Norepinephrine reuptake inhibitors for treating sleep apnea

Abstract

Described herein are methods for treating sleep apnea and snoring, comprising administering a norepinephrine reuptake inhibitor, optionally in the absence of an antimuscarinic agent, optionally as monotherapy. Also described are pharmaceutical compositions comprising norepinephrine reuptake inhibitors, such as edivoxetine and viloxazine.

Description

[Technical field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority under 35 USC § 119(a) and (e) to U.S. Provisional Application No. 63 / 211,673, filed June 17, 2021, and U.S. Provisional Application No. 63 / 319,035, filed March 11, 2022, the entire contents of each of which are incorporated herein by reference.

[0002] Technical Field The present invention provides a method of treating sleep apnea and snoring comprising administering a norepinephrine reuptake inhibitor, optionally in the absence of antimuscarinic therapy, which method of treatment is a monotherapy. [Background technology]

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

[0004] overview One aspect of the invention provides a method of treating a subject having a condition associated with pharyngeal airway collapse, the method comprising administering to a subject in need of treatment an effective amount of a norepinephrine reuptake inhibitor (NRI).

[0005] Embodiments of this aspect of the invention may include any one or more of the following features. In some embodiments, the method is performed in the absence of antimuscarinic therapy. In some embodiments, the method excludes antimuscarinic therapy. In some embodiments, the subject does not receive antimuscarinic therapy at the same time, i.e., is not administered an antimuscarinic agent at the same time. In some embodiments, the NRI is reboxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is edivoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is viloxazine or a pharmaceutically acceptable salt thereof. In some embodiments, the method is a monotherapy with reboxetine or a pharmaceutically acceptable salt thereof as the only pharmaceutical active ingredient. In some embodiments, the reboxetine or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 8 mg. In some embodiments, the reboxetine or a pharmaceutically acceptable salt thereof is administered at a dose of about 2 mg to about 6 mg. In some embodiments, the reboxetine is administered daily. In some embodiments, the reboxetine or a pharma- ceutically acceptable salt thereof is (S,S)-reboxetine or a pharma- ceutically acceptable salt thereof. In some embodiments, the NRI is atomoxetine or a pharma- ceutically acceptable salt thereof. In some embodiments, the method is a monotherapy using edivoxetine or a pharma- ceutically acceptable salt thereof as the only pharma- ceutical active ingredient. In some embodiments, the edivoxetine or a pharma- ceutically acceptable salt thereof is administered at a dose of about 5 mg to about 50 mg. In some embodiments, the edivoxetine or a pharma- ceutical acceptable salt thereof is administered at a dose of about 6 mg to about 36 mg. In some embodiments, the edivoxetine is administered daily. In some embodiments, the edivoxetine is administered in combination with oxybutynin, for example, at a dose of about 1 to about 20 mg of oxybutynin. The oxybutynin can be racemic oxybutynin or substantially enantiomerically pure R-oxybutynin.In some embodiments, edivoxetine is administered in combination with trazodone or a pharma- ceutically acceptable salt thereof, for example, at a dose of about 12.5 to about 200 mg. In some embodiments, the method is a monotherapy using viloxazine or a pharma- ceutically acceptable salt thereof as the only pharma- ceutical active ingredient. In some embodiments, viloxazine or a pharma- ceutically acceptable salt thereof is administered in a dose of about 50 mg to about 800 mg. In some embodiments, viloxazine is administered daily. In some embodiments, viloxazine is administered in combination with oxybutynin, for example, at a dose of about 1 to about 20 mg of oxybutynin. Oxybutynin can be racemic oxybutynin or substantially enantiomerically pure R-oxybutynin. In some embodiments, viloxazine is administered in combination with trazodone or a pharma- ceutical acceptable salt thereof, for example, at a dose of about 12.5 to about 200 mg. In some embodiments, the condition associated with pharyngeal airway collapse is sleep apnea, e.g., obstructive sleep apnea (OSA). In some embodiments, the condition associated with pharyngeal airway collapse is snoring, e.g., simple snoring. In some embodiments, the subject is in a non-fully conscious state. In some embodiments, the non-fully conscious state is sleep. In some embodiments, the NRI or a pharma- ceutically acceptable salt thereof is administered in an oral dosage form. In some embodiments, the oral dosage form is a syrup, pill, tablet, lozenge, capsule or patch.

