Methods and Compositions for Treating Sleep Apnea - Patent application

Abstract

Described herein are pharmaceutical compositions comprising a norepinephrine reuptake inhibitor (NRI) and a mineralocorticoid antagonist, and optionally a muscarinic receptor antagonist (MRA), and methods for treating sleep apnea.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 165,342, filed March 24, 2021, the entire contents of which are incorporated herein by reference.

[0002] The present invention provides pharmaceutical compositions comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a mineralocorticoid antagonist, and optionally further comprising (iii) a muscarinic receptor antagonist (MRA), and further provides methods for treating sleep apnea. [Background technology]

[0003] Obstructive sleep apnea (OSA) is a common disorder caused by the collapse of the pharyngeal airway during sleep. OSA can pose serious health risks. Summary of the Invention

[0004] One aspect of the invention provides a method of treating a subject having a disease associated with pharyngeal airway collapse, the method comprising administering to a subject in need of treatment effective amounts of (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a mineralocorticoid antagonist.

[0005] Embodiments of the invention according to this aspect may include one or more of the following optional features: In some embodiments, the NRI is a norepinephrine selective reuptake inhibitor (NSRI). In some embodiments, the NSRI is selected from the group consisting of amidaline, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine, or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is a norepinephrine nonselective reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, radafaxine, tapentadol, teniloxazine, and venlafaxine, or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is selected from the group consisting of atomoxetine, or a pharmaceutically acceptable salt thereof, and reboxetine, or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is atomoxetine, or a pharmaceutically acceptable salt thereof. In some embodiments, the mineralocorticoid antagonist is selected from the group consisting of spironolactone, eplerenone, canrenone, finerenone, mexrenone, canrenoic acid, drospirenone, prorenone, apararenone, and esaxerenone, or a pharmaceutically acceptable salt thereof. In some embodiments, the mineralocorticoid antagonist is spironolactone or a pharmaceutically acceptable salt thereof. In some embodiments, the mineralocorticoid antagonist is spironolactone. In some embodiments, the method further comprises (iii) administering a muscarinic receptor antagonist (MRA) to the subject.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, cyclimine, 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 one embodiment, the MRA is (R)-oxybutynin or a pharma- ceutically acceptable salt thereof. In one embodiment, the atomoxetine or a pharma- ceutically acceptable salt thereof is administered at a dose of about 20 mg to about 200 mg. In one embodiment, the atomoxetine or a pharma- ceutically acceptable salt thereof is administered at a dose of about 25 mg to about 100 mg. In one embodiment, the spironolactone or a pharma- ceutically acceptable salt thereof is administered at a dose of about 10 mg to about 100 mg. In one embodiment, the spironolactone or a pharma- ceutically acceptable salt thereof is administered at a dose of about 20 mg to about 80 mg. In one embodiment, the oxybutynin or a pharma- ceutically acceptable salt thereof is administered at a dose of about 1 mg to about 15 mg. In one embodiment, the oxybutynin or a pharma- ceutically acceptable salt thereof is administered at a dose of about 2 mg to about 10 mg. In some embodiments, the (R)-oxybutynin or a pharma- ceutically acceptable salt thereof is administered at a dose of about 0.5 mg to about 10 mg. In some embodiments, the (R)-oxybutynin or a pharma- ceutically acceptable salt thereof is administered at a dose of about 1 mg to about 5 mg. In some embodiments, the NRI and mineralocorticoid antagonist are administered in a single composition.In some embodiments, the NRI, MRA, and mineralocorticoid antagonist are administered in a single composition. In some embodiments, the single composition is an oral dosage form. In some embodiments, the oral dosage form is a syrup, pill, tablet, lozenge, capsule, or patch. In some embodiments, the disease associated with the collapse of the pharyngeal airway is sleep apnea. In some embodiments, the disease associated with the collapse of the pharyngeal airway is obstructive sleep apnea (OSA). In some embodiments, the disease associated with the collapse of the pharyngeal airway is snoring. In some embodiments, the disease associated with the collapse of the pharyngeal airway is simple snoring. In some embodiments, the subject is in a state of insufficient consciousness. In some embodiments, the state of insufficient consciousness is sleep. In some embodiments, the subject has hypertension.

[0006] Another aspect of the present invention provides a pharmaceutical composition comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a mineralocorticoid antagonist in a pharma- ceutically acceptable carrier.

