Methods of treating sleep apnea with combination of cannabinoid and carbonic anhydrase inhibitor

Abstract

Described herein are methods of treating sleep apnea and snoring comprising administering a combination of cannabinoid and a carbonic anhydrase inhibitor (CAI), and optionally a muscarinic receptor antagonist (MRA). Also described are pharmaceutical compositions comprising a cannabinoid and a carbonic anhydrase inhibitor (CAI), and optionally MRA. In some embodiments, the cannabinoid is a non-THC cannabinoid. In some embodiments, the CAI is selected from the group consisting of diclofenamide, zonisamide, ethozolamide, topiramate, and sulthiamethoxam, or a pharmaceutically acceptable salt thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 353,903, filed on June 21, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention provides a method of treating sleep apnea and snoring comprising administering a cannabinoid and a carbonic anhydrase inhibitor (CAI). Background Art

[0004] Obstructive sleep apnea (OSA) is a common condition caused by the collapse of the pharyngeal airway during sleep. OSA can have serious health consequences. Summary of the invention

[0005] One aspect of the invention provides a method of treating a subject suffering from a condition associated with pharyngeal airway collapse, the method comprising administering to a subject in need thereof, 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 sultiame, or a pharmaceutically acceptable salt thereof.

[0006] Embodiments of this aspect of the invention may include one or more of the following optional features. In some embodiments, (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), cannabinolpropyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), and tetrahydrocannabivarinic acid (THCA). In some embodiments, the cannabinoid is CBD. In some embodiments, the cannabinoid is THC. In some embodiments, (i) the cannabinoid is dronabinol. In some embodiments, CAI is suthiame or a pharmaceutically acceptable salt thereof. In some embodiments, suthiame or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg to about 400 mg. In some embodiments, CBD is administered at a dose of about 0.5 mg to about 300 mg. In some embodiments, THC is administered at a dose of about 0.1 mg to about 30 mg. In some embodiments, the method further comprises administering to the subject (iii) a muscarinic receptor antagonist (MRA). In some embodiments, 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, MRA is oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, 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 mg 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 mg 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) cannabinoids and (ii) CAI are administered in a single composition. In some embodiments, (i) cannabinoids, (ii) CAI, and (iii) MRA are administered in a single composition. In some embodiments, a single composition is in an oral administration form. In some embodiments, the oral administration form is a syrup, a pill, a tablet, a lozenge, a capsule, or a 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, wherein the condition associated with pharyngeal airway collapse is simple snoring. In some embodiments, the subject is in a state of non-full consciousness. In some embodiments, the state of non-full consciousness is sleep.

[0007] 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 thereof an effective amount of (i) a non-tetrahydrocannabinol (non-THC) cannabinoid and (ii) a carbonic anhydrase inhibitor (CAI), or a pharmaceutically acceptable salt thereof, in the absence of norepinephrine reuptake inhibitor (NRI) therapy.

[0008] Embodiments of this aspect of the present invention may include one or more of the following optional features. In some embodiments, (i) non-THC cannabinoids are selected from the group consisting of cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidiol (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV) and cannabicycline (CBL), or any combination thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, non-THC cannabinoids are CBD. In some embodiments, (ii) CAI is selected from the group consisting of acetazolamide, dichlorphenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, esoxazolamide, topiramate, sultimide, or a pharmaceutically acceptable salt thereof. In some embodiments, CAI is acetazolamide or a pharmaceutically acceptable salt thereof. In some embodiments, CAIs such as acetazolamide or pharmaceutically acceptable salts thereof are administered at a dosage of about 250 mg to about 750 mg. In some embodiments, CAIs such as acetazolamide or pharmaceutically acceptable salts thereof are administered at a dosage of about 500 mg. In some embodiments, CBD is administered at a dosage of about 0.5 mg to about 300 mg. In some embodiments, the method further comprises administering (iii) a muscarinic receptor antagonist (MRA) to the subject. In some embodiments, MRA is selected from the group consisting of: atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium chloride and oxybutynin, or pharmaceutically acceptable salts thereof. In some embodiments, the MRA is selected from the group consisting of: cintropine, benztropine, biperiden, collidine, cyclamine, dicyclomine, diphenylmanil, diphenidol, epromidine, glycopyrrolate, hexamethylenetetramine, isopropylamide, mepenzolate, methicillin, methylscopolamine, hydroxybenzylamine, oxphenamium, procyclidine, scopolamine, trimethoprim 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 mg 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 mg 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 non-THC cannabinoid and (ii) a CAI are administered in a single composition.In some embodiments, (i) non-THC cannabinoids, (ii) CAI, and (iii) MRA are administered in a single composition. In some embodiments, the single composition is in an oral administration form. In some embodiments, the oral administration form is a syrup, a pill, a tablet, a lozenge, a capsule, or a 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 incomplete consciousness. In some embodiments, the state of incomplete consciousness is sleep.

[0009] 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, esoxozolid, topiramate and sultiamide, 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).

[0010] Embodiments of this aspect of the present invention may include one or more of the following optional features. In some embodiments, (i) cannabinoids are selected from the group consisting of cannabichromene (CBC), cannabichromene acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidiol (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicycline (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), dihydroxycannabinol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THCV) and tetrahydrocannabinolic acid (THCVA), or any combination thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the cannabinoid is CBD. In some embodiments, the cannabinoid is THC. In some embodiments, (i) cannabinoid is dronabinol. In some embodiments, CAI is suthiame or a pharmaceutically acceptable salt thereof. In some embodiments, suthiame or a pharmaceutically acceptable salt thereof is present in an amount of about 200 mg to about 400 mg. In some embodiments, CBD is present in an amount of about 0.5 mg to about 300 mg. In some embodiments, THC is present in an amount of about 0.1 mg to about 30 mg.

