Methods and compositions for treating sleep apnea

Abstract

Methods and compositions for treating conditions associated with pharyngeal airway muscle collapse, such as sleep apnea or simple snoring, in which a subject is in a partially conscious state, comprising administering (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a non-muscle relaxant hypnotic and / or a 5-HT2A inverse agonist or antagonist.

Description

Technical Field

[0001] Claims of Priority This application claims the benefit of U.S. Provisional Patent Application No. 62 / 803,223, filed Feb. 8, 2019. The entire contents of the foregoing are incorporated herein by reference.

[0002] Research or Development with Federal Government Funds This invention was made with government support under grants numbers HL102321 and HL095491 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0003] The present invention is based, at least in part, on the discovery of methods and compositions for the treatment of conditions in which a subject is in an incomplete state of consciousness and concomitantly experiencing pharyngeal airway collapse, such as snoring and sleep apnea, and includes the administration of a norepinephrine reuptake inhibitor (NRI) and a non-muscle relaxant sleep aid or a 5-HT2A inverse agonist or antagonist.

Background Art

[0004] Obstructive sleep apnea (OSA) is a common disorder caused by collapse of the pharyngeal airway during sleep (Young et al., Am J Respir Crit Care Med 2002;165:1217-39). OSA can lead to serious health consequences.

Summary of the Invention

[0005] The present disclosure is based on the administration of noradrenergic agents and non-muscle relaxant sleep aids increasing pharyngeal muscle activity in humans during sleep and, for example, reducing snoring and sleep apnea severity in OSA patients.

[0006] Accordingly, provided herein is a method for treating a subject having a state of incomplete consciousness and at the same time having pharyngeal airway collapse. Such methods involve administering to a subject in need an effective amount of (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a non-muscle relaxant sleeping pill and / or a 5-HT2A inverse agonist or antagonist.

[0007] In some embodiments, the NRI is a norepinephrine selective reuptake inhibitor (NSRI), for example, an NSRI selected from the group consisting of amedalin, atomoxetine, CP-39,332, daledalin, edivoxetine, escitalopram, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine.

[0008] In some embodiments, the NRI is a norepinephrine non-selective reuptake inhibitor (NNRI), for example, an NNRI selected from the group consisting of amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dextromethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phenmetrazine, phentermine, protriptyline, radfaxine, tapentadol, teniloxazine, and venlafaxine.

[0009] In some embodiments, the NRI is selected from the group consisting of atomoxetine and reboxetine.

[0010] In some embodiments, the NRI is atomoxetine, and in certain embodiments, the dosage of atomoxetine is 20-100 mg, such as 25-75 mg.

[0011] In some embodiments, the non-muscle relaxant sleeping pill is a benzodiazepine sleeping pill, such as temazepam, brotizolam, flurazepam, nitrazepam or triazolam; or a non-benzodiazepine sleeping pill, such as a cyclopyrrolone sleeping pill, such as zolpidem, zopiclone or eszopiclone which is a stereoisomer of zopiclone; gabapentin; trazodone; diphenhydramine; suvorexant; tasimelteon; ramelteon; agomelatine; doxepin; zaleplon; doxylamine; sodium oxybate; or tiagabine.

[0012] In some embodiments, the 5-HT2A inverse agonist is AC-90179, ketanserin, nerotanserin, eplivanserin, pimavanserin, or volinanserin; or the 5-HT2A antagonist is trazodone, mirtazapine, ketanserin, clozapine, olanzapine, quetiapine, risperidone, iloperidone, perospirone, asenapine, nefazodone, MDL-100,907, cyproheptadine, pizotifen, LY-367,265, 2-alkyl-4-aryl-tetrahydropyrimidazepine, haloperidol, chlorpromazine, hydroxyzine (Atarax), 5-MeO-NBpBrT, or niaprazine. In some embodiments, the 5-HT2A antagonist is ketanserin, iloperidone, perospirone, risperidone or nefazodone.

[0013] In some embodiments, the 5-HT2A inverse agonist or antagonist is pimavanserin, preferably administered at a dose of 20-40 mg, preferably 34 mg.

[0014] In some embodiments, the non-muscle relaxant sleeping pill or the 5-HT2A inverse agonist or antagonist is in an immediate-release formulation.

[0015] In some embodiments, the non-muscle relaxant sleeping pill or the 5-HT2A inverse agonist or antagonist is in a sustained-release formulation.

[0016] In some embodiments, the non-muscle relaxant sleeping pill is zolpidem, and in certain embodiments, the dosage of zolpidem is 2 to 12.5 mg.

[0017] In some embodiments, zolpidem is in an immediate release formulation at a dosage of, for example, 2 to 10 mg.

[0018] In some embodiments, zolpidem is in a sustained release formulation at a dosage of, for example, 5 to 12.5 mg.

[0019] In some embodiments, the disease or disorder is obstructive sleep apnea (e.g., an AHI of 10 events or more per hour) or simple snoring.

[0020] In some embodiments, the incomplete state of consciousness is sleep.

[0021] In some embodiments, the NRI and the non-muscle relaxant sleeping pill are administered in a single composition.

[0022] In some embodiments, the NRI and the 5-HT2A inverse agonist or antagonist are administered in a single composition.

[0023] In some embodiments, the single composition is in an oral dosage form.

[0024] In some embodiments, the oral dosage form is a syrup, pill, tablet, lozenge, or capsule.

[0025] In some embodiments, the single composition is in a transdermal dosage form, such as a patch.

[0026] Also provided herein is a pharmaceutical composition comprising (i) a norepinephrine reuptake inhibitor (NRI), (ii) a non-muscle relaxant sleeping pill and / or a 5-HT2A inverse agonist or antagonist, and (iii) a pharmaceutically acceptable carrier.

[0027] In some embodiments, the NRI is a norepinephrine selective reuptake inhibitor (NSRI) selected from the group consisting of, for example, amedalin, atomoxetine, CP-39,332, daledalin, edivoxetine, esreboxetine, roltilamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine. In some embodiments, the NRI is a norepinephrine non-selective reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dextromethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phentermine, fenmetrazine, protriptyline, radfaxine, tapentadol (Nucynta), teniloxazine (Lucelan, Metatone) and venlafaxine.

[0028] In some embodiments, the NRI is selected from the group consisting of atomoxetine and reboxetine.

[0029] In some embodiments, the NRI is atomoxetine, and in certain embodiments, the dosage of atomoxetine is 20-100 mg.

