 5-005), tandamine (AY-23,946), viloxazine (Vivalan); and non-selective NRIs such as amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dextromethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine (GW-320,659), maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phentermine, phenmetrazine, protriptyline, radfaxine (GW-353,162), tapentadol (Nucynta), teniloxazine (Lucelan, Metatone) and venlafaxine; and pharmaceutically acceptable salts thereof. A subject undergoing treatment according to the present disclosure in the absence of NRI therapy does not receive administration of a norepinephrine reuptake inhibitor.

[0034] As used herein, "pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or State government or corresponding agency of a country other than the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals and more specifically in humans.

[0035] Examples of "pharmaceutically acceptable salts" include "pharmaceutically acceptable acid addition salts" and "pharmaceutically acceptable base addition salts". "Pharmaceutically acceptable acid addition salts" are those salts formed by inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc., which retain the biological effectiveness of the free base and are not biologically or otherwise undesirable.

[0036] Examples of "pharmaceutically acceptable basic addition salts" include those derived from inorganic bases such as salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Exemplary salts are salts of ammonium, potassium, sodium, calcium and magnesium. Salts derived from pharmaceutically acceptable non-toxic organic bases include, but are not limited to, primary, secondary and tertiary amines, substituted amines such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, salts of polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. (See, for example, Berge, SM, et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977;66:1-19, which is incorporated herein by reference.)

[0037] As used herein, the term "unit dosage form" is defined to mean the form in which a compound is administered to a subject. Specifically, the unit dosage form can be, for example, a pill, a capsule or a tablet. In some embodiments, the unit dosage form is a capsule.

[0038] As used herein, "solid dosage form" means a solid pharmaceutical dosage (one or more), such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewables.

[0039] For the compounds disclosed herein, single stereochemical isomers, as well as enantiomers, diastereomers, cis / trans conformational isomers, and rotational isomers, and their racemic and non-racemic mixtures are within the scope of the present invention. Unless otherwise indicated, all tautomeric forms of the compounds disclosed herein are within the scope of the present invention.

[0040] Oxybutynin is the generic name for a pharmaceutical substance having the chemical name 4-diethylamino-2-butynylphenylcyclohexyl glycolate or 4-(diethylamino)but-2-ynyl 2-cyclohexyl-2-hydroxy-2-phenylacetate and pharmaceutically acceptable salts thereof. In various embodiments, oxybutynin can be a racemic mixture of R- and S-enantiomers or an isolated enantiomer, such as the R-enantiomer. In various embodiments, oxybutynin can be oxybutynin chloride or (R)-oxybutynin chloride.

[0041] Acetazolamide is the generic name for a pharmaceutical substance having the chemical name N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide and its pharmaceutical salts. Acetazolamide is available as a generic pharmaceutical and is sold under the trade names Diamox, Dacarb, and others.

[0042] "Cannabinoid" is a group of compounds including endocannabinoids, phytocannabinoids, and those that are neither endocannabinoids nor phytocannabinoids, hereinafter referred to as "synthetic cannabinoids". "Endocannabinoid" is an endogenous cannabinoid that is a high-affinity ligand for CB1 and CB2 receptors. "Phytocannabinoid" is a cannabinoid of natural origin that can be found in the cannabis plant. Phytocannabinoids can be present in extracts containing phytopharmaceutical substances, or can be isolated or synthetically regenerated. "Synthetic cannabinoid" is a compound that can interact with cannabinoid receptors (CB1 and / or CB2), but is not found endogenously or within the cannabis plant.