[0011] Another aspect of the present 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 comprise a norepinephrine reuptake inhibitor (NRI).

[0012] Embodiments of this aspect of the present invention may include one or more of the following optional features. In some embodiments, (i) non-THC cannabinoids are selected from the group consisting of cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidiol (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV) and cannabicycline (CBL), or any combination thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, non-THC cannabinoids are CBD. In some embodiments, (ii) CAI is selected from the group consisting of acetazolamide, dichlorphenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, esoxazolamide, topiramate, sulthiame, or a pharmaceutically acceptable salt thereof. In some embodiments, CAI is acetazolamide or a pharmaceutically acceptable salt thereof. In some embodiments, 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 embodiments, CAI such as acetazolamide or its pharmaceutically acceptable salt is present in an amount of about 500 mg. In some embodiments, CBD is present in an amount of about 0.5 mg to about 300 mg. In some embodiments, the composition further comprises (iii) a muscarinic receptor antagonist (MRA). In some embodiments, MRA is selected from the group consisting of: atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium chloride and oxybutynin, or its pharmaceutically acceptable salt. In some embodiments, the MRA is selected from the group consisting of: cintropine, benztropine, biperiden, cleridinium, cyclamine, dicyclomine, diphenylmanil, diphenidol, epromidine, glycopyrrolate, hexamethylenetetramine, isopropylamide, mepenzolate, methicillin, methylscopolamine, hydroxybenzylamine, oxphenamium, procyclidine, scopolamine, trimethoprim 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 present in an amount of about 1 mg 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 mg 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) cannabinoids, (ii) CAI, and optionally (iii) MRA are formulated in a single composition. In some embodiments, (i) non-THC cannabinoids, (ii) CAI, and optionally (iii) MRA are formulated in a single composition.In some embodiments, the single composition is in an oral administration form. In some embodiments, the oral administration form is a syrup, a pill, a tablet, a lozenge, a capsule, or a patch.

[0013] In some embodiments, the pharmaceutical composition is used to treat 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 incomplete consciousness. In some embodiments, the state of incomplete consciousness is sleep.

[0014] Another aspect of the present invention provides a kit comprising (i) a cannabinoid and (ii) a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, esoxozolid, topiramate and sultiamide, or a pharmaceutically acceptable salt thereof, and optionally (iii) a muscarinic receptor antagonist (MRA), wherein the kit does not contain a norepinephrine reuptake inhibitor (NRI).

[0015] 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 contain a norepinephrine reuptake inhibitor (NRI). In some embodiments, the kit is used to treat a subject having a condition associated with pharyngeal airway collapse.

[0016] Another aspect of the invention provides a cannabinoid and a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, esoxozolid, topiramate and sultiamide, or a pharmaceutically acceptable salt thereof, and optionally a muscarinic receptor antagonist (MRA) for use in treating a subject suffering from a condition associated with pharyngeal airway collapse in the absence of norepinephrine reuptake inhibitor (NRI) therapy.

[0017] 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 treating a subject with a condition associated with pharyngeal airway collapse in the absence of norepinephrine reuptake inhibitor (NRI) therapy. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated herein by reference in their entirety. In the event of a conflict, the present specification (including definitions) shall prevail.

[0018] Other features and advantages of the invention will be apparent from the following detailed description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The following drawings are provided by way of example and are not intended to limit the scope of the claimed invention.

[0020] Figure 1 is a graphic representation of obstructive apnea. The top channel shows an electroencephalogram (EEG) graphic representation of sleep. The next channel represents airflow. The next three channels show the ventilatory effort caused by the movement of the chest and abdomen and the changes in esophageal pressure, all of which reflect the effort of breathing against the obstructed upper airway. The last channel indicates oxyhemoglobin saturation. DETAILED DESCRIPTION

[0021] In humans, the pharyngeal airway area has no bone or cartilage support and is held open by muscles. When these muscles relax during sleep, the pharynx collapses, resulting in cessation of airflow. Figure 1 As shown, ventilatory effort continues and increases in an attempt to overcome the obstruction, as evidenced by increased esophageal pressure changes. The chest and abdomen move in opposite directions because the diaphragm contracts to press against the obstructed airway, forcing the abdominal wall to expand outward and the chest wall to collapse inward.

[0022] Increased breathing effort leads to arousals from sleep, which can be seen on the EEG ( Figure 1 ) and results in the opening of the airway and restoration of normal breathing. The lack of airflow during apnea also results in hypoxia, which is manifested by a decrease in oxyhemoglobin saturation ( Figure 1Severity is usually measured using the apnea-hypopnea index (AHI), which is the combined average number of apneas (stopping breathing for at least ten seconds) and hypopneas (reduced airflow and oxygen saturation) that occur per hour of sleep (Ruehland et al., The new AASM criteria for scoringhypopneas: Impact on the apnea hypopnea index. SLEEP 2009; 32(2): 150-157).

[0023] Figure 1 is a graphic representation of obstructive apnea. The top channel shows an electroencephalogram (EEG) graphic representation of sleep. The next channel represents airflow. The next three channels show the ventilatory effort caused by the movement of the chest and abdomen and the changes in esophageal pressure, all of which reflect the effort of breathing against an obstructed upper airway. The last channel indicates oxyhemoglobin saturation.