[0006] Another aspect of the invention provides a norepinephrine reuptake inhibitor for use in the treatment of conditions associated with pharyngeal airway collapse.

[0007] Another aspect of the invention provides the use of a norepinephrine reuptake inhibitor in the treatment of a condition associated with pharyngeal airway collapse.

[0008] Another aspect of the invention provides the use of a norepinephrine reuptake inhibitor for the manufacture of a medicament for treating a condition associated with pharyngeal airway collapse.

[0009] 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 are described herein for use in the present invention, and other suitable methods and materials known in the art can also be used.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 case of conflict, the present specification, including definitions, will control.

[0010] 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]

[0011] BRIEF DESCRIPTION OF THE DRAWINGS The following drawings are provided by way of illustration and are not intended to limit the scope of the claimed invention. [Figure 1] Figure 1 is a graphical representation of obstructive apnea. The top channel shows the electroencephalogram (EEG) pattern of sleep. The next channel shows airflow. The next three channels show ventilator effort due to rib cage and abdominal movement and changes in esophageal pressure, all of which reflect the effort of breathing into an obstructed upper airway. The final channel shows oxyhemoglobin saturation. [Diagram 2] Figures 2A and 2B are individual and group data showing the effect of placebo and reboxetine on AHI (4% definition for hypopnea) in 16 individuals with a previous diagnosis of OSA. Group data show median and interquartile ranges. Placebo and reboxetine were administered overnight in random order approximately 1 week apart during a double-blind crossover study. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Detailed Description In humans, the pharyngeal airway region has no bony or cartilage support and is held open by muscles. When these muscles relax during sleep, the pharynx can collapse causing airflow to stop. As shown in Figure 1, ventilatory effort continues with increasing attempts to overcome the obstruction indicated by increasing esophageal pressure changes. The rib cage and abdominal movements are in opposite directions, with the abdominal wall expanding outwards and the chest wall collapsing inwards as a result of the diaphragm contracting against the blocked airway.

[0013] Increased effort to breathe results in arousal from sleep that can be visualized on the EEG (Figure 1), with the airway opening and resumption of normal breathing. The lack of airflow during apnea also causes hypoxia, indicated by a drop in oxyhemoglobin saturation (Figure 1). Severity is commonly measured using the apnea-hypopnea index (AHI), which is the combined average number of apneas (cessation of breathing for at least 10 seconds) and hypopneas (drops in airflow and oxygen saturation) that occur per hour of sleep (Ruehland et al., The new AASM criteria for scoring hypopneas: Impact on the apnea hypopnea index. SLEEP 2009;32(2):150-157).

[0014] Figure 1 is a graphical representation of obstructive apnea. The top channel shows the electroencephalogram (EEG) pattern of sleep. The next channel shows airflow. The next three channels show ventilatory effort due to rib cage and abdominal movements and changes in esophageal pressure, all of which reflect the effort of breathing against an obstructed upper airway. The final channel shows oxyhemoglobin saturation.

[0015] When strict definitions of OSA are used (AHI >15 events per hour or AHI >5 events per hour with daytime sleepiness), the estimated prevalence is about 15% in men and 5% in women. An estimated 30 million individuals in the United States have OSA, of which about 6 million are diagnosed. The prevalence of OSA in the United States appears to be increasing due to aging and increasing rates of obesity. OSA is associated with major comorbidities and economic costs, e.g.: 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.)

[0016] The current primary treatment is continuous positive airway pressure (CPAP). Although CPAP is effective for virtually all patients, and approximately 85% of diagnosed patients are prescribed CPAP, compliance is low. Patients find CPAP uncomfortable and sometimes intolerable, and at least 30% (up to 80%) of patients are regularly non-adherent and therefore not treated (Weaver, Proc Am Thorac Soc. 2008 Feb 15; 5(2): 173-178). Other treatment modalities with variable success rates include oral appliances (10%) and surgery (5%), neither of which may be effective in all of the general population.