[0043] "Non-THC cannabinoid" is a cannabinoid as described herein that is not any of THC (delta-9-tetrahydrocannabinol (Δ9-THC)) or its homologs or isomers (e.g., THC, dronabinol, CBN, CBO, D8-THC, trans-A10-THC, cis-A10-THC, THCV, A8-THCV or A9-THCV). "Non-TCH cannabinoid" can also be a cannabinoid that does not have delta-9-tetrahydrocannabinol. In some embodiments, the non-THC cannabinoid is cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV) and cannabicyclol (CBL) or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the method includes administering a dose of CBD of about 0.5 to about 300 mg (e.g., daily). In some embodiments, the dose of CBD or a pharmaceutically acceptable salt thereof is about 1 to about 100 mg. In some embodiments, the dose of CBD or a pharmaceutically acceptable salt thereof is about 1 mg to about 10 mg. In some embodiments, the dose of CBD or a pharmaceutically acceptable salt thereof is about 10 mg to about 100 mg. In some embodiments, CBD is administered orally. In some embodiments, CBD is administered sublingually.

[0045] In some embodiments, the method includes administering a dose of sulthiame or a pharmaceutically acceptable salt thereof of about 100 mg to about 500 mg (e.g., daily). In some embodiments, the dose of sulthiame or a pharmaceutically acceptable salt thereof is about 200 mg to about 400 mg. In some embodiments, sulthiame is administered orally.

[0046] In some embodiments, the method includes administering a dose of THC of about 0.1 to about 30 mg. In some embodiments, the method includes administering a dose of THC of about 1 to about 20 mg. In some embodiments, the dose of THC or a pharmaceutically acceptable salt thereof is about 0.5 to about 20 mg. In some embodiments, the dose of THC or a pharmaceutically acceptable salt thereof is about 0.25 to about 10 mg. In some embodiments, THC is administered orally. In some embodiments, THC is administered sublingually.

[0047] In some embodiments, the method includes administering dronabinol in a dose of about 1 mg to about 20 mg (e.g., daily). In some embodiments, the method includes administering dronabinol in a dose of about 2.5 mg to about 10 mg (e.g., daily). In some embodiments, the method includes administering dronabinol in a dose of about 5 mg to about 10 mg (e.g., daily). In some embodiments, the method includes administering dronabinol in a dose of about 5 mg (e.g., daily). In some embodiments, the method includes administering dronabinol in a dose of about 10 mg (e.g., daily).

[0048] In some embodiments, the method includes administering nabilone in a dose of about 0.25 mg to about 20 mg (e.g., about 0.25 mg to about 2 mg) (e.g., daily).

[0049] In some embodiments, the method includes administering a dose of about 50 mg to about 1000 mg of CAI (e.g., acetazolamide), about 100 mg to about 800 mg of CAI (e.g., acetazolamide), about 250 mg to about 750 mg of CAI (e.g., acetazolamide), about 500 mg to about 750 mg of CAI (e.g., acetazolamide), or about 450 mg to about 650 mg of CAI (e.g., acetazolamide). In some embodiments, the CAI is administered daily. In some embodiments, the CAI or a pharmaceutically acceptable salt thereof is administered daily before bedtime, e.g., immediately before bedtime or 15 to 60 minutes before bedtime.

[0050] In a method comprising administration of an MRA, such as oxybutynin or (R)-oxybutynin or a pharmaceutically acceptable salt thereof (or another MRA), the dosage of oxybutynin or (R)-oxybutynin or a pharmaceutically acceptable salt thereof can be from about 1 mg to about 25 mg (or a dosage equivalent to that of another MRA), or in some embodiments from about 2 mg to about 15 mg. In some embodiments, the dosage of oxybutynin or a pharmaceutically acceptable salt thereof is from about 2.5 mg to about 10 mg, such as 5 mg. In some embodiments, the dosage of (R)-oxybutynin or a pharmaceutically acceptable salt thereof is from about 1 mg to about 5 mg, such as 2.5 mg. In some embodiments, the dosage of oxybutynin or (R)-oxybutynin or a pharmaceutically acceptable salt thereof is from about 1 mg to about 10 mg.