[0024] When using a strict definition of OSA (AHI>15 events / hour or AHI>5 events / hour with daytime sleepiness), the estimated prevalence is about 15% in men and about 5% in women. An estimated 30 million people in the United States suffer from OSA, of which about 6 million have been diagnosed. The prevalence of OSA in the United States appears to be increasing due to aging and increased obesity rates. OSA is associated with major comorbidities and economic costs including: hypertension, diabetes, cardiovascular disease, motor vehicle accidents, workplace accidents, and fatigue / loss of productivity. (Young et al., WMJ 2009; 108:246; Peppard et al., Am J Epidemiol 2013; 177:1006.).

[0025] The mainstay of treatment is continuous positive airway pressure (CPAP). CPAP is effective in nearly all patients, and approximately 85% of diagnosed patients are prescribed CPAP, but compliance is low. Patients find CPAP uncomfortable and often difficult to tolerate; at least 30% (and up to 80%) of patients are often noncompliant and therefore do not receive treatment (Weaver, Proc Am Thorac Soc. 2008 Feb 15;5(2):173-178). Other treatments with varying success rates include oral appliances (10%) and surgery (5%), but both are unlikely to be effective in the general population.

[0026] The search for drugs that activate pharyngeal muscles in sleeping humans has been frustrating; agents such as serotonin reuptake inhibitors, tricyclic antidepressants, and sedatives have all been tested in humans and proven ineffective in reducing OSA severity. See, e.g., 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).

[0027] In recent studies, a combination of atomoxetine and oxybutynin (called "ato-oxy") administered before bed has been shown to reduce OSA in patients with a wide range of severity. In an unselected group of patients with OSA, the administration of the ato-oxy combination for one night reduced the number of obstructive events, improved overnight oxygen desaturation, and enhanced genioglossus muscle activity. Data collected in a proof-of-concept trial suggest that systemically administered drugs with specific neurotransmitter characteristics can be used to improve or eliminate OSA. 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.

[0028] There remains a need for further therapies to treat conditions associated with pharyngeal airway collapse, such as sleep apnea.

[0029] Treatment

[0030] The methods described herein include methods for treating a condition associated with collapse of the pharyngeal airway muscles during sleep. In some embodiments, the condition is sleep apnea (e.g., obstructive sleep apnea (OSA)) or snoring (e.g., simple snoring). Typically, the method comprises administering an effective amount of (i) a cannabinoid and (ii) a carbonic anhydrase inhibitor (CAI) to a subject in need of such treatment or to a subject who has been determined to be in need of such treatment in the absence of norepinephrine reuptake inhibitor (NRI) therapy. In other embodiments, the method further administers a muscarinic receptor antagonist (MRA).

[0031] As used in this context, "treatment" means improving at least one symptom of a condition associated with pharyngeal airway collapse. Typically, pharyngeal airway collapse during sleep leads to snoring and / or interrupted breathing (apnea or hypopnea), waking up from sleep, and reduced oxygenation (hypoxemia); therefore, treatment can result in reduced snoring, apnea / hypopnea, sleep fragmentation, and hypoxemia. Administering a therapeutically effective amount of a compound described herein to treat a subject with OSA can result in a reduced AHI. Measurement of OSA disease and symptoms can be performed, for example, by polysomnography (PSG).

[0032] In general, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response, e.g., an amount sufficient to treat a condition associated with pharyngeal airway collapse, e.g., an amount sufficient to treat sleep apnea or snoring. As will be appreciated by one of ordinary skill in the art, an effective amount of a compound of the invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health and condition of the subject. An effective amount encompasses both therapeutic and prophylactic treatments.

[0033] The effective amount can be administered in one or more administrations, applications or dosages. The composition can be administered once or more per day to once or more per week; including administration every other day. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily before sleep time, for example, immediately before sleep time or 15-60 minutes before sleep time. The skilled person will understand that certain factors may affect the dose and timing required to effectively treat the subject, including but not limited to the severity of the disease or condition, previous treatment, the overall health and / or age of the subject, and other diseases present. In addition, treating a subject with a therapeutically effective amount of a therapeutic compound described herein may include a single treatment or a series of treatments.

[0034] As used herein and 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 an amount sufficient to delay or minimize one or more symptoms associated with a 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 encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0035] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds, such as chickens, quail or turkeys, or mammals), specifically "mammals" including non-primates (e.g., cattle, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs and mice) and primates (e.g., monkeys, chimpanzees and humans), and more specifically humans. In one embodiment, the subject is a non-human animal, such as a farm animal (e.g., horse, cattle, pig or sheep), or a pet (e.g., dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject is a human.

[0036] 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 amitriptiline, amoxapine, bupropion, ciclazindol, desipramine, desvenlafaxine, dexmethilphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, ifaxine (GW-320,659), maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protryptyline, radafaxine (GW-353,162), tapentadol (Nucynta), teniloxazine (Lucelan, Metatone) and venlafaxine; and pharmaceutically acceptable salts thereof.Subjects receiving treatment according to the present disclosure in the absence of NRI therapy do not receive administration of a norepinephrine reuptake inhibitor.

[0037] As used herein, "pharmaceutically acceptable" means approved or acceptable by a regulatory agency of the Federal or a state government or corresponding agency in a country outside the United States, or listed in the US Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0038] "Pharmaceutically acceptable salts" include "pharmaceutically acceptable acid addition salts" and "pharmaceutically acceptable base addition salts". "Pharmaceutically acceptable acid addition salts" refer to those salts which retain the biological effectiveness of the free bases and which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, 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 and salicylic acid.

[0039] "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases, such as sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts and aluminum salts, etc. Exemplary salts are ammonium salts, potassium salts, sodium salts, calcium salts and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines (including 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 and polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine (see, e.g., Berge, SM. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, which is incorporated herein by reference).