[0017] Research for pharmaceuticals to activate pharyngeal muscles in sleeping humans has been disappointing; drugs such as serotonin reuptake inhibitors, tricyclic antidepressants and sedatives have all been tested in humans and shown to be ineffective in reducing OSA severity. For example, Proia and Hudgel, Chest. 1991 Aug;100(2):416-21;Brownell et al., N Engl J Med 1982, 307:1037-1042;Sangal et al., Sleep Med. 2008 Jul;9(5):506-10. Epub 2007 Sep 27;Marshall et al. p. 2008 Jun;31(6):824-31;Eckert et al., Clin Sci (Lond). 2011 Jun;120(12);505-14;Taranto-Montemurro et al., Sleep. See 2017 Feb 1;40(2).

[0018] In a recent study, a combination of atomoxetine and oxybutynin, termed "ato-oxy" and administered before bedtime, has been shown to reduce OSA in patients with a wide range of severity. The ato-oxy combination administered overnight reduced the number of obstructive events, improved overnight oxygen desaturation, and increased genioglossus activity in an unselected group of patients with OSA. Data collected in a proof-of-concept study showed that it is possible to improve or abolish OSA using drugs with specific neurotransmitter profiles administered systemically. See Taranto-Montemurro, L. et al., The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover Trial. Am J Respir Crit Care Med 2019 May 15;199(10):1267-1276.

[0019] There remains a need for additional therapies to treat conditions associated with pharyngeal airway collapse, such as sleep apnea.

[0020] Treatment method The methods described herein include methods for the treatment of disorders associated with the 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). In general, the methods include administering a therapeutically effective amount of a norepinephrine reuptake inhibitor to a subject in need of such treatment or determined to be in need of such treatment. In some embodiments, the NRI is reboxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is edivoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is viloxazine or a pharmaceutically acceptable salt thereof.

[0021] As used in this context, "treat" means to improve at least one symptom of the disorder related to pharyngeal airway collapse. Often, pharyngeal airway collapse during sleep leads to snoring and / or breathing interruption (apnea or hypopnea), awakening from sleep and reduced oxygen enrichment (hypoxemia), so treatment can result in reduced snoring, apnea / hypopnea, sleep fragmentation and hypoxemia. Administration of a therapeutically effective amount of the compound described herein for treating a subject with OSA can result in reduced AHI. Measurement of OSA disease and symptoms can be, for example, by polysomnography (PSG).

[0022] In general, the "effective amount" of a compound refers to an amount sufficient to show a desired biological response, for example, to treat conditions related to pharyngeal airway collapse, for example, to treat sleep apnea or snoring.As will be understood by those skilled in the art, the effective amount of the compound of the present invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the form of administration, and the age, weight, health and condition of the subject.The effective amount includes therapeutic and prophylactic treatments.

[0023] An effective amount may be administered in one or more administrations, applications or doses. The composition may be administered from one or more times per day to one or more times per week; for example, once every other day. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily before sleep time, for example, just before sleep time or 15-60 minutes before sleep time. One of skill in the art will appreciate that certain factors, including, but not limited to, the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present, may affect the dosage and timing required to effectively treat a subject. Furthermore, treatment of a subject with a therapeutically effective amount of a therapeutic compound described herein may include a single treatment or a series of treatments.

[0024] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent that provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0025] As used herein, "monotherapy" refers to the use of a drug that does not have another active ingredient, for example, to treat the same indication, such as sleep apnea or snoring, individually (also referred to herein as single).For example, in this context, the term monotherapy includes the use of reboxetine or its pharmaceutically acceptable salt, individually or alone, to treat sleep apnea or snoring.

[0026] As used herein, "antimuscarinic therapy" refers to the administration of antimuscarinic agents, including, but not limited to, atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium, oxybutynin, anisotropine, benztropine, biperiden, clidinium, cycrimine, dicyclomine, diphemanil, diphenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixene, methscopolamine, oxyphencyclimine, oxyphenonium, procyclidine, scopolamine, tridihexethyl, and trihexyphenidyl. Subjects receiving treatment according to the present disclosure in the absence of antimuscarinic therapy do not receive an antimuscarinic agent.