[0007] Embodiments of the invention according to this aspect may include one or more of the following optional features: In some embodiments, the NRI is a norepinephrine selective reuptake inhibitor (NSRI). In some embodiments, the NSRI is selected from the group consisting of amidaline, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine, or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is a norepinephrine nonselective reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, radafaxine, tapentadol, teniloxazine, and venlafaxine, or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is selected from the group consisting of atomoxetine, or a pharmaceutically acceptable salt thereof, and reboxetine, or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is atomoxetine, or a pharmaceutically acceptable salt thereof. In some embodiments, the mineralocorticoid antagonist is selected from the group consisting of spironolactone, eplerenone, canrenone, finerenone, mexrenone, canrenoic acid, drospirenone, prorenone, apararenone, and esaxerenone, or a pharmaceutically acceptable salt thereof. In some embodiments, the mineralocorticoid antagonist is spironolactone or a pharmaceutically acceptable salt thereof. In some embodiments, the mineralocorticoid antagonist is spironolactone. In some embodiments, the composition further comprises (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, cyclimine, 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 one embodiment, the MRA is (R)-oxybutynin or a pharma- ceutically acceptable salt thereof. In one embodiment, the atomoxetine or a pharma- ceutically acceptable salt thereof is present in an amount of about 20 mg to about 200 mg. In one embodiment, the atomoxetine or a pharma- ceutically acceptable salt thereof is present in an amount of about 25 mg to about 100 mg. In one embodiment, the spironolactone or a pharma- ceutically acceptable salt thereof is present in an amount of about 10 mg to about 100 mg. In one embodiment, the spironolactone or a pharma- ceutically acceptable salt thereof is present in an amount of about 20 mg to about 80 mg. In one embodiment, the oxybutynin or a pharma- ceutically acceptable salt thereof is present in an amount of about 1 mg to about 15 mg. In one embodiment, the oxybutynin or a pharma- ceutically acceptable salt thereof is present in an amount of about 2 mg to about 10 mg. In one embodiment, the (R)-oxybutynin or a pharma- ceutically acceptable salt thereof is present in an amount of about 0.5 mg to about 10 mg. In some embodiments, the (R)-oxybutynin or a pharma- ceutically acceptable salt thereof is present in an amount of about 1 mg to about 5 mg. In some embodiments, the NRI and mineralocorticoid antagonist are formulated in a single composition. In some embodiments, the NRI, MRA, and mineralocorticoid antagonist 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, pill, tablet, lozenge, capsule, or patch. In some embodiments, the composition is for treating a subject with a disease associated with collapse of the pharyngeal airway. In some embodiments, the disease associated with collapse of the pharyngeal airway is sleep apnea. In some embodiments, the disease associated with collapse of the pharyngeal airway is obstructive sleep apnea (OSA). In some embodiments, the disease associated with collapse of the pharyngeal airway is snoring. In some embodiments, the disease associated with collapse of the pharyngeal airway is simple snoring. In some embodiments, the subject is in a state of insufficient consciousness. In some embodiments, the state of insufficient consciousness is sleep. In some embodiments, the subject has high blood pressure.

[0008] Another aspect of the invention provides a kit comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a mineralocorticoid antagonist, and optionally further comprising (iii) a muscarinic receptor antagonist, in one embodiment for treating a subject having a disorder associated with collapse of the pharyngeal airway.

[0009] Another aspect of the invention provides a norepinephrine reuptake inhibitor (NRI) and a mineralocorticoid antagonist, and optionally a muscarinic receptor antagonist, for the treatment of a subject having a disorder associated with collapse of the pharyngeal airway.

[0010] Another aspect of the present invention provides a therapeutic combination of (i) a norepinephrine reuptake inhibitor (NRI), (ii) a mineralocorticoid antagonist, and optionally (iii) a muscarinic receptor antagonist, for the treatment of a subject having a disease associated with collapse of the pharyngeal airway.

[0011] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Methods and materials for use in the present invention are described herein, but other suitable methods and materials known in the art can 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 by reference in their entirety. In the event of any conflict, the present specification, including definitions, will control.

[0012] Other features and advantages of the invention will be apparent from the following detailed description and drawings, and from the claims.

[0013] The figures described below are illustrative and are not intended to limit the invention as recited in the claims. [Brief description of the drawings]

[0014] [Figure 1] Figure 1 shows a graph of obstructive apnea. The top channel shows the sleep electroencephalogram (EEG) pattern. The next channel shows airflow. The next three channels show ventilatory efforts due to rib cage and abdominal movements and changes in esophageal pressure, all reflecting the effort of breathing into an obstructed upper airway. The final channel shows oxyhemoglobin saturation. [Diagram 2] FIG. 1 shows the test plan for Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] In humans, the pharyngeal airway region is held open by muscles, without bony or cartilaginous support. When these muscles relax during sleep, the pharynx can collapse and airflow can cease. As shown in Figure 1, ventilatory efforts continue and there are increasing attempts to overcome the obstruction, as indicated by increasing esophageal pressure changes. The diaphragm contracts against the obstructed airway, resulting in opposing rib cage and abdominal movements, forcing the abdominal wall to inflate and the chest wall to retract inward.

[0016] Increased respiratory effort results in arousal from sleep, visible on the EEG (Figure 1), to open the airway and resume normal breathing. The lack of airflow during apnea also results in hypoxia, indicated by a drop in oxyhemoglobin saturation (Figure 1). Severity is commonly measured using the apnea-hypopnea index (AHI). The AHI is the average number of combined apneas (cessation of breathing for at least 10 seconds) and hypopneas (drops in airflow and oxygen saturation) occurring 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).