[0040] As used herein, the term "unit dosage form" is defined to refer to the form in which a compound is administered to a subject. Specifically, the unit dosage form can be, for example, a pill, capsule, or tablet. In some embodiments, the unit dosage form is a capsule.

[0041] As used herein, "solid dosage form" means a drug dosage(s) in solid form, such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers, and chewable tablets.

[0042] For the compounds disclosed herein, single stereochemical isomers as well as enantiomers, diastereomers, cis / trans conformers and rotational isomers and their racemic and non-racemic mixtures are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.

[0043] Oxybutynin is the common name for a drug substance with the chemical name 4-diethylamino-2-butynylphenylcyclohexyl glycolate or 4-(diethylamino)but-2-ynyl 2-cyclohexyl-2-hydroxy-2-phenyl acetate and its pharmaceutically acceptable salts. In various embodiments, oxybutynin can be a racemic mixture of R- and S-enantiomers, or a separated enantiomer, such as the R-enantiomer. In various embodiments, oxybutynin can be oxybutynin hydrochloride or (R)-oxybutynin hydrochloride.

[0044] Acetazolamide is the common name for a drug substance with the chemical name N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide and its pharmaceutically acceptable salts. Acetazolamide is available as a generic medication and is sold under the trade names Diamox, Dacarb, etc.

[0045] "Cannabinoids" are a group of compounds including endocannabinoids, phytocannabinoids and compounds that are neither endocannabinoids nor phytocannabinoids (hereinafter "synthetic cannabinoids"). "Endocannabinoids" are endogenous cannabinoids that are high affinity ligands for CB1 and CB2 receptors. "Phytocannabinoids" are cannabinoids that originate from nature and can be found in the cannabis plant. Phytocannabinoids can be present in extracts including plant drug substances that have been isolated or synthetically regenerated. "Synthetic cannabinoids" are those compounds that are able to interact with cannabinoid receptors (CB1 and / or CB2) but cannot be found endogenously or in the cannabis plant.

[0046] A "non-THC cannabinoid" is a cannabinoid described herein that is not THC (Δ-9-tetrahydrocannabinol (Δ9-THC)) or any homologue or isomer thereof (e.g., THC, dronabinol, CBN, CBO, D8-THC, trans-A10-THC, cis-A10-THC, THCV, A8-THCV, or A9-THCV). A "non-TCH cannabinoid" may also be a cannabinoid that does not contain Δ-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 cannabichromene (CBL), or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the method includes administering a dose of about 0.5 mg to about 300 mg of CBD (e.g., every day). In some embodiments, the dose of CBD or a pharmaceutically acceptable salt thereof is about 1 mg 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.

[0048] In some embodiments, the method comprises administering a dose of about 100 mg to about 500 mg of sultiazem or a pharmaceutically acceptable salt thereof (e.g., per day). In some embodiments, the dose of sultiazem or a pharmaceutically acceptable salt thereof is about 200 mg to about 400 mg. In some embodiments, sultiazem is administered orally.

[0049] In some embodiments, the method comprises administering a dose of about 0.1 mg to about 30 mg of THC. In some embodiments, the method comprises administering a dose of about 1 mg to about 20 mg of THC. In some embodiments, the dose of THC or a pharmaceutically acceptable salt thereof is about 0.5 mg to about 20 mg. In some embodiments, the dose of THC or a pharmaceutically acceptable salt thereof is about 0.25 mg to about 10 mg. In some embodiments, THC is administered orally. In some embodiments, THC is administered sublingually.

[0050] In some embodiments, the method comprises administering a dose of about 1 mg to about 20 mg of dronabinol (e.g., per day). In some embodiments, the method comprises administering a dose of about 2.5 mg to about 10 mg of dronabinol (e.g., per day). In some embodiments, the method comprises administering a dose of about 5 mg to about 10 mg of dronabinol (e.g., per day). In some embodiments, the method comprises administering a dose of about 5 mg of dronabinol (e.g., per day). In some embodiments, the method comprises administering a dose of about 10 mg of dronabinol (e.g., per day).

[0051] In some embodiments, the method comprises administering nabilone (eg, daily) at a dose of about 0.25 mg to about 20 mg (eg, about 0.25 mg to about 2 mg).

[0052] In some embodiments, the method includes administering a dose of about 50 mg to about 1000 mg of CAI (e.g., acetazolamide), a dose of about 100 mg to about 800 mg of CAI (e.g., acetazolamide), a dose of about 250 mg to about 750 mg of CAI (e.g., acetazolamide), a dose of about 500 mg to about 750 mg of CAI (e.g., acetazolamide), or a dose of about 450 mg to about 650 mg of CAI (e.g., acetazolamide). In some embodiments, CAI is administered daily. In some embodiments, CAI or a pharmaceutically acceptable salt thereof is administered daily before sleep time, for example, immediately before sleep time or 15-60 minutes before sleep time.

[0053] In methods comprising administering an MRA such as oxybutynin or (R)-oxybutynin, or a pharmaceutically acceptable salt thereof (or another MRA), the dose of oxybutynin or (R)-oxybutynin, or a pharmaceutically acceptable salt thereof, can be from about 1 mg to about 25 mg (or an equivalent dose of another MRA), or in some embodiments, from about 2 mg to about 15 mg. In some embodiments, the dose of oxybutynin or a pharmaceutically acceptable salt thereof is from about 2.5 mg to about 10 mg, for example, 5 mg. In some embodiments, the dose of (R)-oxybutynin or a pharmaceutically acceptable salt thereof is from about 1 mg to about 5 mg, for example, 2.5 mg. In some embodiments, the dose of oxybutynin or (R)-oxybutynin, or a pharmaceutically acceptable salt thereof, is from about 1 mg to about 10 mg.