[0051] Pharmaceutical composition (i) A cannabinoid and (ii) a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, ethoxzolamide, topiramate and sulthiame or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients are also provided herein, and the composition does not contain a norepinephrine reuptake inhibitor (NRI). Also provided herein is a pharmaceutical composition comprising a non-tetrahydrocannabinol (non-THC) cannabinoid and (ii) a carbonic anhydrase inhibitor (CAI) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, and the composition does not contain a norepinephrine reuptake inhibitor (NRI). In some embodiments, the pharmaceutical composition further comprises a muscarinic receptor antagonist (MRA). The cannabinoid, non-THC cannabinoid, CAI and optionally the MRA are the active pharmaceutical ingredients of the pharmaceutical composition. The active pharmaceutical ingredients can be in a single composition or in separate compositions. In some embodiments, the pharmaceutical composition does not contain a norepinephrine reuptake inhibitor (NRI).

[0052] Exemplary cannabinoids include cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabinotriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), and tetrahydrocannabivarinic acid (THCVA), as well as pharmaceutically acceptable salts thereof or any combination thereof.

[0053] In some embodiments, the cannabinoid is CBD.

[0054] In some embodiments, the cannabinoid is THC. In some embodiments, the cannabinoid is synthetic THC. In some embodiments, the cannabinoid is a synthetic THC derivative (e.g., nabron). In some embodiments, the cannabinoid is THC in enantiomerically pure form (e.g., dronabinol). Dronabinol is synthetic delta-9-tetrahydrocannabinol (delta-9-THC).

[0055] Further exemplary cannabinoids include commercially available cannabinoids such as Epidiolex® (CBD oral solution), Sativex® (nabiximols), Cesamet® (nabron), Marinol® (dronabinol), and Acomplia® (rimonabant).

[0056] Additional exemplary cannabinoids include investigational cannabinoids such as SCI-110 (THX-110), AM-251, AM-630, HU-308, ABX-1431, RAD-011, liquid structured CBD, ART12.11 (CBD co-crystal), GWP-42006), CMX-020, ECP022A, dronabinol buccal, nabron controlled release, NE-1940, oromucosal, Drinabant, MDMB-FUBINACA, 5F-AB-PINACA, 5F-ADB, 5F-AMB, 5F-APINACA, AB-FUBINACA, AB-CHFUPYCA, AB-CHMINACA, AB-PINACA, ADB-CHMINACA, ADB-FUBINACA, ADSB-FUB-187, ADB-PINACA, ADBICA, APICA, adamantyl-THPINACA, STS-135, AB-001, A-834,735, A-796,260, A-836,339, JWH-200, JWH-018, GUB-APINACA, APP-FUBINACA, MDMB-CHMICA, PX-1, PX-2, PX-3, CP-55,940, dimethylheptylpyran, HU-210, HU-331, SR144528, WIN 55,212-2, levorphanol, AM-2201, MEPIRAPIM, JWH-133 and levorphanol.

[0057] Exemplary non-THC cannabinoids include cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV) and cannabicyclol (CBL) or any combination thereof or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the non-THC cannabinoid is CBD or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, CBD or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5 to about 300 mg. In some embodiments, CBD or a pharmaceutically acceptable salt thereof is present in an amount of about 1 to about 100 mg. In some embodiments, CBD or a pharmaceutically acceptable salt thereof is present in an amount of about 1 mg to about 10 mg. In some embodiments, CBD or a pharmaceutically acceptable salt thereof is present in an amount of about 10 mg to about 100 mg.

[0060] In some embodiments, THC or a pharmaceutically acceptable salt thereof is present in an amount of about 0.1 to about 30 mg. In some embodiments, THC or a pharmaceutically acceptable salt thereof is present in an amount of about 1 to about 20 mg. In some embodiments, THC or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5 to about 20 mg. In some embodiments, THC or a pharmaceutically acceptable salt thereof is present in an amount of about 0.25 to about 10 mg.

[0061] Exemplary CAIs include acetazolamide, dichlorphenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide, topiramate, sulthiame, and any combination thereof, such as pharmaceutically acceptable salts thereof.