[0017] Figure 1 shows a graph of obstructive apnea. The top channel shows the sleep electroencephalogram (EEG) pattern. The next channel shows airflow. The next three channels show ventilatory efforts due to rib cage and abdominal movements and changes in esophageal pressure, all of which reflect the effort of breathing into an obstructed upper airway. The final channel shows oxyhemoglobin saturation.

[0018] Using a strict definition of OSA (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 people 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 an aging population and increasing rates of obesity. OSA is associated with significant morbidity and economic costs, including hypertension, diabetes, cardiovascular disease, motor vehicle accidents, occupational injuries, and fatigue / reduced productivity (Young et al.,WMJ 2009;108:246; Peppard et al.,Am J Epidemiol 2013;177:1006).

[0019] The current primary treatment is continuous positive airway pressure (CPAP). Although CPAP is effective in almost all patients, with approximately 85% of diagnosed patients being prescribed CPAP, compliance is low. Patients find CPAP uncomfortable and often cannot tolerate it. At least 30% of patients (up to 80%) are typically noncompliant and therefore untreated (Weaver, Proc Am Thorac Soc. 2008 Feb 15;5(2):173-178). Other treatments with variable success rates include oral appliances (10%) and surgery (5%), neither of which are considered effective in the general population.

[0020] Searches for drugs that would activate pharyngeal muscles in sleeping humans have been disappointing: serotonin reuptake inhibitors, tricyclic antidepressants and sedatives have all been tested in humans and shown to be ineffective in reducing the severity of OSA. 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. See 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).

[0021] A recent study showed that a combination of atomoxetine and oxybutynin, called "Atomoxetine," administered before bedtime, reduced OSA in patients with a wide range of severity. The combination of atomoxetine and oxybutynin, administered overnight, reduced the number of obstructive events, improved overnight oxygen desaturation, and improved genioglossus activity in a randomized group of patients with OSA. Data collected in a proof-of-concept study showed that it is possible to improve or eliminate OSA by systemically administering a drug with a specific neurotransmitter profile. See Taranto-Montemurro, Luigi et al. "The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover Trial." American journal of respiratory and critical care medicine vol.199,10(2019):1267-1276.

[0022] There remains a need for additional therapies to treat disorders associated with pharyngeal airway collapse, such as sleep apnea.

[0023] Treatment method

[0024] The methods described herein include methods for treating disorders associated with collapse of pharyngeal airway muscles during sleep. In some embodiments, the disorder is sleep apnea (e.g., obstructive sleep apnea (OSA)) or snoring (e.g., simple snoring syndrome). In general, the methods include administering to a subject in need of treatment or determined to be in need of treatment a therapeutically effective amount of a norepinephrine reuptake inhibitor (NRI) and a mineralocorticoid antagonist, and optionally a muscarinic receptor antagonist (MRA), as known in the art and / or described herein. In some embodiments, the methods include administering to a subject in need of treatment or determined to be in need of treatment a therapeutically effective amount of atomoxetine or a pharmacologic acceptable salt thereof and spironolactone or a pharmacologic acceptable salt thereof, and optionally oxybutynin (e.g., (R)-oxybutynin) or a pharmacologic acceptable salt thereof.

[0025] The term "treatment" as used in this context means improving at least one symptom of a disease associated with collapse of the pharyngeal airway. In many cases, collapse of the pharyngeal airway during sleep leads to snoring and / or interruption of breathing (apnea or hypopnea), awakening from sleep, and reduced oxygen supply (hypoxemia). Thus, treatment can result in a reduction in snoring, apnea / hypopnea, sleep fragmentation, and hypoxemia. Administering a therapeutically effective amount of a compound described herein for treating a subject with OSA can result in a reduction in AHI. Measurement of OSA disease and symptoms can be performed, for example, by polysomnography (PSG).

[0026] In general, the "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response, for example, an amount sufficient to treat a disease associated with the collapse of the pharyngeal airway, for example, an amount sufficient to treat sleep apnea or snoring.As will be apparent to those skilled in the art, the effective amount of the compound of the present invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, weight, health condition, etc. of the subject.The effective amount includes therapeutic and prophylactic treatments.

[0027] An effective amount can be provided in one or more administrations, applications or dosages. The composition can be administered from one or more times daily to one or more times weekly (including once every other day). In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily before sleep time, e.g., immediately before sleep time or 15-60 minutes before sleep time. As will be apparent to one of skill in the art, there are factors that can affect the dosage and timing required to effectively treat a subject, 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. Furthermore, treatment of a subject with a therapeutically effective amount of a therapeutic compound described herein can include a single treatment or a series of multiple treatments.

[0028] Unless otherwise specified, the term "therapeutically effective amount" of a compound as used herein refers to an amount sufficient to provide a therapeutically beneficial effect in the treatment of a disease, disorder, or condition, or an amount sufficient to slow or minimize the progression of one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent that provides a therapeutically beneficial effect, alone or in combination with other therapies, in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or eliminates the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0029] 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, quails, turkeys, or mammals), specifically "mammals," including non-primates (e.g., cows, 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 livestock animal (e.g., horses, cows, pigs, or sheep), a pet (e.g., a dog, cat, guinea pig, or rabbit), or the like. In a preferred embodiment, the subject is a human.