[0054] Pharmaceutical composition

[0055] Also provided herein is a pharmaceutical composition comprising (i) a cannabinoid and (ii) a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, esoxazolid, topiramate and sultiamide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, wherein the composition does not comprise 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, wherein the composition does not comprise a norepinephrine reuptake inhibitor (NRI). In some embodiments, the pharmaceutical composition further comprises a muscarinic receptor antagonist (MRA). Cannabinoids, non-THC cannabinoids, CAI and optionally MRA are active pharmaceutical ingredients of the pharmaceutical composition. The active pharmaceutical ingredient may be in a single composition or in separate compositions. In some embodiments, the pharmaceutical composition does not comprise a norepinephrine reuptake inhibitor (NRI).

[0056] Exemplary cannabinoids include cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabichromene (CBL), cannabinol (CBN), cannabigerol propyl variant (CBNV), dihydroxycannabinol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THCV) and tetrahydrocannabinolic acid (THCVA), and pharmaceutically acceptable salts thereof, or any combination thereof.

[0057] In some embodiments, the cannabinoid is CBD.

[0058] 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., nabilone). In some embodiments, the cannabinoid is an enantiomerically pure form of THC (e.g., dronabinol). Dronabinol is synthetic delta-9-tetrahydrocannabinol (delta-9-THC).

[0059] Additional exemplary cannabinoids include commercially available cannabinoids, e.g. (CBD oral solution), (nabiximols), (Nabilon), (Dronabinol) and (rimonabant).

[0060] 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 cocrystal), GWP-42006), CMX-020, ECP022A, Dronabinol buccal, Nabiolone controlled release controlled release), NE-1940, Olorinab, Drinabant, MDMB-FUBINACA, 5F-AB-PINACA, 5F-ADB, 5F-AMB, 5F-APINAC A. AB-FUBINACA, AB-CHFUPYCA, AB-CHMINACA, AB-PINACA, ADB-CHMINACA, ADB-FUBINACA, ADSB-FUB-187, ADB-PINACA, ADB ICA, 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, Levonantradol, AM-2201, MEPIRAPIM, JWH-133 and Levonantradol.

[0061] Exemplary non-THC cannabinoids include cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV) and cannabichromene (CBL), or any combination thereof, or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the non-THC cannabinoid is CBD or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, CBD or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5 mg to about 300 mg. In some embodiments, CBD or a pharmaceutically acceptable salt thereof is present in an amount of about 1 mg 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.

[0064] In some embodiments, THC or a pharmaceutically acceptable salt thereof is present in an amount of about 0.1 mg to about 30 mg. In some embodiments, THC or a pharmaceutically acceptable salt thereof is present in an amount of about 1 mg to about 20 mg. In some embodiments, THC or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5 mg to about 20 mg. In some embodiments, THC or a pharmaceutically acceptable salt thereof is present in an amount of about 0.25 mg to about 10 mg.

[0065] Exemplary CAIs include acetazolamide, dichlorphenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, esoxazolid, topiramate, sultiamide, and any combination thereof, including pharmaceutically acceptable salts thereof.

[0066] In some embodiments, the CAI is sultiamex or a pharmaceutically acceptable salt thereof. In some embodiments, sultiamex is present in an amount of about 200 mg to about 400 mg.

[0067] Exemplary muscarinic receptor antagonists (MRAs) include atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium chloride and oxybutynin, and pharmaceutically acceptable salts thereof, which are active on the M2 receptor. Other exemplary antimuscarinics include cintropine, benztropine, biperiden, cleridinium, cyclamine, dicyclomine, diphenylmanil, diphenidol, apromezine, glycopyrrolate, hexacycline, isopropylamide, mepenate, methicillin, methylscopolamine, hydroxybenzylamine, orphenamium, procyclidine, scopolamine, trimethoprim and trihexyphenidyl, and pharmaceutically acceptable salts thereof.

[0068] 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 substantially free of other stereoisomers of oxybutynin.

[0069] In some embodiments, oxybutynin or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 1 mg 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 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 1 mg to about 5 mg. In some embodiments, (i) cannabinoids, (ii) CAI, and optionally (iii) MRA are formulated in a single composition. In some embodiments, (i) non-THC cannabinoids, (ii) CAI, and optionally (iii) MRA are formulated in a single composition.

[0070] As used herein, the language "pharmaceutically acceptable carrier" includes saline, solvents, dispersion media, diluents, fillers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.

[0071] The active pharmaceutical ingredients (API) used in the present invention may be provided as pharmaceutically acceptable salts. For example, in some embodiments, when an MRA is present, oxybutynin is oxybutynin hydrochloride. In some embodiments, (R)-oxybutynin is (R)-oxybutynin hydrochloride.

[0072] A pharmaceutical composition is typically formulated to be compatible with its intended route of administration. Examples of routes of administration include systemic oral administration or transdermal administration.

[0073] Methods for preparing suitable pharmaceutical compositions are known in the art, see, for example, Remington: The Science and Practice of Pharmacy, 21st edition, 2005; and books in the series Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, oral compositions typically include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound (one or more) can be combined with an excipient and used in the form of a pill, tablet, lozenge or capsule (e.g., gelatin capsule). Oral compositions can also be prepared using a fluid carrier. In some embodiments, the composition according to the present invention can be a unit dosage form. In some embodiments, the composition according to the present invention can be a solid dosage form, such as a tablet or capsule.

[0074] Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, and the like may contain any of the following ingredients or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, 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 flavorings such as peppermint, methyl salicylate, or orange flavoring.