[0027] 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, or turkeys, or mammals), specifically "mammals" such as 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 farm animal (e.g., horses, cows, pigs, or sheep) or a pet (e.g., dog, cat, guinea pig, or rabbit). In a preferred embodiment, the subject is a human.

[0028] As used herein, "pharmaceutical acceptable" means approved or approvable by a regulatory agency of the Federal or State government or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, and more specifically, in humans.

[0029] "Pharmaceutically acceptable salts" include "pharmaceutically acceptable acid addition salts" and "pharmaceutically acceptable base addition salts". "Pharmaceutically acceptable acid addition salts" refers to those salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc., which retain the biological effectiveness of the free base and are not biologically or otherwise undesirable.

[0030] "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. 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, incorporated herein by reference.)

[0031] As used herein, the term "unit dosage form" is defined as 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] As used herein, "solid dosage form" means a solid pharmaceutical dose or doses, such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewables.

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

[0034] 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, 4-hydroxyatomoxetine, 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). In some embodiments, the NNRI is 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, protriptyline, radafaxine, tapentadol, teniloxazine and venlafaxine or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is 4-hydroxyatomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is reboxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is edivoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is viloxazine or a pharma- ceutically acceptable salt thereof.

[0035] Reboxetine is the generic name for the drug substance having the chemical name 2-((2-ethoxyphenoxy)(phenyl)methyl)morpholine or 2-[α-(2-ethoxyphenoxy)benzyl]-morpholine and its pharma- ceutically acceptable salts. In various embodiments, reboxetine can be a racemic mixture of the R,R- and S,S-enantiomers or an isolated enantiomer, such as the S,S-enantiomer. In some embodiments, reboxetine can be reboxetine hydrochloride. In some embodiments, reboxetine can be reboxetine mesylate.

[0036] Edivoxetine is the generic name for the drug substance having the chemical name (1R)-2-(5-fluoro-2-methoxyphenyl)-1-[(2S)-morpholin-2-yl]-1-(oxan-4-yl)ethanol and its pharma- ceutically acceptable salts.

[0037] Viloxazine is the generic name for the drug substance that has the chemical name 2-[(2-ethoxyphenoxy)methyl]morpholine and its pharma- ceutically acceptable salts.

[0038] Oxybutynin is the generic name for the drug substance with 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 an isolated enantiomer, such as R-enantiomer.In various embodiments, oxybutynin can be oxybutynin chloride or (R)-oxybutynin chloride.

[0039] In some embodiments, the method includes administering a dose of about 0.2 mg to about 12 mg of reboxetine or a pharma- ceutically acceptable salt thereof. In some embodiments, the dose of reboxetine or a pharma- ceutically acceptable salt thereof is about 1 mg to about 8 mg. In some embodiments, the dose of reboxetine or a pharma- ceutically acceptable salt thereof is about 0.5 mg to about 6 mg. In some embodiments, the dose of reboxetine or a pharma- ceutically acceptable salt thereof is about 2 mg to about 6 mg. In some embodiments, the dose of reboxetine or a pharma- ceutically acceptable salt thereof is about 4 mg. In some embodiments, the dose of reboxetine or a pharma- ceutically acceptable salt thereof is about 6 mg. In some embodiments, the dose of reboxetine or a pharma- ceutically acceptable salt thereof is about 2 mg. In some embodiments, the dose of reboxetine or a pharma- ceutically acceptable salt thereof is about 3 mg.

[0040] In some embodiments, reboxetine or a pharma- ceutically acceptable salt thereof is (S,S)-reboxetine or a pharma- ceutically acceptable salt thereof. As used herein, (S,S)-reboxetine refers to the (S,S)-reboxetine stereoisomer that is substantially free of other stereoisomers of reboxetine.

[0041] In some embodiments, reboxetine or a pharma- ceutically acceptable salt thereof is administered daily. In some embodiments, reboxetine or a pharma- ceutically acceptable salt thereof is administered daily before sleep time, e.g., immediately before sleep time or 15-60 minutes before sleep time.