[0030] As used herein, the term "pharmaceutical acceptable" means approved or approvable by a regulatory agency of the U.S. Federal or state government, or a corresponding agency in a country other than the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0031] The term "unit dosage form" as used herein 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, a capsule, or a tablet.In some embodiments, the unit dosage form is a capsule.

[0032] The term "solid dosage form" as used herein means a solid pharmaceutical dosage form(s), such as, for example, tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalants and chewables.

[0033] For the compounds disclosed herein, single stereochemical isomers as well as enantiomers, diastereomers, cis / trans conformers, and rotamers, as well as racemic and non-racemic mixtures thereof, are within the scope of the invention. Unless otherwise specified, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.

[0034] Atomoxetine is the generic name for the pharmaceutical agent whose chemical name is (-)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine and its pharmaceutical salts. Atomoxetine is the R(-) isomer as determined by X-ray diffraction. In some embodiments, atomoxetine can be atomoxetine hydrochloride.

[0035] Spironolactone is the generic name for the drug substance whose chemical name is 7α-acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone or S-[(7R,8R,9S,10R,13S,14S,17R)-10,13-dimethyl-3,5'-dioxospiro[2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-17,2'-oxolan]-7-yl]ethanethioate, and its pharmaceutical salts.

[0036] Oxybutynin is the generic name of the pharmaceutical substance whose chemical name is 4-diethylamino-2-butynylphenylcyclohexyl glycolate or 4-(diethylamino)but-2-ynyl 2-cyclohexyl-2-hydroxy-2-phenyl acetate and its pharma- ceutically acceptable salts.In various embodiments, oxybutynin can be a racemic mixture of R-enantiomer and S-enantiomer, or an isolated enantiomer, such as R-enantiomer.In various embodiments, oxybutynin can be oxybutynin chloride or (R)-oxybutynin chloride.

[0037] In certain embodiments, the method comprises administering a dose of atomoxetine or a pharma- ceutically acceptable salt thereof (or an equivalent dose of another NRI) of about 20 mg to about 200 mg. In certain embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 25 mg to about 100 mg. In certain embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 40 mg to about 80 mg. In certain embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 20 mg to about 50 mg. In certain embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 50 mg to about 100 mg. In certain embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 40 mg. In certain embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 80 mg.

[0038] In some embodiments, the method includes administering a dose of about 10 mg to about 200 mg of spironolactone or a pharma- ceutically acceptable salt thereof (or an equivalent dose of another mineralocorticoid antagonist). In some embodiments, the dose of spironolactone or a pharma- ceutically acceptable salt thereof is about 15 mg to about 100 mg. In some embodiments, the dose of spironolactone or a pharma- ceutically acceptable salt thereof is about 20 mg to about 80 mg. In some embodiments, the dose of spironolactone or a pharma- ceutically acceptable salt thereof is about 20 mg to about 40 mg. In some embodiments, the dose of spironolactone or a pharma- ceutically acceptable salt thereof is about 40 mg to about 80 mg. In some embodiments, the dose of spironolactone or a pharma- ceutically acceptable salt thereof is about 25 mg. In some embodiments, the dose of spironolactone or a pharma- ceutically acceptable salt thereof is about 50 mg.

[0039] In methods comprising administering oxybutynin or (R)-oxybutynin or a pharma- ceutically acceptable salt thereof (or another MRA), the dose of oxybutynin or (R)-oxybutynin or a pharma- ceutically acceptable salt thereof can be about 1 mg to about 25 mg (or the equivalent dose of another MRA), or in some embodiments, about 2 mg to about 15 mg. In some embodiments, the dose of oxybutynin or a pharma- ceutically acceptable salt thereof is about 2.5 mg to about 10 mg, for example, 5 mg. In some embodiments, the dose of (R)-oxybutynin or a pharma- ceutically acceptable salt thereof is about 1 mg to about 5 mg, for example, 2.5 mg. In some embodiments, the dose of oxybutynin or (R)-oxybutynin or a pharma- ceutically acceptable salt thereof is about 1 mg to about 10 mg.

[0040] In some embodiments, the method comprises administering 40 mg of atomoxetine hydrochloride and 25 mg of spironolactone. In some embodiments, the method comprises administering 40 mg of atomoxetine hydrochloride and 50 mg of spironolactone. In some embodiments, the method comprises administering 80 mg of atomoxetine hydrochloride and 25 mg of spironolactone. In some embodiments, the method comprises administering 80 mg of atomoxetine hydrochloride and 50 mg of spironolactone.

[0041] In some embodiments, the method further comprises administering (iv) an additional active agent that is a diuretic. The (iv) diuretic may or may not be used in combination with an MRA. In some embodiments, the diuretic is selected from the group consisting of chlorothiazide, hydrochlorothiazide, bendroflumethiazide, chlorthalidone, methyclothiazide, polythiazide, triamterene, furosemide, ethacrynic acid, metolazone, bumetanide, indapamide, amiloride, and torsemide, or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the subject has hypertension. In some embodiments, the subject is in a fluid retention state. For example, the fluid retention state can be due to hypertension, heart failure, or end-stage renal failure.