[0030] In some embodiments, the non-muscle relaxant sleeping pill is a benzodiazepine sleeping pill, such as temazepam, brotizolam, flurazepam, nitrazepam or triazolam; or a non-benzodiazepine sleeping pill, such as a cyclopyrrolone sleeping pill, preferably zolpidem, zopiclone and eszopiclone; gabapentin; trazodone; diphenhydramine; suvorexant; tasimelteon; ramelteon; agomelatine; doxepin; zaleplon; doxylamine; sodium oxybate; or tiagabine, selected from the group consisting of. In some embodiments, the non-muscle relaxant sleeping pill is in an immediate release formulation. In some embodiments, the non-muscle relaxant sleeping pill is in a sustained release formulation.

[0031] In some embodiments, the non-muscle relaxant sleeping pill is zolpidem. In some embodiments, zolpidem is, for example, in an immediate-release formulation at a dose of 2 to 10 mg. In some embodiments, zolpidem is, for example, in a sustained-release formulation at a dose of 5 to 12.5 mg.

[0032] In some embodiments, the 5-HT2A inverse agonist is AC-90179, ketanserin, nerotanserin, eplivanserin, pimavanserin, or volinanserin; alternatively, the 5-HT2A antagonist is trazodone, mirtazapine, ketanserin, clozapine, olanzapine, quetiapine, risperidone, iloperidone, perospirone, asenapine, nefazodone, MDL-100,907, cyproheptadine, pizotifen, LY-367,265, 2-alkyl-4-aryl-tetrahydropyrimidoazepine, haloperidol, chlorpromazine, hydroxyzine (Atarax), 5-MeO-NBpBrT, or niaprazine. In some embodiments, the 5-HT2A antagonist is ketanserin, iloperidone, perospirone, risperidone or nefazodone.

[0033] In some embodiments, the 5-HT2A inverse agonist or antagonist is pimavanserin and is present at a dose of 20 to 40 mg or 30 to 40 mg, preferably 34 mg.

[0034] Also provided herein is the use of the compositions described herein for the treatment of a subject having a condition that is an incomplete state of consciousness and is accompanied by pharyngeal airway collapse. In some embodiments, the disease or disorder is sleep apnea or simple snoring. In some embodiments, the disease or disorder is obstructive sleep apnea.

[0035] In some embodiments, the incomplete state of consciousness is sleep.

[0036] In some embodiments, the NRI and the non-muscle relaxant sleeping pill are administered in a single composition.

[0037] In some embodiments, the single composition is an oral dosage form.

[0038] In some embodiments, the oral dosage form is a pill, tablet, troche, or capsule.

[0039] Also provided herein are norepinephrine reuptake inhibitors (NRIs), as well as non-muscle relaxant sleep aids and / or 5-HT2A inverse agonists or antagonists, for use in the treatment of a subject having a condition associated with pharyngeal airway collapse while in an incomplete state of consciousness.

[0040] Further, for example, for use in the methods described herein, for example, to treat a subject having a condition associated with pharyngeal airway collapse while in an incomplete state of consciousness, a kit comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a non-muscle relaxant sleep aid and / or 5-HT2A inverse agonist or antagonist is also provided herein. The kit can comprise, for example, separate pharmaceutical compositions of any of the individual active agents claimed herein together with a pharmaceutically acceptable salt or carrier, and the kit can comprise (a) separate or common bottles or packets that potentially allow for separate dosings, and (b) optionally a set of kit instructions.

[0041] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention, and other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references described herein are incorporated herein by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0042] Other features and advantages of the present invention will become apparent from the following detailed description, drawings, and claims.

Brief Description of the Drawings

[0043]

Figure 1

Figure 2

Figure 3A

Figure 3B

Figure 4

Figure 5A-B

Figure 6

Mode for Carrying Out the Invention

[0044] In humans, the pharyngeal airway region is not supported by bone or cartilage and is kept open by muscles. When these muscles relax during sleep, the pharynx collapses, and as a result, the airflow can stop. As shown in FIG. 1, as indicated by the increase in the amplitude of the fluctuations in esophageal pressure, ventilation efforts continue and increase in an attempt to overcome the obstruction. The movements of the thorax and abdomen are in opposite directions as a result of the diaphragm contracting against the obstructed airway, with the abdominal wall expanding and the chest wall caving inwards.

[0045] As the breathing effort increases, it is led from sleep to arousal, which can be visualized by EEG (FIG. 1), and as a result, the airway is opened and normal breathing resumes. The lack of airflow during apnea also causes hypoxia, indicated by the decrease in oxyhemoglobin saturation (FIG. 1). The severity is generally measured using the apnea - hypopnea index (AHI), which is the average of the number of apneas (respiratory pauses of at least 10 seconds) and hypopneas (decrease in airflow and oxygen saturation) that occur per hour of sleep. See, for example, Ruehland et al., The new AASM criteria for scoring hypopneas: Impact on the apnea hypopnea index. SLEEP 2009; 32(2):150 - 157.

[0046] When a strict definition of OSA is used (AHI of 15 events or more per hour or AHI of 5 events or more per hour with daytime sleepiness), the estimated prevalence is approximately 15 percent in men and 5 percent in women. An estimated 30 million people in the United States have OSA, and approximately 6 million of them have been diagnosed. The prevalence of OSA in the United States is thought to be increasing because of the rates of aging and obesity. OSA is associated with major co-morbidities and economic costs, such as hypertension, diabetes, cardiovascular disease, motor vehicle accidents, workplace accidents, and fatigue / productivity loss. See, e.g., Young et al., WMJ 2009; 108:246; Peppard et al., Am J Epidemiol 2013;177:1006.

[0047] The current main treatment (Engleman and Wild, Sleep Med Rev 2003;7:81-99; Kribbs et al., The American review of respiratory disease 1993;147:887-95) is continuous positive airway pressure (CPAP). CPAP is effective in substantially all patients, and approximately 85% of diagnosed patients are treated, but compliance is low. Patients often find CPAP uncomfortable and intolerable; at least 30% (up to 80%) of patients do not normally follow instructions and are thus untreated (Weaver, Proc Am Thorac Soc. 2008 Feb 15; 5(2): 173-178). Other treatment modalities with varying success rates include oral appliances (10%) and surgery (5%), but neither appears to be effective across the general population. Pharmacological treatments have not been shown to be effective to date.

[0048] The search for a drug that activates the pharyngeal muscles in humans during sleep is unpromising; drugs such as serotonin reuptake inhibitors, tricyclic antidepressants, and sedatives have all been tested in humans and have been shown to be ineffective in reducing the severity of OSA. When taken alone, noradrenergic agents such as norepinephrine reuptake inhibitors only slightly reduce the severity of OSA, and only in some patients. See, for example, Proia and Hudgel, Chest. 1991 Aug; 100(2): 416-21; Brownell et al., N Engl J Med 1982, 307:1037-1042; Sangal et al., Sleep Med. 2008 Jul; 9(5):506-10. Epub 2007 Sep 27; Marshall et al., Sleep. 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).