[0075] Systemic administration of compounds as described herein can also be by transdermal means, for example, using a patch, gel or lotion to be applied to the skin. For transdermal administration, a penetrant suitable for penetrating the epidermal barrier can be used in the formulation. Such penetrants are generally known in the art. For example, for transdermal administration, the active compound can be formulated into an ointment, salve, gel or cream as generally known in the art. The gel and / or lotion can be provided in a separate pouch or by a metered pump for daily application; see, for example, Cohn et al., Ther Adv Urol. April 2016; 8(2): 83-90.

[0076] In one embodiment, the therapeutic compound is prepared with a carrier that will protect the therapeutic compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Such preparations can be prepared using standard techniques, or commercially available, for example, from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal 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 described in U.S. Patent No. 4,522,811.

[0077] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration or use in the methods described herein.

[0078] In some embodiments, the pharmaceutical compositions disclosed herein are used to treat conditions associated with collapse of the pharyngeal airway muscles during sleep. In some embodiments, the condition associated with collapse of the pharyngeal airway muscles is sleep apnea (e.g., obstructive sleep apnea (OSA)) or snoring (e.g., simple snoring).

[0079] Kits and Combos

[0080] Also provided herein is a kit comprising (i) a cannabinoid and (ii) a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, esoxazolid, topiramate and sultiamide, or a pharmaceutically acceptable salt thereof, and optionally (iii) a muscarinic receptor antagonist (MRA), wherein the kit does not contain a norepinephrine reuptake inhibitor (NRI). Also provided herein is 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 contain a norepinephrine reuptake inhibitor (NRI). For example, the kit may include separate pharmaceutical compositions, wherein each composition lacks a norepinephrine reuptake inhibitor (NRI). The kit can be used to treat a subject suffering from a condition associated with pharyngeal airway collapse. Various embodiments of the kit will be apparent from the detailed description provided herein, including from the compositions and methods described herein.

[0081] Also provided herein is a cannabinoid and a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, esoxozolamide, topiramate and sultiamide, or a pharmaceutically acceptable salt thereof, and optionally a muscarinic receptor antagonist (MRA) for use in treating a subject suffering from a condition associated with pharyngeal airway collapse in the absence of NRI therapy.

[0082] Also provided herein are non-THC cannabinoids and carbonic anhydrase inhibitors (CAIs), or pharmaceutically acceptable salts thereof, and optionally muscarinic receptor antagonists (MRAs), for use in the treatment of subjects with conditions associated with pharyngeal airway collapse in the absence of NRI therapy. Also provided herein are cannabinoids and carbonic anhydrase inhibitors (CAIs) selected from the group consisting of dichlorphenamide, zonisamide, esoxozolamide, topiramate and sultiamide, or pharmaceutically acceptable salts thereof, and optionally muscarinic receptor antagonists (MRAs), for use in the treatment of subjects with conditions associated with pharyngeal airway collapse in the absence of NRI therapy. Also provided herein are non-THC cannabinoids and carbonic anhydrase inhibitors (CAIs), or pharmaceutically acceptable salts thereof, and optionally muscarinic receptor antagonists (MRAs), for use in the treatment of subjects with conditions associated with pharyngeal airway collapse in the absence of NRI therapy. The therapeutic combination may be used to treat conditions associated with pharyngeal airway collapse, such as sleep apnea or snoring.

[0083] Various embodiments of combinations and therapeutic combinations will be apparent from the detailed description provided herein, including from the compositions and methods described herein.

[0084] Example

[0085] The present invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0086] Example 1. Crossover study

[0087] A placebo-controlled, double-blind, randomized, crossover trial was conducted in human patients with OSA. Participants received the following treatments in random order 30 minutes before sleep: (1) a cannabinoid (e.g., CBD or THC) once daily plus a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, esoxozolid, topiramate, and sulthiamide, or placebo; or (2) a non-THC cannabinoid (e.g., CBD) once daily plus a CAI or placebo. The ability of the treatment to reduce the apnea-hypopnea index and improve OSA severity was evaluated. Other benefits evaluated may be increased genioglossus responsiveness to ventilatory drive, increased upper airway muscle activity, improved ventilation, increased oxygen levels (SaO2), increased total sleep time, improved hypoxic burden, and improved sleep efficiency.

[0088] Other Implementations

[0089] It should be understood that although the invention has been described in conjunction with the detailed description of the invention, the foregoing description is intended to illustrate rather than limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the appended claims.

Claims

1. A method of treating a subject suffering from a condition associated with pharyngeal airway collapse, the method comprising administering to a subject in need thereof, 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 dichlorphenamide, zonisamide, esoxozolid, topiramate and sultiamide, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the (i) 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), cannabichromene (CBL), cannabinol (CBN), cannabigerol propyl variant (CBNV), dihydroxycannabinol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THCV) and tetrahydrocannabinolic acid (THCVA), or any combination thereof, or a pharmaceutically acceptable salt thereof.

3. The method of claim 2, wherein the cannabinoid is CBD.

4. The method of claim 2, wherein the cannabinoid is THC.

5. The method of claim 1, wherein the (i) cannabinoid is dronabinol.

6. The method according to any one of claims 1-5, wherein the CAI is sultiazem or a pharmaceutically acceptable salt thereof.

7. The method of claim 6, wherein the sultiazem or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg to about 400 mg.

8. The method of claim 3, wherein CBD is administered at a dose of about 0.5 mg to about 300 mg.

9. The method of claim 4, wherein THC is administered at a dose of about 0.1 mg to about 30 mg.

10. The method of any one of claims 1-9, wherein the method further comprises administering to the subject (iii) a muscarinic receptor antagonist (MRA).