[0062] In some embodiments, the CAI is sulthiame or a pharmaceutically acceptable salt thereof. In some embodiments, sulthiame is present in an amount of about 200 mg to about 400 mg.

[0063] Exemplary muscarinic receptor antagonists (MRAs) include atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium, and oxybutynin, which are active on the M2 receptor, and pharmaceutically acceptable salts thereof. Other exemplary antimuscarinics include anisotropine, benztropine, biperiden, clidinium, cycrimine, dicyclomine, diphemanil, diphenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixene, methscopolamine, oxyfencyclimine, oxyfenonium, procyclidine, scopolamine, tridihexethyl, and trihexyphenidyl, and pharmaceutically acceptable salts thereof.

[0064] In some embodiments, the muscarinic receptor antagonist is oxybutynin or (R)-oxybutynin or a pharmaceutically acceptable salt thereof. As used herein, (R)-oxybutynin refers to the (R)-oxybutynin stereoisomer that is substantially free of other stereoisomers of oxybutynin.

[0065] In some embodiments, oxybutynin or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 1 to about 15 mg. In some embodiments, oxybutynin or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 2 mg to about 10 mg. In some embodiments, (R)-oxybutynin or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.5 to about 10 mg. In some embodiments, (R)-oxybutynin or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 1 mg to about 5 mg. In some embodiments, (i) a cannabinoid, (ii) a CAI, and optionally (iii) an MRA are formulated in a single composition. In some embodiments, (i) a non-THC cannabinoid, (ii) a CAI, and optionally (iii) an MRA are formulated in a single composition.

[0066] As used herein, the term "pharmaceutically acceptable carrier" includes saline, solvents, dispersion media, diluents, fillers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., which are compatible with pharmaceutical administration.

[0067] The active pharmaceutical ingredient (API) for use in the present invention may be provided as a pharmaceutically acceptable salt. For example, in some embodiments, when MRA is present, oxybutynin is oxybutynin chloride. In some embodiments, (R)-oxybutynin is (R)-oxybutynin chloride.

[0068] Pharmaceutical compositions are typically formulated to be compatible with their intended route of administration. Examples of routes of administration include systemic oral or transdermal administration.

[0069] Methods for formulating appropriate pharmaceutical compositions are known in the art, see, for example, Remington: The Science and Practice of Pharmacy, 21st ed., 2005; and the series of books Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound(s) can be incorporated with excipients and used in the form of pills, tablets, troches, or capsules, such as gelatin capsules. Oral compositions can also be prepared using a liquid carrier. In some embodiments, the compositions of the present invention can be in unit dosage form. In some embodiments, the compositions of the present invention can be in solid dosage forms, such as tablets or capsules.

[0070] A pharmaceutically compatible binder and / or adjuvant material may be included as part of the composition. Tablets, pills, capsules, troches, etc. may contain the following components or compounds having similar properties: binders such as microcrystalline cellulose, tragacanth gum or gelatin; excipients such as starch or lactose, disintegrants such as alginic acid, primogel or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring and odor-masking agents such as peppermint, methyl salicylate or orange flavoring.

[0071] Systemic administration of the compounds described herein can also be effected by transdermal means, for example, using patches, gels or lotions applied to the skin. For transdermal administration, penetration enhancers suitable for penetration of the epithelial barrier can be used in the formulation. Such penetration enhancers are generally known in the art. For example, for transdermal administration, the active compounds can be formulated in ointments, salves, gels or creams as generally known in the art. Gels and / or lotions can be provided in individual sachets or via metered pumps for daily application; see, for example, Cohn et al., Ther Adv Urol. 2016, Apr; 8(2): 83-90.

[0072] In one aspect, the therapeutic compound is prepared using a carrier that protects the therapeutic compound against rapid elimination from the body, such as a controlled release formulation like an implant and a microencapsulation delivery system. Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Such formulations can be prepared using standard techniques or can be obtained commercially, for example, from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, such as those described in U.S. Patent No. 4,522,811.