[0049] The tricyclic antidepressants protriptyline (Brownell et al. N Engl J Med 1982; 307:1037-1042; Smith et al. Am Rev Respir Dis 1983; 127:8-139) and desipramine (Taranto-Montemurro et al. Eur Respir J 2016; 48:1340-135) have been tested in all patients with OSA, like atomoxetine (Bart Sangal et al. Sleep Med 2008; 9:506-510), a selective norepinephrine reuptake inhibitor, and have had modest success in reducing the severity of the disorder. Three randomized controlled trials (Brownell et al. 1982, see above; Whyte et al. Sleep 1988; 11:463-472; Hanzel et al. Chest 1991; 100:416-421) and several observational studies (Smith et al., see above; Conway et al. Thorax 1982; 37:49-53; Clark et al. Neurology 1979; 29:1287-1292) have evaluated the effect of protriptyline on the severity of OSA. Brownell and colleagues (Brownell et al. 1982, see above) found no change in AHI during non-REM sleep after 4 weeks of treatment with 20 mg of protriptyline in a group of 5 obese men with severe OSA. However, because of improvements in the patients' oxygen saturation and daytime sleepiness, it was thought that there was at least some beneficial drug effect on sleep breathing. In another double-blind trial, Whyte and colleagues (Whyte et al 1988, see above) found no change in non-REM AHI as a group, but wide interindividual variability in response, with administration of 20 mg of protriptyline for 14 days in 10 patients with moderate to severe OSA. Finally, in an open-label crossover trial in 9 patients for 4 weeks, Hanzel et al. (Chest 1991; 100:416-421) showed a statistically significant 42% decrease in AHI from baseline.Collectively, these results suggest that protriptyline may be useful in a subgroup of OSA patients that has yet to be identified.

[0050] Similar to protriptyline, another tricyclic drug, desipramine, was tested in a placebo-controlled double-blind crossover trial lasting one night. However, various results were obtained regarding the reduction in AHI in the 14 patients studied (see Taranto-Montemurro et al 2016, supra). The effect on OSA severity was not significant as a group, but patients showed a lower airway collapse with desipramine compared to placebo. Additionally, post hoc analysis identified a subgroup of patients with minimal muscle compensation as the phenotype that responded best to treatment. In addition, in tests performed on healthy controls, desipramine increased genioglossus muscle activity during sleep and decreased upper airway collapse.

[0051] Atomoxetine, a selective norepinephrine reuptake inhibitor, was tested by Bart-Sangal et al (2008, supra) in a prospective observational study on 15 patients with mild OSA. The drug did not improve AHI but significantly improved daytime sleepiness. As shown herein, atomoxetine administered alone did not improve OSA severity in a sample of 9 patients with moderate to severe OSA (Taranto-Montemurro et al. Am J Respir Crit Care Med 2019; 199:1267-1276).

[0052] Over the past decade, studies in animals 1、2 and humans 3 have shown that the withdrawal of noradrenergic agents in the central nervous system plays a major role in determining the decreased muscle tone of the upper airway dilator muscles during sleep. Recently, translation work conducted in the inventors' laboratory has shown that drugs with noradrenergic activity, such as desipramine, can increase genioglossus muscle activity 3 and decrease upper airway collapse during human sleep4 has been shown. However, the inventors' team and other researchers have shown that taking noradrenergic agents alone cannot reduce the severity of OSA. Protriptyline 5、6 , desipramine 4 , and atomoxetine 7 have been tested in patients with OSA but did not succeed in reducing AHI. Nevertheless, in a randomized double-blind crossover trial conducted overnight in the inventors' laboratory, when atomoxetine was administered in combination with oxybutynin, which has antimuscarinic effects, the severity of OSA decreased by 63% in 20 unselected patients compared to placebo 8 . Initially, the reason for combining oxybutynin with atomoxetine was to contrast with the inhibitory mechanism via muscarinic receptors. According to the group of Richard Horner 9 , muscarinic receptors are responsible for the expression of the main suppression of genioglossus muscle activity during REM sleep. However, the inhibitory role of muscarinic receptors is not supported in all animal experiments; for example, Kubin et al. showed that in an anesthetized rat model, the suppression of genioglossus muscle activity related to REM sleep can be fully explained by the combined blockade of two excitatory inputs, noradrenergic and serotonergic 10、11 .

[0053] A second possible mechanism by which the combination of atomoxetine and oxybutynin acts is that oxybutynin can act as a sleep aid by increasing the arousal threshold and strengthening sleep, thus being in contrast to the wake-promoting effect of atomoxetine. Prior literature has reported that antimuscarinic drugs administered at low doses have a mild sedative effect 12 and induce drowsiness 13 . Furthermore, it has recently been shown that oxybutynin can improve sleep quality by reducing the symptoms of nocturia, which is consistent with this hypothesis 14 .

[0054] A low respiratory arousal threshold (easy to wake up in response to upper airway obstruction) can limit upper airway neuromuscular compensation and can cause many people to develop sleep-related hypopnea and apnea. When ventilation during sleep decreases during obstructive apnea / hypopnea, there is an accumulation of CO2, which increases the ventilatory drive that can reduce upper airway resistance by activating pharyngeal muscles and stiffening the upper airway. However, if the respiratory arousal threshold is low, this important compensatory mechanism can be suppressed. Therefore, arousal is a life-saving mechanism for protecting people from sleep apnea during sleep for those with a high arousal threshold, but for patients with a low arousal threshold, it can be destabilizing because premature arousal can perpetuate the cycle of upper airway collapse that occurs repeatedly. Therefore, in patients taking an arousal activator such as atomoxetine that induces a low arousal threshold, preventing arousal with a drug having a specific profile may result in more stable breathing and less OSA.

[0055] Specifically, previous animal data have shown that administration of atropine, which has an antimuscarinic effect, abolishes the high-speed and low-amplitude EEG activity induced by a central nervous system adrenergic stimulant (amphetamine) and induces slow-wave and high-amplitude brain waves typical of non-REM sleep. 15 Even if a pharyngeal muscle is activated with an adrenergic drug such as atomoxetine, if the patient wakes up even with a minimal decrease in ventilation (i.e., has a low arousal threshold), it may be insufficient for the treatment of OSA. Pharmacological resolution of OSA may be possible in many patients by co-administering a strong sedative with a strong activator of upper airway dilator muscles such as atomoxetine.