11. The method of claim 10, wherein the MRA is selected from the group consisting of atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium chloride and oxybutynin, or a pharmaceutically acceptable salt thereof.

12. The method of claim 10, wherein the MRA is selected from the group consisting of: sinotropin, benztropine, biperiden, cleridinium, cyclamine, dicyclomine, diphenylmanil, diphenidol, epromezine, glycopyrrolate, hexacycline, isopropylamide, mepenzolate, methicillin, methylscopolamine, hydroxybenzylamine, orphenadrine, procyclidine, scopolamine, trimethoprim, and trihexyphenidyl, or a pharmaceutically acceptable salt thereof.

13. The method of claim 11, wherein the MRA is oxybutynin or a pharmaceutically acceptable salt thereof.

14. The method of claim 11, wherein the MRA is (R)-oxybutynin or a pharmaceutically acceptable salt thereof.

15. The method of claim 13, wherein the oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 15 mg.

16. The method of claim 15, wherein the oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 2 mg to about 10 mg.

17. The method of claim 14, wherein the (R)-oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 mg to about 10 mg.

18. The method of claim 17, wherein the (R)-oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 5 mg.

19. The method of any one of claims 1-9, wherein the (i) cannabinoid and (ii) CAI are administered as a single composition.

20. The method of any one of claims 10-19, wherein the (i) cannabinoid, (ii) CAI, and (iii) MRA are administered as a single composition.

21. The method of claim 19 or 20, wherein the single composition is in an oral administration form.

22. The method of claim 21, wherein the oral administration form is a syrup, pill, tablet, lozenge, capsule or patch.

23. The method of any one of claims 1-22, wherein the condition associated with pharyngeal airway collapse is sleep apnea.

24. The method of claim 23, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA).

25. The method of any one of claims 1-22, wherein the condition associated with pharyngeal airway collapse is snoring.

26. The method of claim 25, wherein the condition associated with pharyngeal airway collapse is snoring alone.

27. The method of any one of claims 1-26, wherein the subject is in a non-fully conscious state.

28. The method of claim 27, wherein the non-fully conscious state is sleep.

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

30. The method of claim 29, wherein the (i) 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 cannabichromene (CBL), or any combination thereof, or a pharmaceutically acceptable salt thereof.

31. The method of claim 30, wherein the non-THC cannabinoid is CBD.

32. The method of claim 29, wherein the (ii) CAI is selected from the group consisting of acetazolamide, dichlorphenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, esoxazolidone, topiramate, sultiamethane, or a pharmaceutically acceptable salt thereof.

33. The method of claim 32, wherein the CAI is acetazolamide or a pharmaceutically acceptable salt thereof.

34. The method of any one of claims 29-33, wherein the CAI, such as acetazolamide, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 250 mg to about 750 mg.

35. The method of claim 34, wherein the CAI, such as acetazolamide, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 500 mg.

36. The method of claim 31 , wherein the CBD is administered at a dose of about 0.5 mg to about 300 mg.

37. The method of any one of claims 29-36, wherein the method further comprises administering to the subject (iii) a muscarinic receptor antagonist (MRA).

38. The method of claim 37, wherein the MRA is selected from the group consisting of atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium chloride, and oxybutynin, or a pharmaceutically acceptable salt thereof.

39. The method of claim 37, wherein the MRA is selected from the group consisting of: sinotropin, benztropine, biperiden, cleridinium, cyclimine, dicyclomine, diphenylmanil, diphenidol, epromezine, glycopyrrolate, hexacycline, isopropylamide, mepenzolate, methicillin, methylscopolamine, hydroxybenzylamine, orphenadrine, procyclidine, scopolamine, trimethoprim, and trihexyphenidyl, or a pharmaceutically acceptable salt thereof.

40. The method of claim 38, wherein the MRA is oxybutynin or a pharmaceutically acceptable salt thereof.

41. The method of claim 38, wherein the MRA is (R)-oxybutynin or a pharmaceutically acceptable salt thereof.

42. The method of claim 40, wherein the oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 15 mg.

43. The method of claim 42, wherein the oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 2 mg to about 10 mg.

44. The method of claim 41, wherein the (R)-oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 mg to about 10 mg.

45. The method of claim 44, wherein the (R)-oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 5 mg.

46. ​​The method of any one of claims 29-36, wherein the (i) non-THC cannabinoid and (ii) CAI are administered in a single composition.

47. The method of any one of claims 37-45, wherein the (i) non-THC cannabinoid, (ii) CAI, and (iii) MRA are administered in a single composition.

48. The method of claim 46 or 47, wherein the single composition is in an oral administration form.

49. The method of claim 48, wherein the oral administration form is a syrup, pill, tablet, lozenge, capsule or patch.

50. The method of any one of claims 29-49, wherein the condition associated with pharyngeal airway collapse is sleep apnea.

51. The method of claim 50, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA).

52. The method of any one of claims 29-49, wherein the condition associated with pharyngeal airway collapse is snoring.

53. The method of claim 52, wherein the condition associated with pharyngeal airway collapse is simple snoring.

54. The method of any one of claims 29-53, wherein the subject is in a non-fully conscious state.

55. The method of claim 54, wherein the non-fully conscious state is sleep.

56. A pharmaceutical composition comprising (i) a cannabinoid and (ii) a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, esoxazolidone, topiramate and sultiamide, 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).

57. The composition of claim 56, wherein the (i) 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), cannabichromene (CBL), cannabinol (CBN), cannabigerol propyl variant (CBNV), dihydroxycannabinol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THCV) and tetrahydrocannabinolic acid (THCVA), or any combination thereof, or a pharmaceutically acceptable salt thereof.