[0043] Pharmaceutical Compositions

[0044] Also provided herein is a pharmaceutical composition, which includes a norepinephrine reuptake inhibitor (NRI) and a mineralocorticoid antagonist as active ingredients, and may further include a muscarinic receptor antagonist (MRA) as an active ingredient. The active ingredients may be present in a single composition or in separate compositions. In one embodiment, the pharmaceutical composition includes atomoxetine or a pharma- ceutical acceptable salt thereof and spironolactone or a pharma-ceutical acceptable salt thereof as active ingredients, and may further include oxybutynin (e.g., (R)-oxybutynin) or a pharma-ceutical acceptable salt thereof as an active ingredient.

[0045] Specific norepinephrine reuptake inhibitors (NRIs) include selective NRIs, such as amidabutyric acid (UK-3540-1), atomoxetine (Strattera), CP-39,332, daredalin (UK-3557-15), edivoxetine (LY-2216684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY-94,939), reboxetine (Edronax, Vestra), talopram (Lu 3-010 ... 5-005), tandamin (AY-23,946), and viloxazine (Vivalan), as well as nonselective NRIs such as amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxin (GW-320659), and cyclosporine (cyclosporine). ), maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, radafaxine (GW-353,162), tapentadol (Nucynta), teniloxazine (Lucelan, Metatone) and venlafaxine, and pharmaceutically acceptable salts thereof.

[0046] In certain embodiments, the NRI is atomoxetine or a pharma- ceutically acceptable salt thereof.

[0047] Specific mineralocorticoid antagonists include spironolactone, eplerenone, canrenone, finerenone, mexrenone, canrenoic acid, drospirenone, prorenone, apararenone, and esaxerenone, and pharma- ceutically acceptable salts thereof.

[0048] In certain embodiments, the mineralocorticoid antagonist is spironolactone or a pharma- ceutically acceptable salt thereof.

[0049] Specific muscarinic receptor antagonists (MRAs) include atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium, and oxybutynin, and pharmaceutically acceptable salts thereof, which have activity at the M2 receptor. Other specific antimuscarinic agents include anisotropine, benztropine, biperiden, clidinium, cyclimine, dicyclomine, diphemanil, diphenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixene, methscopolamine, oxyphencyclimine, oxyphenonium, procyclidine, scopolamine, tridihexethyl, and trihexyphenidyl, and pharmaceutically acceptable salts thereof.

[0050] In some embodiments, the muscarinic receptor antagonist is oxybutynin or (R)-oxybutynin, or a pharma- ceutically acceptable salt thereof. As used herein, the term "(R)-oxybutynin" refers to the (R)-oxybutynin stereoisomer substantially free of other stereoisomers of oxybutynin. In some embodiments, the muscarinic receptor antagonist is fesoterodine.

[0051] In some embodiments, the pharmaceutical composition further comprises (iv) an additional active agent that is a diuretic. (iv) The composition that comprises a diuretic may or may not include an MRA. In some embodiments, the diuretic is selected from the group consisting of chlorothiazide, hydrochlorothiazide, bendroflumethiazide, chlorthalidone, methyclothiazide, polythiazide, triamterene, furosemide, ethacrynic acid, metolazone, bumetanide, indapamide, amiloride, and torsemide, or a pharmaceutically acceptable salt thereof.

[0052] Pharmaceutical compositions typically include a pharma- ceutically acceptable carrier. As used herein, the term "pharma- ceutically acceptable carrier" includes saline, solvents, dispersion media, diluents, fillers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration.

[0053] The active ingredient used in the present invention may be provided as a pharma- ceutically acceptable salt.For example, in some embodiments, oxybutynin is oxybutynin chloride.In some embodiments, (R)-oxybutynin is (R)-oxybutynin chloride.In some embodiments, atomoxetine is atomoxetine hydrochloride.

[0054] A pharmaceutical composition is typically formulated to be compatible with its intended route of administration, which includes systemic, oral, or transdermal administration.

[0055] Methods for formulating suitable pharmaceutical compositions are known in the art, see, for example, Remington: The Science and Practice of Pharmacy, 21st ed., 2005, and Drugs and the Pharmaceutical Sciences, a Series of Textbooks and Monographs (Dekker, NY). For example, oral compositions generally contain an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound(s) can be combined with an excipient and used in the form of pills, tablets, lozenges, or capsules (e.g., gelatin capsules). Oral compositions can also be prepared using fluid carriers. In some embodiments, the composition according to the present invention can be in unit dosage form. In some embodiments, the composition according to the present invention can be in solid dosage form, for example, tablets or capsules.

[0056] Pharmaceutically compatible binders and / or excipients can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; a filler such as starch or lactose; a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.