[0056] As described herein, while co - administration of atomoxetine and oxybutynin decreased the severity of OSA (Figure 2) in both REM and non - REM sleep, when atomoxetine and oxybutynin were administered alone, they did not improve non - REM and REM - specific AHI as originally hypothesized. Through accurate analysis of overnight ventilation parameters, atomoxetine alone accounted for at least 70% of the improvement in ventilation during sleep and improved oxygen saturation compared to placebo, while oxybutynin had a minor effect on ventilation and was shown not to improve oxygen levels (Figures 3A - 3B).

[0057] Atomoxetine was probably involved, through its adrenergic properties, in lowering the arousal threshold (more easily waking up). However, when atomoxetine was co - administered with oxybutynin, the decrease in arousal threshold due to the combination was a statistically non - significant 7% (p > 0.7, Figure 4). These data suggest that the most important effect of oxybutynin in the combination was to attenuate the arousal effect of atomoxetine.

[0058] This unexpected finding suggests that oxybutynin can be replaced with non - muscle - relaxant sleeping pills that have a more potent effect on the arousal threshold, such as z - drugs (i.e., zolpidem, zopiclone) or drugs that enhance sleep depth and slow - wave sleep (i.e., gabapentin, tiagabine). Recently, Carberry et al. tested the effects of zolpidem and other commonly used sleeping pills (zopiclone, temazepam) on genioglossus muscle activity and arousal threshold in 21 subjects regardless of the presence of OSA. Among the sleeping pills tested, zolpidem improved the arousal threshold by approximately 30% compared to placebo and, unexpectedly, also tripled the median responsiveness of the genioglossus muscle (p = 0.03). 16 。

[0059] As described herein, drugs that increase sleep depth (and particularly slow-wave sleep (SWS)), such as tiagabine or gabapentin, may be useful in the resolution of OSA. The inventors administered the anti-epileptic drug tiagabine to 14 OSA subjects, and this did not worsen the AHI or oxygen saturation during sleep in these patients. 17 The EEG showed a 16% increase in slow-wave activity, suggesting that the drug gently increased sleep depth. Pharmacologically increasing slow-wave sleep (SWS) may be an ideal mechanism for treating OSA by raising the arousal threshold, particularly since SWS is considered a "protective state" against OSA. Ratnavadivel et al. found that 82% of patients with moderate to severe OSA achieved an AHI of less than 15 events / hour in SWS. 18 The reason for the improvement is likely related to changes in non-anatomical factors that cause OSA during SWS, such as a decrease in arousal, which allows for higher activation of the upper airway dilator muscles. Furthermore, recently, the inventors showed that after inducing reflex activation of the genioglossus muscle by transient upper airway occlusion during sleep, the time that the activity of the genioglossus muscle remained elevated above the baseline value after removing the occlusion stimulus (also called post-emission, see Figure 5) was twice as long during SWS as compared to non-REM2 sleep. These data suggest that a form of neural memory exists in the upper airway dilator muscles and may selectively stiffen the pharynx during SWS in OSA, helping to stabilize breathing. 19 Therefore, drugs such as gabapentin, which increase SWS by 20 - 60% as described herein 20、21 are ideal candidates for the treatment of OSA in combination with atomoxetine.

[0060] Brainstem serotonin neurons are important for eliciting both cortical and respiratory motor responses to hypercapnia. Serotonin neuron-deficient mice have a defect in the hypercapnic ventilatory response (HCVR) 26 and are unable to wake from sleep in response to CO2. 27。Buchanan demonstrated that stimulation of the 5-HT2A receptor could restore EEG arousal in these mice, suggesting that this specific subtype receptor plays a role in activating the central nervous system in response to chemoreceptive (respiratory) stimuli. This idea is supported by human data; Heinzer et al. 28 showed that administration of 100 mg of trazodone (a 5-HT2A antagonist) before bedtime to eight OSA patients increased the arousal threshold in response to hypercapnia, allowing them to tolerate higher CO2 levels without arousal. Eckert et al. 29 showed that in seven patients with a low arousal threshold, trazodone was able to improve the arousal threshold by 30%, but had no effect on AHI compared to placebo. On the other hand, Smales et al. 30 showed that in 15 randomly selected OSA patients, 100 mg of trazodone reduced AHI by 26%.

[0061] To increase the arousal threshold, other sleeping pills and sedatives (zolpidem, zopiclone, eszopiclone, temazepam, tiagabine) have been previously tested in OSA patients. These sedatives act by activating the GABA receptor and reducing the overall excitability of the central nervous system rather than targeting the 5-HT2A receptor, and can be used in combination with atomoxetine and other noradrenergic agents to reduce the severity of OSA.

[0062] In a physiological study involving 21 subjects with or without OSA, 10 mg of zolpidem increased the arousal threshold by 25% compared to placebo, and unexpectedly, also increased the genioglossus muscle response to negative pharyngeal pressure. 33 Among the Z drugs, eszopiclone and zopiclone have been studied in OSA patients to measure their effects on the arousal threshold. Eckert et al. 34In an overnight crossover trial involving 17 OSA patients, eszopiclone was shown to increase the arousal threshold by approximately 30%. Group data did not show an overall significant decrease in AHI, but in those with a low baseline arousal threshold (8 / 17), AHI decreased by 43%. Carter et al. 35 showed that when zopiclone 7.5 mg was administered for one night (n = 12), the arousal threshold increased by 20% compared to placebo, but there was no significant change in AHI. A subsequent parallel-group comparison study in the same group testing zopiclone (n = 14) versus placebo (n = 16) showed a non-significant decrease in AHI between the two groups (-25% from baseline and -15% from placebo) after 30 days of treatment. 36 Carberry and co-investigators 33 In a four-group comparison study by, in a group of 21 healthy subjects and OSA patients, zopiclone 7.5 mg significantly increased the arousal threshold compared to placebo (however, AHI did not change).

[0063] Treatment methods The methods described herein include methods for the treatment of disorders associated with pharyngeal airway muscle collapse during sleep. In some embodiments, the disorder is obstructive sleep apnea (OSA) (defined as an AHI of 10 events or more per hour) or simple snoring. Generally, such methods involve administering to a subject in need of or determined to be in need of such treatment a therapeutically effective amount of (i) a norepinephrine reuptake inhibitor and (ii) a non-muscle relaxant sleep aid and / or a 5-HT2A inverse agonist or antagonist known in the art and / or described herein.

[0064] As used in this context, "treating" means alleviating at least one symptom of a disorder associated with pharyngeal airway collapse. Often, pharyngeal airway collapse during sleep results in snoring and / or breathing interruptions (apnea or hypopnea), awakenings from sleep, and a reduction in oxygenation (hypoxemia); thus, treatment can reduce one or more of snoring, apnea / hypopnea, sleep fragmentation, and hypoxemia.