[0042] In some embodiments, reboxetine or a pharma- ceutically acceptable salt thereof is administered in the absence of antimuscarinic therapy.

[0043] In some embodiments, reboxetine or a pharma- ceutically acceptable salt thereof is administered as monotherapy.

[0044] In some embodiments, reboxetine or a pharma- ceutically acceptable salt thereof is administered as a combination therapy with one or more additional, ie, non-antimuscarinic, active agents.

[0045] In some embodiments, the method includes administering a dose of about 5 to about 50 mg of edivoxetine or a pharma- ceutically acceptable salt thereof. In some embodiments, the dose of edivoxetine or a pharma- ceutically acceptable salt thereof is about 6 mg to about 36 mg. In some embodiments, the dose of edivoxetine or a pharma- ceutically acceptable salt thereof is about 6 mg to about 20 mg. In some embodiments, the dose of edivoxetine or a pharma- ceutically acceptable salt thereof is about 20 mg to about 36 mg. In some embodiments, the dose of edivoxetine or a pharma- ceutically acceptable salt thereof is about 10 mg to about 25 mg.

[0046] In some embodiments, edivoxetine or a pharma- ceutically acceptable salt thereof is administered daily, hi some embodiments, edivoxetine or a pharma- ceutically acceptable salt thereof is administered daily before sleep time, e.g., immediately before sleep time or 15-60 minutes before sleep time.

[0047] In some embodiments, edivoxetine or a pharma- ceutically acceptable salt thereof is administered in the absence of antimuscarinic therapy.

[0048] In some embodiments, edivoxetine or a pharma- ceutically acceptable salt thereof is administered as monotherapy.

[0049] In some embodiments, edivoxetine, or a pharma- ceutically acceptable salt thereof, is administered as a combination therapy with one or more additional active agents.

[0050] In some embodiments, edivoxetine or a pharma- ceutically acceptable salt thereof is administered as a combination therapy with oxybutynin or a pharma- ceutically acceptable salt thereof (eg, racemic oxybutynin or R-oxybutynin).

[0051] In some embodiments, edivoxetine, or a pharma- ceutically acceptable salt thereof, is administered as combination therapy with a hypnotic selected from the group consisting of trazodone, zolpidem, eszopiclone, benzodiazepines, gabapentin, tiagabine, and sodium oxybate, or a pharma- ceutically acceptable salt thereof.

[0052] In some embodiments, edivoxetine or a pharma- ceutically acceptable salt thereof is administered as a combination therapy with trazodone or a pharma- ceutically acceptable salt thereof. In some embodiments, trazodone or a pharma- ceutically acceptable salt thereof is administered at a dose of about 12.5 to about 200 mg. In some embodiments, trazodone or a pharma- ceutically acceptable salt thereof is administered at a dose of about 12.5 to about 50 mg. In some embodiments, trazodone or a pharma- ceutically acceptable salt thereof is administered at a dose of about 50 to about 200 mg. In some embodiments, trazodone or a pharma- ceutically acceptable salt thereof is administered at a dose of about 25 to about 100 mg.

[0053] In some embodiments, the method includes administering a dose of about 50 to about 800 mg of viloxazine or a pharma- ceutically acceptable salt thereof. In some embodiments, the dose of viloxazine or a pharma- ceutically acceptable salt thereof is about 50 mg to about 300 mg. In some embodiments, the dose of viloxazine or a pharma- ceutically acceptable salt thereof is about 300 mg to about 800 mg. In some embodiments, the dose of viloxazine or a pharma- ceutically acceptable salt thereof is about 100 mg to about 500 mg.

[0054] In some embodiments, viloxazine or a pharma- ceutically acceptable salt thereof is administered daily. In some embodiments, viloxazine or a pharma- ceutically acceptable salt thereof is administered daily before sleep time, e.g., immediately before sleep time or 15-60 minutes before sleep time.

[0055] In some embodiments, viloxazine or a pharma- ceutically acceptable salt thereof is administered in the absence of antimuscarinic therapy.

[0056] In some embodiments, viloxazine or a pharma- ceutically acceptable salt thereof is administered as monotherapy.