58. The composition of claim 57, wherein the cannabinoid is CBD.

59. The composition of claim 57, wherein the cannabinoid is THC.

60. The composition of claim 56, wherein the (i) cannabinoid is dronabinol.

61. The composition of any one of claims 56-60, wherein the CAI is sultiazem or a pharmaceutically acceptable salt thereof.

62. The composition of claim 61, wherein the sultiamethane or a pharmaceutically acceptable salt thereof is present in an amount of about 200 mg to about 400 mg.

63. The composition of claim 58, wherein CBD is present in an amount of about 0.5 mg to about 300 mg.

64. The composition of claim 59, wherein THC is present in an amount of about 0.1 mg to about 30 mg.

65. 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 comprise a norepinephrine reuptake inhibitor (NRI).

66. The composition of claim 65, wherein the (i) 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 cannabichromene (CBL), or any combination thereof, or a pharmaceutically acceptable salt thereof.

67. The composition of claim 66, wherein the non-THC cannabinoid is CBD.

68. The composition of claim 65, wherein the (ii) CAI is selected from the group consisting of acetazolamide, dichlorphenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, esoxazolidone, topiramate, sultiamethane, or a pharmaceutically acceptable salt thereof.

69. The composition of claim 68, wherein the CAI is acetazolamide or a pharmaceutically acceptable salt thereof.

70. The composition of any one of claims 65-69, wherein the CAI, such as acetazolamide, or a pharmaceutically acceptable salt thereof is present in an amount of about 250 mg to about 750 mg.

71. The composition of claim 70, wherein the CAI, such as acetazolamide, or a pharmaceutically acceptable salt thereof, is present in an amount of about 500 mg.

72. The composition of claim 67, wherein CBD is present in an amount of about 0.5 mg to about 300 mg.

73. The composition of any one of claims 56-72, wherein the composition further comprises (iii) a muscarinic receptor antagonist (MRA).

74. The composition of claim 73, wherein the MRA is selected from the group consisting of atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium chloride and oxybutynin, or a pharmaceutically acceptable salt thereof.

75. The composition of claim 73, wherein the MRA is selected from the group consisting of: sinotropin, benztropine, biperiden, cleridinium, cyclamine, dicyclomine, diphenylmanil, diphenidol, epromezine, glycopyrrolate, hexacycline, isopropylamide, mepenzolate, methicillin, methylscopolamine, hydroxybenzylamine, orphenadrine, procyclidine, scopolamine, trimethoprim, and trihexyphenidyl, or a pharmaceutically acceptable salt thereof.

76. The composition of claim 74, wherein the MRA is oxybutynin or a pharmaceutically acceptable salt thereof.

77. The composition of claim 74, wherein the MRA is (R)-oxybutynin or a pharmaceutically acceptable salt thereof.

78. The composition of claim 76, wherein the oxybutynin or a pharmaceutically acceptable salt thereof is present in an amount of about 1 mg to about 15 mg.

79. The composition of claim 76, wherein the oxybutynin or a pharmaceutically acceptable salt thereof is present in an amount of about 2 mg to about 10 mg.

80. The composition of claim 77, wherein the (R)-oxybutynin or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5 mg to about 10 mg.

81. The composition of claim 77, wherein the (R)-oxybutynin or a pharmaceutically acceptable salt thereof is present in an amount of about 1 mg to about 5 mg.

82. The composition of any one of claims 56-64, wherein the (i) cannabinoid, (ii) CAI, and optionally (iii) MRA are formulated in a single composition.

83. The composition of any one of claims 65-81, wherein the (i) non-THC cannabinoid, (ii) CAI, and optionally (iii) MRA are formulated in a single composition.

84. The composition of claim 82 or 83, wherein the single composition is in an oral administration form.

85. The composition of claim 84, wherein the oral administration form is a syrup, pill, tablet, lozenge, capsule or patch.

86. A composition according to any one of claims 56-85 for use in treating a subject suffering from a condition associated with pharyngeal airway collapse.

87. The composition of claim 86, wherein the condition associated with pharyngeal airway collapse is sleep apnea.

88. The composition of claim 86, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA).

89. The composition of claim 86, wherein the condition associated with pharyngeal airway collapse is snoring.

90. The composition of claim 89, wherein the condition associated with pharyngeal airway collapse is simple snoring.

91. The composition of any one of claims 86-90, wherein the subject is in a non-fully conscious state.

92. The composition of claim 91, wherein the non-fully conscious state is sleep.

93. A kit comprising (i) a cannabinoid and (ii) a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, esoxozolid, topiramate and sultiamide, or a pharmaceutically acceptable salt thereof, and optionally (iii) a muscarinic receptor antagonist (MRA), wherein the kit does not contain a norepinephrine reuptake inhibitor (NRI).

94. 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 contain a norepinephrine reuptake inhibitor (NRI).

95. A kit according to claim 93 or 94 for use in treating a subject suffering from a condition associated with pharyngeal airway collapse.

96. A cannabinoid and a carbonic anhydrase inhibitor (CAI) selected from the group consisting of dichlorphenamide, zonisamide, esoxozolamide, topiramate and sultiamide, or a pharmaceutically acceptable salt thereof, and optionally a muscarinic receptor antagonist (MRA), for use in treating a subject suffering from a condition associated with pharyngeal airway collapse in the absence of norepinephrine reuptake inhibitor (NRI) therapy.

97. 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 treating a subject suffering from a condition associated with pharyngeal airway collapse in the absence of norepinephrine reuptake inhibitor (NRI) therapy.

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