[0057] Systemic administration of the compounds described herein can also be performed by transdermal means, for example, by using a patch, gel, or lotion that is applied to the skin. For transdermal administration, a penetrant suitable for permeating 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. Gels and / or lotions can be provided in individual sachets or via a metered pump for daily use. See, for example, Cohn et al., Ther Adv Urol. 2016 Apr; 8(2): 83-90.

[0058] In one embodiment, the therapeutic compound is formulated with a carrier that will protect it from rapid elimination from the body, for example, a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and the like. Such formulations can be prepared using standard techniques or are commercially available, for example, from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions can also be used as pharma- ceutically acceptable carriers. They can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0059] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration or use in the methods described herein.

[0060] In some embodiments, the pharmaceutical composition is for treating a disease associated with collapse of the pharyngeal airway. In some embodiments, the disease is sleep apnea (e.g., OSA) or snoring (e.g., simple snoring syndrome). In some embodiments, a pharmaceutical composition for treating sleep apnea (e.g., OSA) or snoring (e.g., simple snoring syndrome) is provided herein, the pharmaceutical composition comprising atomoxetine or a pharmaceutically acceptable salt thereof and spironolactone or a pharmaceutically acceptable salt thereof, and may further comprise oxybutynin (e.g., (R)-oxybutynin) or a pharmaceutically acceptable salt thereof.

[0061] Kits and Combinations

[0062] Further provided herein is a kit, which includes (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a mineralocorticoid antagonist, and may further include (iii) a muscarinic receptor antagonist. For example, the kit may include multiple pharmaceutical compositions, each of which includes a single active ingredient, separately. The kit may be for treating a subject having a disease associated with the collapse of the pharyngeal airway. Various embodiments of the kit will be apparent from the detailed description provided herein. In some embodiments, the kit further includes an additional active agent that is a diuretic (e.g., chlorothiazide, hydrochlorothiazide, bendroflumethiazide, chlorthalidone, methyclothiazide, polythiazide, triamterene, furosemide, ethacrynic acid, metolazone, bumetanide, indapamide, amiloride, or torsemide, or a pharma- ceutically acceptable salt thereof).

[0063] Also provided herein is a norepinephrine reuptake inhibitor (NRI) and a mineralocorticoid antagonist, and optionally a muscarinic receptor antagonist, for treating a subject with a disease associated with the collapse of the pharyngeal airway. Also provided herein is a therapeutic combination of (i) a norepinephrine reuptake inhibitor (NRI), (ii) a mineralocorticoid antagonist, and optionally (iii) a muscarinic receptor antagonist, for treating a subject with a disease associated with the collapse of the pharyngeal airway. Various embodiments of the combination and therapeutic combination are apparent from the detailed description provided herein. In certain embodiments of the kit and combination of the present invention, the NRI is atomoxetine or a pharmaceutically acceptable salt thereof, the mineralocorticoid antagonist is spironolactone or a pharmaceutically acceptable salt thereof, and the MRA, when used, is oxybutynin (e.g., (R)-oxybutynin) or a pharmaceutically acceptable salt thereof. In certain embodiments, the combination or therapeutic combination further comprises an additional active agent that is a diuretic (e.g., chlorothiazide, hydrochlorothiazide, bendroflumethiazide, chlorthalidone, methyclothiazide, polythiazide, triamterene, furosemide, ethacrynic acid, metolazone, bumetanide, indapamide, amiloride, or torsemide, or a pharma- ceutically acceptable salt thereof). EXAMPLES

[0064] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0065] Example 1 A randomized, double-blind, two-period, multiple-dose crossover study to evaluate the efficacy and safety of atomoxetine plus spironolactone versus atomoxetine in patients with OSA and hypertension

[0066] The study in Example 1 is a randomized, double-blind, placebo-controlled, two-period, crossover study in patients with moderate to severe OSA. The study is designed to evaluate whether the addition of spironolactone to atomoxetine increases efficacy in a population with both hypertension and OSA. A screening exam and polysomnography (PSG) will be performed to ensure each participant meets the study inclusion criteria. Each participant will then be randomly assigned to receive a combination of the following for 10 nights: A 3-day low-dose run-in period of atomoxetine 40 mg + spironolactone 25 mg was followed by a 7-day full-dose period of atomoxetine 80 mg + spironolactone 50 mg. A 3-day low-dose run-in period of atomoxetine 40 mg plus spironolactone matching placebo, followed by a 7-day full-dose treatment period of atomoxetine 80 mg plus spironolactone matching placebo.

[0067] On day 9 of each treatment period (day 6 of full dose administration), a WatchPAT test and 24-hour blood pressure monitoring will be performed at home. On day 10 of each treatment period (day 7 of full dose administration), a PSG test and a WatchPAT test will be performed in hospital. There will be a washout period of at least 3 weeks between the two treatment periods.