[0057] In some embodiments, viloxazine, or a pharma- ceutically acceptable salt thereof, is administered as a combination therapy with one or more additional active agents.

[0058] In some embodiments, viloxazine or a pharma- ceutically acceptable salt thereof is administered as a combination therapy with oxybutynin (eg, racemic oxybutynin or R-oxybutynin).

[0059] In some embodiments, viloxazine, or a pharma- ceutically acceptable salt thereof, is administered as combination therapy with a hypnotic selected from the group consisting of trazodone, zolpidem, eszopiclone, benzodiazepines, gabapentin, tiagabine, and sodium oxybate, or a pharma- ceutically acceptable salt thereof.

[0060] In some embodiments, viloxazine or a pharma- ceutically acceptable salt thereof is administered as a combination therapy with trazodone or a pharma- ceutically acceptable salt thereof. In some embodiments, trazodone or a pharma- ceutically acceptable salt thereof is administered at a dose of about 12.5 to about 200 mg. In some embodiments, trazodone or a pharma- ceutically acceptable salt thereof is administered at a dose of about 12.5 to about 50 mg. In some embodiments, trazodone or a pharma- ceutically acceptable salt thereof is administered at a dose of about 50 to about 200 mg. In some embodiments, trazodone or a pharma- ceutically acceptable salt thereof is administered at a dose of about 25 to about 100 mg.

[0061] Pharmaceutical Compositions Also provided herein are pharmaceutical compositions comprising reboxetine, edivoxetine or viloxazine, or pharma- ceutically acceptable salts thereof, as an active ingredient.

[0062] 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, etc., that are compatible with pharmaceutical administration.

[0063] The active pharmaceutical ingredient (API) for use in the present invention can be provided as a pharma- ceutically acceptable salt. In some embodiments, reboxetine is reboxetine hydrochloride. In some embodiments, reboxetine is reboxetine mesylate.

[0064] The API for use in the present invention can be formulated for immediate release or modified release, for example delayed release or extended release.For example, viloxazine or its pharma- ceutically acceptable salt can be formulated for immediate release (i.e. in an immediate release pharmaceutical composition) or extended release (i.e. in an extended release pharmaceutical composition).Viloxazine is available in the United States as extended release capsules.

[0065] For the combination therapy described herein, API can be formulated separately or together.In some embodiments, API is formulated together, for example as a fixed dose combination.In some embodiments, API is formulated separately, for example for simultaneous administration.

[0066] Provided herein is a pharmaceutical composition comprising a pharma- ceutically acceptable carrier or excipient and edivoxetine or a pharma- ceutically acceptable salt thereof, and optionally further comprising oxybutynin or a pharma- ceutically acceptable salt thereof.

[0067] Provided herein is a pharmaceutical composition comprising a pharma- ceutically acceptable carrier or excipient and edivoxetine, or a pharma- ceutically acceptable salt thereof, and optionally further comprising trazodone, or a pharma- ceutically acceptable salt thereof.

[0068] Provided herein are pharmaceutical compositions comprising a pharma- ceutically acceptable carrier or excipient and viloxazine or a pharma- ceutically acceptable salt thereof, and optionally further comprising oxybutynin or a pharma- ceutically acceptable salt thereof.

[0069] Provided herein are pharmaceutical compositions comprising a pharma- ceutically acceptable carrier or excipient and viloxazine or a pharma- ceutically acceptable salt thereof, and optionally further comprising trazodone or a pharma- ceutically acceptable salt thereof.

[0070] In some embodiments, the dosage of edivoxetine, viloxazine, oxybutynin (e.g., racemic oxybutynin or R-oxybutynin) or trazodone or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition may be as described herein, e.g., for the treatment of sleep apnea or snoring.

[0071] A pharmaceutical composition is typically formulated to be compatible with its intended route of administration, examples of which include systemic oral or transdermal administration.

[0072] 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 series of books 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, active compound(s) can be combined with excipients and used in the form of pills, tablets, lozenges or capsules, such as gelatin capsules. Oral compositions can also be prepared using fluid carriers. In some embodiments, the composition of the present invention can be in unit dosage form. In some embodiments, the composition of the present invention can be in solid dosage form, such as tablets or capsules.