[0065] Unexpectedly, for the treatment of a subject having a state of incomplete consciousness such as OSA and at the same time having a state accompanied by pharyngeal airway collapse, by administering a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non-muscle relaxant sleeping pill and / or a 5-HT2A inverse agonist or antagonist, the AHI is reduced. In some embodiments, for the treatment of a subject having a state of incomplete consciousness such as OSA and at the same time having a state accompanied by pharyngeal airway collapse, by administering a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non-muscle relaxant sleeping pill and / or a 5-HT2A inverse agonist or antagonist, the AHI is reduced by 50% or more. In some embodiments, for the treatment of a subject having a state of incomplete consciousness such as OSA and at the same time having a state accompanied by pharyngeal airway collapse, by administering a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non-muscle relaxant sleeping pill and / or a 5-HT2A inverse agonist or antagonist, the AHI is reduced by 75% or more. In other further embodiments, for the treatment of a subject having a state of incomplete consciousness such as OSA and at the same time having a state accompanied by pharyngeal airway collapse, by administering a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non-muscle relaxant sleeping pill and / or a 5-HT2A inverse agonist or antagonist, ventilation increases. In still other embodiments, for the treatment of a subject having a state of incomplete consciousness such as OSA and at the same time having a state accompanied by pharyngeal airway collapse, by administering a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non-muscle relaxant sleeping pill and / or a 5-HT2A inverse agonist or antagonist, the oxygen blood level increases. In yet another embodiment, for the treatment of a subject having a state of incomplete consciousness such as OSA and at the same time having a state accompanied by pharyngeal airway collapse, by administering a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non-muscle relaxant sleeping pill and / or a 5-HT2A inverse agonist or antagonist, the total sleep time is improved, the AHI is decreased, the oxygen addition is increased, the sleep fragmentation is decreased, the total sleep time is increased, and / or the subjective sleep quality is improved.

[0066] An effective amount of a norepinephrine reuptake inhibitor and a non-muscle relaxant sleep agent can be administered simultaneously or separately, in one or more administrations, applications or dosages. When administered simultaneously, the norepinephrine reuptake inhibitor and the non-muscle relaxant sleep agent and / or 5-HT2A inverse agonist or antagonist can be formulated as a single dosage form, e.g., a capsule, tablet or liquid containing both the norepinephrine reuptake inhibitor and the non-muscle relaxant sleep agent, or as separate dosage forms, e.g., one as a capsule, tablet or liquid containing the norepinephrine reuptake inhibitor and the other as a capsule, tablet or liquid containing the non-muscle relaxant sleep agent and / or 5-HT2A inverse agonist or antagonist. Each of the norepinephrine reuptake inhibitor and the non-muscle relaxant sleep agent and / or 5-HT2A inverse agonist or antagonist can be administered simultaneously or separately, once or more than once a day to once or more than once a week; e.g., administered once every other day. In some embodiments, the norepinephrine reuptake inhibitor and the non-muscle relaxant sleep agent and / or 5-HT2A inverse agonist or antagonist are administered daily. In some embodiments, the agent is administered 60 minutes, 45 minutes, 30 minutes, 20 minutes, or less than 15 minutes before the subject desires or intends to go to sleep. One of ordinary skill in the art will understand that certain factors, including but not limited to the severity of the disease or disorder, previous treatment, the general health status and / or age of the subject, and the presence of other diseases, can affect the dosage and timing required to effectively treat the subject. Further, treatment of a subject with a therapeutically effective amount of a therapeutic compound described herein can include a single treatment or a series of treatments.

[0067] The dosage, toxicity and therapeutic efficacy of the therapeutic composition (i.e., NRI and non-muscle relaxant sleeping pills and / or 5-HT2A inverse agonists or antagonists in a single composition or in separate compositions) can be determined by standard pharmaceutical procedures in cell culture or experimental animals, for example, by determining the LD50 (the dose at which 50% of the population dies) and the ED50 (the dose that is therapeutically effective in 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, which can be expressed as the LD50 / ED50 ratio.

[0068] Data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage of such a compound preferably lies within a range of blood concentrations that includes the ED50 with little or no toxicity. The dosage can vary within this range depending on the dosage form used and the route of administration utilized. A therapeutically effective dosage can first be estimated from cell culture assays. The dosage can be formulated in animal models to achieve a plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves a maximum 50% suppression of symptoms) determined in cell culture. Using such information, a dosage useful in humans can be determined more accurately. The levels in plasma can be measured, for example, by high performance liquid chromatography.

[0069] In some embodiments, such methods include administering a dose of atomoxetine of 20 to 100 mg (or an equivalent dose of another NRI) and a dose of zolpidem, for example, a dose of extended-release zolpidem of 2 to 12.5 mg (or an equivalent dose of another non-muscle relaxant sleep aid). In some embodiments, such methods include administering 80 mg atomoxetine / 12.5 mg zolpidem; 75 mg atomoxetine / 10 mg zolpidem; 75 mg atomoxetine / 8 mg zolpidem; 50 mg atomoxetine / 6 mg zolpidem; or 25 mg atomoxetine / 4 mg zolpidem. In other embodiments, such methods include administering a dose of atomoxetine of 20 to 100 mg (or an equivalent dose of another NRI) and a dose of zolpidem of 2 to 12 mg (or an equivalent dose of another non-muscle relaxant sleep aid) within 1 hour of bedtime. In some embodiments, such methods include administering 80 mg atomoxetine / 12 mg zolpidem; 75 mg atomoxetine / 10 mg zolpidem; 75 mg atomoxetine / 8 mg zolpidem; 50 mg atomoxetine / 6 mg zolpidem; or 25 mg atomoxetine / 4 mg zolpidem 15 to 10 minutes before bedtime.

[0070] In further embodiments, such methods include administering atomoxetine / zolpidem in a weight ratio of 6.5:1. In other embodiments, such methods include administering atomoxetine / zolpidem in a weight ratio of 6.5:1 15 to 10 minutes before bedtime.

[0071] In some embodiments, gabapentin, for example 600 mg of gabapentin, is used instead of zolpidem. In some embodiments, pimavanserin, for example 20 to 40 mg, for example 34 mg of pimavanserin, is used in addition to or instead of zolpidem.