[0073] The pharmaceutical composition can be contained in a container, pack, or dispenser, together with instructions for administration or use in the methods described herein.

[0074] In some aspects, the pharmaceutical compositions disclosed herein are for use in the treatment of conditions associated with pharyngeal airway muscle collapse during sleep. In some aspects, the conditions associated with pharyngeal airway muscle collapse are sleep apnea (e.g., obstructive sleep apnea (OSA)) or snoring (e.g., simple snoring).

[0075] Kits and Combinations (i) A cannabinoid and (ii) a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, ethoxzolamide, topiramate and sulthiame or a pharmaceutically acceptable salt thereof, and optionally (iii) a muscarinic receptor antagonist (MRA) are also provided herein, and the kit does not include a norepinephrine reuptake inhibitor (NRI). A kit comprising (i) a non-THC cannabinoid and (ii) a selected carbonic anhydrase inhibitor (CAI) or a pharmaceutically acceptable salt thereof, and optionally (iii) a muscarinic receptor antagonist (MRA) is further provided herein, and the kit does not include a norepinephrine reuptake inhibitor (NRI). For example, the kit may include separate pharmaceutical compositions, each composition lacking a norepinephrine reuptake inhibitor (NRI). The kit can be used to treat a subject having a condition associated with pharyngeal airway collapse. Various aspects of the kit, including the compositions and methods described herein, will be apparent from the detailed description provided herein.

[0076] Also provided herein are cannabinoids and a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, ethoxzolamide, topiramate and sulthiame or a pharmaceutically acceptable salt thereof, and optionally a muscarinic receptor antagonist (MRA) for use in the treatment of a subject having a condition associated with pharyngeal airway collapse in the absence of NRI therapy.

[0077] Non-THC cannabinoids and carbonic anhydrase inhibitors (CAIs) or pharmaceutically acceptable salts thereof, and optionally muscarinic receptor antagonists (MRAs), are also provided herein for use in the treatment of a subject having a condition associated with pharyngeal airway collapse in the absence of NRI therapy. Also provided herein is a therapeutic combination of a cannabinoid and a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, ethoxzolamide, topiramate, and sulthiame or a pharmaceutically acceptable salt thereof, and optionally a muscarinic receptor antagonist (MRA) for use in the treatment of a subject having a condition associated with pharyngeal airway collapse in the absence of NRI therapy. Also provided herein is a therapeutic combination of a non-THC cannabinoid and a carbonic anhydrase inhibitor (CAI) or a pharmaceutically acceptable salt thereof, and optionally a muscarinic receptor antagonist (MRA) for use in the treatment of a subject having a condition associated with pharyngeal airway collapse, such as a condition associated with sleep apnea or snoring. The therapeutic combination can be used to treat pharyngeal airway collapse, such as a condition associated with sleep apnea or snoring.

[0078] The various aspects of the combinations and therapeutic combinations will be apparent from the detailed description provided herein, for example, from the compositions and methods described herein.

Examples

[0079] Examples The invention is further described in the following examples, which do not limit the scope of the invention as claimed.

[0080] Example 1. Crossover Trial A placebo-controlled, double-blind, randomized crossover trial is conducted in OSA human patients. Participants receive treatment in a randomized order 30 minutes before sleep of (1) a cannabinoid (e.g., CBD or THC) once daily + a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, ethoxzolamide, topiramate, and sulthiame or placebo; or (2) a non-THC cannabinoid (e.g., CBD) once daily + CAI or placebo. Treatments are evaluated for their ability to reduce the apnea hypopnea index and improve OSA severity. Further benefits to be evaluated may be an increase in ventilatory drive, improvement in upper airway muscle activity, improvement in ventilation, increase in oxygen level (SaO2), increase in total sleep time, improvement in hypoxic load, and increase in genioglossus responsiveness to the other for improvement in sleep efficiency.