[0073] Pharmaceutically compatible binder and / or adjuvant material can be included as part of composition.Tablet, pill, capsule, lozenge etc. can contain any of the following ingredients or compounds with similar properties: binder such as microcrystalline cellulose, tragacanth or gelatin; excipient such as starch or lactose, disintegrant such as alginic acid, primogel or corn starch; lubricant such as magnesium stearate or sterotes; glidant such as colloidal silicon dioxide; sweetener such as sucrose or saccharin; or flavoring agent such as peppermint, methyl salicylate or orange flavoring.

[0074] Systemic administration of the compounds described herein can also be by transdermal means, for example, using a patch, gel or lotion applied to the skin. For transdermal administration, a penetrant suitable for penetrating the epithelial 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 that is applied daily; see, for example, Cohn et al., Ther Adv Urol. 2016, Apr; 8(2): 83-90.

[0075] In one embodiment, the therapeutic compound is prepared with a carrier that protects the therapeutic compound against rapid elimination from the body, for example, a controlled release formulation, such as implants and microencapsulated delivery systems.Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used.Such formulations can be prepared using standard techniques or can be commercially obtained, 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 the methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0076] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration or use in the methods described herein. EXAMPLES

[0077] Working Example The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0078] Example 1. Reboxetine crossover study. A crossover study for the treatment of OSA with reboxetine was conducted. The study was a double-blind, randomized, placebo-controlled, crossover, multicenter study. On reboxetine nights, participants received 4mg of reboxetine mesylate. On placebo nights, participants received a matching placebo. Reboxetine and placebo nights were separated by at least one week in random order. Participants received reboxetine or placebo between visits for acute overnight laboratory sleep studies. Participants had two nights of polysomonogram (PSG). Oral administration of treatment was performed immediately before bedtime.

[0079] The primary endpoint for the study was OSA severity as measured by the apnea / hypopnea index (AHI), which indicates the number of upper airway obstructions per hour of sleep. Secondary endpoints were sleep parameters and phenotype measures from PSG, sleep efficiency, next-day sleepiness (Karolinksa Sleepiness Scale questionnaire) and next-day alertness (driving simulator test).

[0080] 2A and 2B are individual and group data showing the effect of placebo and reboxetine on AHI (4% definition for hypopnea) in 16 participants from a crossover study with a previous diagnosis of OSA. Group data show median and interquartile areas.

[0081] Example 2. Edivoxetine crossover study. A crossover study for the treatment of OSA with edivoxetine is conducted. The study is a double-blind, randomized, placebo-controlled, crossover, multicenter study. On edivoxetine nights, participants receive edivoxetine. On placebo nights, participants receive a matching placebo. The edivoxetine and placebo nights are separated by at least 1 week in random order. Participants receive edivoxetine or placebo between visits for an acute overnight laboratory sleep study. Participants have two nights of polysomnography (PSG). Oral administration of treatment occurs immediately prior to bedtime.

[0082] The primary endpoint for the study is OSA severity as measured by the apnea / hypopnea index (AHI), which indicates the number of upper airway obstructions per hour of sleep. Secondary endpoints are sleep parameters and phenotype measures from PSG, sleep efficiency, next day sleepiness (Karolinksa Sleepiness Scale questionnaire) and next day alertness (driving simulator test).

[0083] Example 3. Viloxazine crossover study. A crossover study of the treatment of OSA with viloxazine is conducted. The study is a double-blind, randomized, placebo-controlled, crossover, multicenter study. On viloxazine nights, participants receive viloxazine. On placebo nights, participants receive a matching placebo. The viloxazine and placebo nights are separated by at least 1 week in random order. Participants receive viloxazine or placebo between visits for an acute overnight laboratory sleep study. Participants have two nights of polysomnography (PSG). Oral administration of treatment occurs immediately prior to bedtime.

[0084] The primary endpoint for the study is OSA severity as measured by the apnea / hypopnea index (AHI), which indicates the number of upper airway obstructions per hour of sleep. Secondary endpoints are sleep parameters and phenotype measures from PSG, sleep efficiency, next day sleepiness (Karolinksa Sleepiness Scale questionnaire) and next day alertness (driving simulator test).