[0072] Pharmaceutical Compositions and Methods of Administration The methods described herein include the use of a pharmaceutical composition comprising a norepinephrine reuptake inhibitor and a non-muscle relaxant sleep aid and / or a 5-HT2A inverse agonist or antagonist as an active ingredient. The norepinephrine reuptake inhibitor and the non-muscle relaxant sleep aid and / or a 5-HT2A inverse agonist or antagonist can be administered in a single composition or in separate compositions. In some embodiments, such methods include administering a norepinephrine reuptake inhibitor and a non-muscle relaxant sleep aid and / or a 5-HT2A inverse agonist or antagonist and do not include administering other active ingredients, i.e., the norepinephrine reuptake inhibitor and the non-muscle relaxant sleep aid and / or a 5-HT2A inverse agonist or antagonist are the only agents.

[0073] Exemplary norepinephrine reuptake inhibitors (NRIs) include selective NRIs such as amedalin (UK-3540-1), atomoxetine (Strattera), CP-39,332, daledalin (UK-3557-15), edivoxetine (LY-2216684), escitalopram, lortalamine (LM-1404), nisoxetine (LY-94,939), reboxetine (Edronax, Vestra), talopram (Lu 3-010), talsupram (Lu 5-005), tandamine (AY-23,946), viloxazine (Vivalan); and non-selective NRIs such as amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine (GW-320,659), maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phentermine, phenmetrazine, protriptyline, radfaxine (GW-353,162), tapentadol (Nucynta), teniloxazine (Lucelan, Metatone) and venlafaxine.

[0074] Although not limited, suitable examples of non-sedating hypnotics include benzodiazepine hypnotics such as temazepam, brotizolam, flurazepam, nitrazepam or triazolam; or non-benzodiazepine hypnotics such as cyclopyrrolone hypnotics, preferably zolpidem, zopiclone and eszopiclone; gabapentin; trazodone; diphenhydramine; suvorexant; tasimelteon; ramelteon; agomelatine; doxepin; zaleplon; doxylamine; sodium oxybate; or tiagabine, selected from the group consisting of.

[0075] Exemplary 5-HT2A inverse agonists include AC-90179 (Weiner et al., The Journal of Pharmacology and Experimental Therapeutics. 299 (1): 268-76), ketanserin, nerotanserin, eplivanserin, pimavanserin, and volinanserin; antagonists include trazodone, mirtazapine, ketanserin, clozapine, olanzapine, quetiapine, risperidone, iloperidone, perospirone, asenapine, nefazodone, MDL-100,907, cyproheptadine, pizotifen, LY-367,265, 2-alkyl-4-aryl tetrahydropyrimidoazepine, haloperidol, chlorpromazine, hydroxyzine (Atarax), 5-MeO-NBpBrT, and niaprazine. In some embodiments, the 5-HT2A antagonist is ketanserin, iloperidone, perospirone, risperidone or nefazodone.

[0076] In some embodiments, the norepinephrine reuptake inhibitor is atomoxetine. In some embodiments, the non-sedating hypnotic is zolpidem. In some embodiments, the 5-HT2A inverse agonist is pimavanserin.

[0077] The pharmaceutical composition usually contains a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" includes physiological saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, etc., which are compatible with pharmaceutical administration. Auxiliary active compounds can also be incorporated into the composition, but the composition does not include antimuscarinic agents (for example, those described in WO 2018 / 200775 pamphlet).

[0078] The pharmaceutical composition is usually formulated to be compatible with its intended route of administration. Examples of routes of administration include systemic oral or transdermal administration.

[0079] Methods for formulating appropriate pharmaceutical compositions are known in the art. See, for example, Remington: The Science and Practice of Pharmacy, 21st ed., 2005; and the books in the series 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 therapeutic oral administration, the active compound can be incorporated into an excipient and used in the form of tablets, pills, troches, or capsules, such as gelatin capsules. Oral compositions can also be prepared using a liquid carrier. Pharmaceutically compatible binders and / or auxiliary substances can be included as part of the composition. Tablets, pills, capsules, troches, etc. can contain any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth gum or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; flow promoting agents such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavor.

[0080] Systemic administration of one or both of the compounds described herein (i.e., one or both of the norepinephrine reuptake inhibitor and the non-muscle relaxant sleep aid) can also be applied to the skin by transdermal means, for example, using a patch, gel, lotion, or film. For transdermal administration, a penetration enhancer appropriate for penetration of the epidermal barrier can be used in the formulation. Such penetration enhancers are generally known in the art. For example, in transdermal administration, the active compound can be formulated into an ointment, ointment, gel, or cream as generally known in the art. The gel and / or lotion can be provided in separate sachets or via a metered pump for daily application; see, for example, Cohn et al., Ther Adv Urol. 2016 Apr; 8(2):83-90.

[0081] In one embodiment, the therapeutic compound is prepared using a carrier that prevents the rapid excretion of the therapeutic compound from the body, such as a controlled release formulation including an implantable tablet and a microencapsulated delivery system. Biodegradable, 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 a pharmaceutically acceptable carrier. These can be prepared, for example, according to methods known to those skilled in the art described in U.S. Patent No. 4,522,811.

[0082] For administration or use in the methods described herein, the pharmaceutical composition can be included in a container, pack, or dispenser together with instructions.

Examples

[0083] The present invention is further illustrated in the following examples, which do not limit the scope of the present invention as set forth in the claims.

[0084] [Example 1] In a preliminary investigation, sleep tests were conducted on 9 patients wearing a respiratory airflow meter attached to a nose and mouth mask to measure ventilation and an esophageal catheter to estimate the arousal threshold, under four conditions: placebo, atomoxetine alone, oxybutynin alone, and ato-oxy. By administering atomoxetine and oxybutynin simultaneously, the severity of OSA decreased in both REM and non-REM sleep (Figure 2). However, when administered alone, atomoxetine and oxybutynin did not improve the non-REM and REM-specific AHI as originally hypothesized. Through accurate analysis of overnight ventilation parameters, atomoxetine alone accounted for at least 70% of the improvement in ventilation during sleep compared to placebo and improved oxygen saturation, while oxybutynin had a minor effect on ventilation (Figures 3A - 3B) and did not improve oxygen levels. Unfortunately, atomoxetine decreased the arousal threshold (easier to wake up) by 18% (p = 0.03) compared to placebo, which is likely due to adrenergic activity. However, when atomoxetine was administered with oxybutynin, the decrease in the arousal threshold due to the combination was 7% (p > 0.7, Figure 4), which was not statistically significant. These data suggest that the most important effect of oxybutynin in the combination was to weaken the arousal effect of atomoxetine.