[0068] The following endpoints are used: [Table 1]

[0069] Patients who met all inclusion criteria were randomly assigned to receive the experimental treatment for 10 days, 9 of which were administered at home and the final day in the laboratory prior to the evening of the PSG scan. A 3-day low-dose run-in period of atomoxetine 40 mg + spironolactone 25 mg was followed by a 7-day full-dose period of atomoxetine 80 mg + spironolactone 50 mg. A 3-day low-dose run-in period of atomoxetine 40 mg plus spironolactone matching placebo, followed by a 7-day full-dose treatment period of atomoxetine 80 mg plus spironolactone matching placebo.

[0070] After randomization, at Visit 2 (V2), patients are given study medication for the first dosing period. Study medication consists of a 3-day lead-in dose and a 7-day full dose. At Visit 2, patients are also given a WatchPad and ambulatory blood pressure monitor. At Visit 3 (V3), patients are asked to return any unused study medication, as well as the WatchPad and ambulatory blood pressure monitor. At Visit 3, patients are also given home study medication and equipment for the second dosing period, which are also asked to return to the study site at Visit 4 (V4).

[0071] Study medication is administered at the patient's usual bedtime each night, both at home and on the night of the inpatient PSG. On day 9 of dosing, a home watchpad test and 24-hour blood pressure monitoring are performed, and study site personnel contact the patient via video call (or voice if video is not possible) to assist and ensure proper use of the equipment. The watchpad is removed by the patient in the morning, but the 24-hour blood pressure monitor is used until the patient arrives at the clinic on the night of the PSG (visits 3 and 4).

[0072] During the crossover period, ESS, PGI-S, SAQLI, and PROMIS instrumental measurements will be taken on the evening of each inpatient's PSG examination. Vital signs including sitting blood pressure (three times), pulse, respiratory rate, and weight will also be measured on the evening of each PSG examination. Each treatment period will be separated by a washout period of at least 3 weeks.

[0073] Figure 2 shows an overview of the study design.

[0074] The study treatment consisted of a combination of atomoxetine and spironolactone or a matching placebo tablet taken just before participants planned to go to bed. The spironolactone and placebo tablets, as well as the atomoxetine tablet, were overencapsulated for masking purposes. [Table 2]

[0075] The testing procedures and timing are outlined in the Schedule of Actions (SOA) below. [Table 3-1] [Table 3-2] [Table 3-3]

[0076] During the study, the following will be evaluated:

[0077] Polysomnography Standard overnight PSG recordings and data interpretation will be performed according to the American Academy of Sleep Medicine (AASM) scoring manual. Participants will be fitted with standard PSG electrodes. Lights-out time will be set according to the participant's habitual schedule and will remain constant throughout the night of PSG testing. Participants will be allowed 8 hours to sleep. All PSG tests (including the screening PSG test) will be scored by an on-site PSG technician blinded to treatment allocation. Scoring will be performed according to the scoring criteria of the AASM manual.

[0078] WatchPAT Inspection Standard WatchPat recordings will be performed at home and in the laboratory for PSG V2, V3, and V4 according to the AASM HSAT Clinical Practice Guidelines for Adults with OSA. Participants will wear the standard WatchPat device and sensors (finger probe and snoring / position sensor). Participants will sleep as usual at home and will also wear the full PSG device in the laboratory. All WatchPat tests will be scored by qualified on-site technicians blinded to treatment allocation. Scoring will be performed according to validated evidence-based guidelines. The WatchPat test is a sleep apnea test that utilizes peripheral arterial signals (PAT). The WatchPat test measures up to seven channels (PAT signal, heart rate, oximetry, actigraphy, position, snoring, and chest motion) with three points of contact. The WatchPat test provides AHI, AHIc, RDI, and ODI based on true sleep time and sleep stage classification. The WatchPAT test has been clinically validated with an 89% correlation with PSG. WatchPAT is a registered trademark of Itamar Medical Ltd.

[0079] Other assessments included safety, physical examination, vital signs, electrocardiogram, clinical safety laboratory assessments, adverse events, and serious adverse events.

[0080] Other embodiments Although the present invention has been described in conjunction with the detailed description, it is to be understood that the foregoing description is illustrative rather than limiting of the scope of the invention, the scope of which is defined in the appended claims. Other aspects, advantages, and modifications are also encompassed within the following claims.

Claims

1. A pharmaceutical for use in the treatment of a disease associated with pharyngeal airway collapse comprising a norepinephrine reuptake inhibitor (NRI) or a mineralocorticoid antagonist, wherein the norepinephrine reuptake inhibitor (NRI) and the mineralocorticoid antagonist are administered in combination for said treatment.

2. The pharmaceutical composition of claim 1, wherein the NRI is a norepinephrine selective reuptake inhibitor (NSRI).

3. 3. The pharmaceutical composition according to claim 2, wherein the NSRI is selected from the group consisting of amidabutyric acid, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine, or a pharmaceutical acceptable salt thereof.

4. The method of claim 1, wherein the NRI is atomoxetine or a pharma- ceutical acceptable salt thereof.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the mineralocorticoid antagonist is selected from the group consisting of spironolactone, eplerenone, canrenone, finerenone, mexrenone, canrenoic acid, drospirenone, prorenone, apararenone, and esaxerenone, or a pharma- ceutically acceptable salt thereof.