[0085] Other Aspects Although the present invention will be described in conjunction with its detailed description, it will be understood that the foregoing description is intended to be illustrative and not limiting of the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

A pharmaceutical for use in the treatment of a condition associated with pharyngeal airway collapse in the absence of a muscarinic therapy, the pharmaceutical comprising a norepinephrine reuptake inhibitor (NRI).

2. The pharmaceutical according to claim 1, wherein the NRI is administered as monotherapy.

3. The pharmaceutical according to claim 1 or 2, wherein the NRI is reboxetine or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical according to claim 3, wherein reboxetine or a pharmaceutically acceptable salt thereof is administered in a dose of about 1 mg to about 8 mg.

5. The pharmaceutical according to claim 4, wherein reboxetine or a pharmaceutically acceptable salt thereof is administered in a dose of about 2 mg to about 6 mg.

6. The pharmaceutical according to claim 1 or 2, wherein the NRI is edivoxetine or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical according to claim 6, wherein edivoxetine or a pharmaceutically acceptable salt thereof is administered in a dose of about 6 mg to about 36 mg.

8. The pharmaceutical according to claim 1 or 2, wherein the NRI is viloxazine or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical according to claim 8, wherein viloxazine or a pharmaceutically acceptable salt thereof is administered in a dose of about 50 mg to about 800 mg.

10. The pharmaceutical according to claim 1, wherein the NRI is edivoxetine or a pharmaceutically acceptable salt thereof and trazodone or a pharmaceutically acceptable salt thereof is administered to a subject.

11. The pharmaceutical according to claim 1, wherein the NRI is viloxazine or a pharmaceutically acceptable salt thereof and trazodone or a pharmaceutically acceptable salt thereof is administered to a subject.

12. The pharmaceutical according to claim 1 or 2, wherein the NRI is administered daily.

13. The pharmaceutical according to claim 1 or 2, wherein the NRI is administered in an oral dosage form.

14. The pharmaceutical according to claim 13, wherein the oral dosage form is a syrup, pill, tablet, lozenge or capsule.

15. The pharmaceutical according to claim 1 or 2, wherein the NRI is (S,S)-reboxetine or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical according to claim 1 or 2, wherein the condition associated with pharyngeal airway collapse is sleep apnea.

17. The pharmaceutical according to claim 16, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA).

18. The pharmaceutical according to claim 1 or 2, wherein the condition associated with pharyngeal airway collapse is snoring.

19. The medicament according to claim 18, wherein the condition associated with pharyngeal airway collapse is simple snoring.

20. The medicament according to claim 1 or 2, which is for a subject in a condition of incomplete consciousness during treatment.

21. The medicament according to claim 20, wherein the condition of incomplete consciousness is sleep.

22. A pharmaceutical composition comprising (i) edivoxetine or a pharmaceutically acceptable salt thereof, (ii) trazodone or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable excipient or carrier.

23. A pharmaceutical composition comprising (i) viloxazine or a pharmaceutically acceptable salt thereof, (ii) trazodone or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable excipient or carrier.

24. A medicament for use in the treatment of a condition associated with pharyngeal airway collapse, comprising edivoxetine or a pharmaceutically acceptable salt thereof, and trazodone or a pharmaceutically acceptable salt thereof.

25. A medicament for use in the treatment of a condition associated with pharyngeal airway collapse, comprising viloxazine or a pharmaceutically acceptable salt thereof, and trazodone or a pharmaceutically acceptable salt thereof.

26. The medicament according to claim 24 or 25, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea.

27. The medicament according to claim 8, wherein viloxazine or a pharmaceutically acceptable salt thereof is present as a single enantiomer.

28. The medicament according to claim 27, wherein the single enantiomer is (S)-viloxazine or a pharmaceutically acceptable salt thereof.

29. The pharmaceutical composition according to claim 23, wherein viloxazine or a pharmaceutically acceptable salt thereof is present as a single enantiomer.

30. The pharmaceutical composition according to claim 29, wherein the single enantiomer is (S)-viloxazine or a pharmaceutically acceptable salt thereof.

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