[0085] Furthermore, after inducing reflex activation of the genioglossus muscle with a transient upper airway obstruction during sleep and then removing the occlusion stimulus (also called post-emission, see Figures 5A - B and reference 19), the time during which the activity of the genioglossus muscle remained elevated above the baseline value was twice as long during slow-wave sleep (SWS) compared to non-REM 2 sleep. These data suggest that there is a form of neural memory in the upper airway dilator muscles that may selectively stiffen the pharynx and help stabilize breathing during SWS in OSA. 19 。

[0086] [Example 2] Pilot study Subjects Patients with OSA with a wide range of apnea severity (higher than 10 - 60 / hour) were tested in a double - blind, placebo - controlled, crossover trial. Since we did not want to delay treatment to conduct these experiments, treated OSA patients were enrolled. These people are healthy in other respects (except for well - controlled hypertension, diabetes, or hyperlipidemia), have no active medical problems, and are not taking medications that can affect respiration or muscle control. The subjects are between 21 and 70 years old. Both men and women will have an apnea - hypopnea index (AHI) > 10 events / hour during supine non - REM sleep.

[0087] Equipment Subjects are fitted with sensors for standard polysomnography (PSG) recording. Sleep stages and arousal are measured by electrodes (EEG, EOG, EKG, mental EMG) attached to the scalp, face, chin, and chest. Adhesive EMG electrodes are placed over the anterior tibial muscles to detect leg movements. Respiratory effort belts are worn around the chest and abdomen to measure respiratory movements. Oxygen saturation is continuously measured with a pulse oximetry probe attached to the fingertip. Snoring is detected with a small microphone placed over the suprasternal notch. A sensor attached to the chest belt records body position. All of these devices are standard for diagnostic PSG and are non - intrusive. To measure airflow, a standard CPAP mask is worn over the mouth and nose and secured with straps. The mask allows monitoring of respiration (inspiratory flow by a pneumotachograph that can integrate the produced tidal volume) and the level of carbon dioxide in exhaled air (PCO2) using a calibrated infrared CO2 analyzer (capnograph / oximeter monitor).

[0088] Protocol The inventors randomly administered to OSA patients to test the effect of the study treatment on OSA severity. 1) Atomoxetine 80 mg + Zolpidem 10 mg; 2) Atomoxetine 80 mg + Diphenhydramine 50 mg; 3) Atomoxetine 80 mg + Trazodone 100 mg; 4) Atomoxetine 80 mg + Gabapentin 300 mg; or 5) Placebo

[0089] After the baseline sleep polysomnogram, a single night sleep study was conducted in the laboratory on the third day of treatment, in a random order over about one week. Fifteen minutes before lights out, two tablets of placebo or the combination were administered. At least 5 minutes of quiet wakefulness was recorded to quantify the subject's wakefulness ventilation. As much non-REM sleep and REM sleep data as possible were recorded throughout the night. The patients were asked to sleep on their backs for at least 50% of the night.

[0090] Data analysis Apnea, hypopnea, arousal, and sleep stages were scored by a Registered Polysomnographic Technologist (RPSGT) who was blinded to the treatment assignment using the standard guidelines of the American Academy of Sleep Medicine. Hypopnea was defined as a flow reduction of 30% or more from baseline, lasting at least 10 seconds, and associated with arousal from sleep or desaturation of oxyhemoglobin of 3% or more. The phenotypic traits (Vpassive, Vactive, arousal threshold, loop gain) for nights using placebo and drugs were automatically calculated from the sleep polysomnogram using an algorithm developed and validated in the inventors' laboratory. 22 23、24

[0091] The primary outcome of the trial was the change in AHI. One-way analysis of variance followed by post hoc analysis was used to compare between treatment groups, each treatment group with placebo, and p < 0.025 was considered statistically significant to correct for multiple comparisons. Four individual studies (baseline + 3 nights of testing) were required.

[0092] Hypothesized results The tested drug combinations are evaluated for a significant reduction in the severity of OSA (AHI), an increase in oxygen levels (SaO2), and a decrease in collapsibility (Vpassive and Vactive) in both non-REM and REM sleep. The results are explained by determining whether combinations of drugs administered systemically to humans during sleep can improve the severity of sleep apnea and the quality of sleep. Analysis of the phenotypic traits on the night of the reference day provides information on which group of patients is likely to have the best response to the drug, and phenotypic analysis on the nights using placebo and drug will provide information on the mechanism of action of these combinations.

[0093] [Example 3] Alternative hypnotics To determine whether other non-muscle relaxant hypnotics can be used instead of zolpidem or gabapentin, additional tests using zopiclone, eszopiclone, trazodone, or diphenhydramine are conducted in subjects with mild to moderate upper airway collapsibility (ventilation during sleep with normal effort was more than 50% of the placebo resting ventilation) in combination with 80 mg of atomoxetine. The effects on the severity of OSA (AHI), oxygen levels (SaO2), and airway collapsibility (Vpassive and Vactive) are evaluated in both non-REM and REM sleep.

[0094] [Example 4] Combination of atomoxetine and pimavanserin for the treatment of OSA The inventors administered the recently approved selective 5-HT2A inverse agonist pimavanserin, 34 mg, to five patients to block the EEG arousal response to CO2 associated with atomoxetine, 80 mg, and to measure the effect of this combination on OSA severity, arousal threshold, and desaturation. These doses were each selected based on prescribing information, as they are the usual effective doses for attention deficit disorder and delusions / hallucinations in patients with Parkinson's disease. Also, the patients were fitted with a nose / mouth mask, and an esophageal catheter and genioglossus intramuscular electrodes were fitted to 4 / 5 of the patients. Atomoxetine + pimavanserin significantly decreased the AHI from a median [interquartile range] of 31

[34] events / hour to 16

[15] events / hour (median change: 70

[15] %), improved upper airway desaturation (Vpassive 1d ) by 63

[28] % during quiet breathing (p = 0.07), increased the arousal threshold by 32

[20] % (Figure 6), and increased genioglossus muscle activity by 110

[0244] %. Pimavanserin was administered together with atomoxetine, a wake-promoting drug that decreased the arousal threshold by approximately 18% compared to placebo in OSA patients in previous trials as described above, so the effect on the arousal threshold is notable. This means that pimavanserin can substantially increase the respiratory arousal threshold by approximately 50%.