[0081] Other aspects The invention is described with its detailed description, but it is understood that the foregoing description is intended to be illustrative and does not limit the scope of the invention as defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. For treating conditions related to pharyngeal airway collapse, (1) Cannabinoids, (2) Carbonic anhydrase inhibitors (CAIs), (3) Both cannabinoids and carbonic anhydrase inhibitors (CAIs) A pharmaceutical composition comprising, wherein the carbonic anhydrase inhibitor (CAI) is selected from the group consisting of dichlorophenamide, zonisamide, ethoxyzolamide, topiramate, and sultiam or a pharmaceutically acceptable salt thereof, and the treatment is performed in the absence of norepinephrine reuptake inhibitor (NRI) therapy. Here, in the case of (1) above, the pharmaceutical composition is used in combination with a pharmaceutical composition containing a carbonic anhydrase inhibitor (CAI), and in the case of (2) above, the pharmaceutical composition is used in combination with a pharmaceutical composition containing a cannabinoid. Pharmaceutical composition.

2. (i) The pharmaceutical composition according to claim 1, wherein the cannabinoid is selected from the group consisting of cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), and tetrahydrocannabivaric acid (THCVA) or any combination thereof or pharmaceutically acceptable salts thereof.

3. The pharmaceutical composition according to claim 2, wherein the cannabinoid is CBD.

4. The pharmaceutical composition according to claim 2, wherein the cannabinoid is THC or dronabinol.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein CAI is sultium or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to any one of claims 1 to 4, wherein the treatment further comprises administering to a subject (iii) a muscarinic receptor antagonist (MRA), the MRA being selected from the group consisting of atropine, propantheline, bethanechol, solifenacin, dalifenacin, tolterodine, fesoterodine, throspium, and oxybutynin or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to any one of claims 1 to 4, wherein (i) a cannabinoid and (ii) a CAI are administered in a single composition, and the single composition is in an orally administered form.

8. The pharmaceutical composition according to any one of claims 1 to 4, wherein the condition associated with pharyngeal airway collapse is sleep apnea or snoring.

9. The pharmaceutical composition according to claim 8, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA).

10. For treating conditions related to pharyngeal airway collapse, (1) Cannabinoids, (2) Carbonic anhydrase inhibitors (CAIs), (3) Both cannabinoids and carbonic anhydrase inhibitors (CAIs) A pharmaceutical composition comprising a cannabinoid in which the cannabinoid is a non-tetrahydrocannabinol (non-THC) cannabinoid, wherein the treatment is performed in the absence of norepinephrine reuptake inhibitor (NRI) therapy. Here, in the case of (1) above, the pharmaceutical composition is used in combination with a pharmaceutical composition containing a carbonic anhydrase inhibitor (CAI), and in the case of (2) above, the pharmaceutical composition is used in combination with a pharmaceutical composition containing a cannabinoid. Pharmaceutical composition.

11. (i) The pharmaceutical composition according to claim 10, wherein the non-THC cannabinoid is selected from the group consisting of cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), and cannabicyclol (CBL) or any combination thereof or pharmaceutically acceptable salts thereof.

12. The pharmaceutical composition according to claim 11, wherein the non-THC cannabinoid is CBD.

13. The pharmaceutical composition according to any one of claims 10 to 12, wherein the CAI is selected from the group consisting of acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, metazolamide, zonisamide, ethoxyzolamide, topiramate, sultiam, or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition according to claim 13, wherein CAI is sultium or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition according to any one of claims 10 to 12, wherein the treatment further comprises administering a muscarinic receptor antagonist (MRA) to a subject, the MRA being selected from the group consisting of atropine, propantheline, bethanechol, solifenacin, dalifenacin, tolterodine, fesoterodine, throspium, and oxybutynin or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition according to any one of claims 10 to 12, wherein (i) a non-THC cannabinoid and (ii) a CAI are administered in a single composition, and the single composition is in an orally administered form.

17. The pharmaceutical composition according to any one of claims 10 to 12, wherein the condition associated with pharyngeal airway collapse is sleep apnea or snoring.

18. The pharmaceutical composition according to claim 17, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA).

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