6. The pharmaceutical composition according to claim 5, wherein the mineralocorticoid antagonist is spironolactone or a pharma- ceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 6, wherein the mineralocorticoid antagonist is spironolactone.

8. A pharmaceutical described in any one of claims 1 to 7 for use in combination with a muscarinic receptor antagonist (MRA).

9. The medicament according to any one of claims 1 to 8 for use in combination with a diuretic.

10. The method according to any one of claims 1 to 9, wherein the atomoxetine or a pharma- ceutically acceptable salt thereof is administered in a dose of about 20 mg to about 200 mg.

11. The method of claim 10, wherein the atomoxetine or a pharma- ceutically acceptable salt thereof is administered in a dose of about 25 mg to about 100 mg.

12. The method of any one of claims 1 to 11, wherein the spironolactone or a pharma- ceutically acceptable salt thereof is administered in a dose of about 10 mg to about 100 mg.

13. The method of claim 12, wherein the spironolactone or a pharma- ceutically acceptable salt thereof is administered in a dose of about 20 mg to about 80 mg.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the disease associated with collapse of the pharyngeal airway is sleep apnea.

15. The pharmaceutical composition of claim 14, wherein the disease associated with collapse of the pharyngeal airway is obstructive sleep apnea (OSA).

16. The pharmaceutical composition according to any one of claims 1 to 13, wherein the disease associated with collapse of the pharyngeal airway is snoring.

17. The pharmaceutical composition according to claim 16, wherein the disease associated with collapse of the pharyngeal airway is simple snoring.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the use is for the treatment of a disease associated with collapse of the pharyngeal airway in a subject in a state of reduced consciousness, such as sleep.

19. The pharmaceutical according to any one of claims 1 to 18, wherein the use is for the treatment of a disease associated with the collapse of the pharyngeal airway in a subject with hypertension.

20. A pharmaceutical composition comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a mineralocorticoid antagonist and (iii) a pharma- ceutically acceptable carrier.

21. 21. The composition of claim 20, wherein the NRI is a norepinephrine selective reuptake inhibitor (NSRI).

22. 22. The composition of claim 21, wherein the NSRI is selected from the group consisting of amidabutyric acid, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine, or a pharmaceutically acceptable salt thereof.

23. 21. The composition of claim 20, wherein the NRI is atomoxetine or a pharma- ceutically acceptable salt thereof.

24. The composition of any one of claims 20 to 23, wherein the mineralocorticoid antagonist is selected from the group consisting of spironolactone, eplerenone, canrenone, finerenone, mexrenone, canrenoic acid, drospirenone, prorenone, apararenone, and esaxerenone, or a pharma- ceutically acceptable salt thereof.

25. 25. The composition of claim 24, wherein the mineralocorticoid antagonist is spironolactone or a pharma- ceutically acceptable salt thereof.

26. 26. The composition of claim 25, wherein the mineralocorticoid antagonist is spironolactone.

27. ​​A composition described in any one of claims 20 to 26, further comprising a muscarinic receptor antagonist (MRA).

28. The composition of any one of claims 20 to 27, further comprising an additional active agent which is a diuretic.

29. The composition of any one of claims 20 to 28, wherein the atomoxetine or a pharma- ceutically acceptable salt thereof is present in an amount of about 20 mg to about 200 mg.

30. 30. The composition of claim 29, wherein the atomoxetine or a pharma- ceutically acceptable salt thereof is present in an amount of about 25 mg to about 100 mg.

31. The composition of any one of claims 20 to 30, wherein the spironolactone or a pharma- ceutically acceptable salt thereof is present in an amount of about 10 mg to about 100 mg.

32. 32. The composition of claim 31, wherein the spironolactone or a pharma- ceutically acceptable salt thereof is present in an amount of about 20 mg to about 80 mg.

33. The composition of any one of claims 20 to 32, wherein the composition is a syrup, pill, tablet, lozenge, or capsule.

34. A composition according to any one of claims 20 to 33 for use in the treatment of a disease associated with collapse of the pharyngeal airway.

35. 35. The composition of claim 34, wherein the disease associated with collapse of the pharyngeal airway is sleep apnea.

36. 36. The composition of claim 35, wherein the disease associated with collapse of the pharyngeal airway is obstructive sleep apnea (OSA).

37. 35. The composition of claim 34, wherein the disease associated with collapse of the pharyngeal airway is snoring.

38. 38. The composition of claim 37, wherein the disease associated with collapse of the pharyngeal airway is simple snoring.

39. A composition described in any one of claims 34 to 38, wherein the composition is used to treat a disease associated with pharyngeal airway collapse in a subject who is in a state of reduced consciousness, such as sleep.

40. A composition described in any one of claims 34 to 39, for use in treating a disease associated with pharyngeal airway collapse in a subject having hypertension.

41. 1. A kit comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a mineralocorticoid antagonist, and optionally (iii) a muscarinic receptor antagonist (MRA).

Images