[0095] References

[0096]

Table 1-1

[0097]

Table 1-2

[0098]

Table 1-3

[0099]

Table 1-4

[0100] Other embodiments The present invention has been described in conjunction with its detailed description, but it should be understood that the foregoing description is intended to illustrate, and not limit, the scope of the present invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. The inventions described in the original claims of the present application are listed below. [Invention 1] A method for treating a subject having a state of incomplete consciousness and at the same time accompanied by pharyngeal airway collapse, the method comprising administering to a subject in need thereof an effective amount of (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a non-muscle relaxant sleeping pill and / or a 5-HT2A inverse agonist or antagonist. [Invention 2] The method according to Invention 1, wherein the NRI is a norepinephrine selective reuptake inhibitor (NSRI). [Invention 3] The method according to Invention 2, wherein the NSRI is selected from the group consisting of amedalin, atomoxetine, CP-39,332, daledalin, edivoxetine, escitalopram, roltilamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine. [Invention 4] The method according to Invention 1, wherein the NRI is a norepinephrine non-selective reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dextromethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phentermine, fenmetrazine, protriptyline, radfaxine, tapentadol, teniloxazine, and venlafaxine. [Invention 5] The method according to Invention 1, wherein the NRI is selected from the group consisting of atomoxetine and reboxetine. [Invention 6] The method according to Invention 5, wherein the NRI is atomoxetine. [Invention 7] The method according to Invention 6, wherein the atomoxetine is administered in a dose of 20 to 100 mg. [Invention 8] The method according to Invention 7, wherein the atomoxetine is administered in a dose of 25 to 75 mg. [Invention 9] The method according to Invention 1, wherein the non-muscle relaxant sleeping pill is a benzodiazepine sleeping pill, preferably temazepam, brotizolam, flurazepam, nitrazepam or triazolam. [Invention 10] The method according to invention 1, wherein the non-muscle relaxant sleeping pill is a non-benzodiazepine sleeping pill, preferably a cyclopyrrolone sleeping pill, preferably zolpidem, zopiclone and eszopiclone; gabapentin; trazodone; diphenhydramine; suvorexant; tasimelteon; ramelteon; agomelatine; doxepin; zaleplon; doxylamine; sodium oxybate; or tiagabine, selected from the group consisting of. [Invention 11] The method according to invention 1, wherein the non-muscle relaxant sleeping pill is in an immediate-release formulation. [Invention 12] The method according to invention 1, wherein the non-muscle relaxant sleeping pill is in a sustained-release formulation. [Invention 13] The method according to any one of inventions 1 to 12, wherein the non-muscle relaxant sleeping pill is zolpidem. [Invention 14] The method according to invention 13, wherein the zolpidem is administered at a dose of 2 to 12.5 mg. [Invention 15] The method according to invention 14, wherein the zolpidem is in an immediate-release formulation at a dose of 2 to 10 mg. [Invention 16] The method according to invention 14, wherein the zolpidem is in a sustained-release formulation at a dose of 5 to 12.5 mg. [Invention 17] The 5-HT2A inverse agonist is AC-90179, ketanserin, nerotanserin, eplivanserin, pimavanserin, or volinanserin; or the 5-HT2A antagonist is trazodone, mirtazapine, ketanserin, clozapine, olanzapine, quetiapine, risperidone, iloperidone, perospirone, asenapine, nefazodone, MDL-100,907, cyproheptadine, pizotifen, LY-367,265, 2-alkyl-4-aryl-tetrahydro-pyrimidoazepine, haloperidol, chlorpromazine, hydroxyzine (Atarax), 5-MeO-NBpBrT, or niaprazine, the method according to invention 1. [Invention 18] The method according to invention 17, wherein the 5-HT2A inverse agonist or antagonist is pimavanserin, preferably administered at a dose of 20 to 40 mg, preferably 34 mg. [Invention 19] The method according to any one of inventions 1 to 18, wherein the disease or disorder is obstructive sleep apnea or simple snoring. [Invention 20] The method according to invention 19, wherein the disease or disorder is obstructive sleep apnea. [Invention 21] The method according to invention 1, wherein the incomplete state of consciousness is sleep. [Invention 22] The method according to invention 1, wherein the NRI and the non-muscle relaxant sleep aid are administered in a single composition. [Invention 23] The method according to invention 22, wherein the single composition is in an oral administration form. [Invention 24] The method according to invention 23, wherein the oral administration form is a syrup, pill, tablet, troche, or capsule. [Invention 25] A pharmaceutical composition comprising (i) a norepinephrine reuptake inhibitor (NRI), (ii) a non-muscle relaxant sleep aid and / or a 5-HT2A inverse agonist or antagonist, and (iii) a pharmaceutically acceptable carrier. [Invention 26] The composition according to invention 25, wherein the NRI is a norepinephrine selective reuptake inhibitor (NSRI). [Invention 27] The composition according to invention 26, wherein the NSRI is selected from the group consisting of amedalin, atomoxetine, CP-39,332, daledalin, edivoxetine, escitalopram, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine. [Invention 28] The composition according to invention 25, wherein the NRI is a norepinephrine non-selective reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dextromethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phentermine, fenmetrazine, protriptyline, radfaxine, tapentadol (Nucynta), teniloxazine (Lucelan, Metatone), and venlafaxine. [Invention 29] The composition according to invention 25, wherein the NRI is selected from the group consisting of atomoxetine and reboxetine. [Invention 30] The composition according to invention 29, wherein the NRI is atomoxetine. [Invention 31] The composition according to invention 30, wherein the dosage of atomoxetine is 20-100 mg. [Invention 32] The composition according to invention 25, wherein the non-muscle relaxant sleep aid is a benzodiazepine sleep aid, preferably temazepam, brotizolam, flurazepam, nitrazepam, or triazolam. [Invention 33] The non-muscle relaxant sleeping pill is a non-benzodiazepine sleeping pill, preferably a cyclopyrrolone sleeping pill, preferably zolpidem, zopiclone and eszopiclone; gabapentin; trazodone; diphenhydramine; suvorexant; tasimelteon; ramelteon; agomelatine; doxepin; zaleplon; doxylamine; sodium oxybate; or tiagabine, and is the composition according to Invention 25 selected from the group consisting of. [Invention 34] The composition according to Invention 25, wherein the non-muscle relaxant sleeping pill is in an immediate-release formulation. [Invention 35] The composition according to Invention 25, wherein the non-muscle relaxant sleeping pill is in a sustained-release formulation. [Invention 36] The composition according to any one of Inventions 25 to 35, wherein the non-muscle relaxant sleeping pill is zolpidem. [Invention 37] The composition according to Invention 36, wherein the zolpidem is in an immediate-release formulation with a dose of 2 to 10 mg. [Invention 38] The composition according to Invention 36, wherein the zolpidem is in a sustained-release formulation with a dose of 5 to 12.5 mg. [Invention 39] The composition according to Invention 25, wherein the NRI and the non-muscle relaxant sleeping pill are formulated into a single composition. [Invention 40] The composition according to Invention 39, wherein the single composition is in an oral administration form. [Invention 41] The composition according to Invention 40, wherein the oral administration form is a pill, tablet, lozenge, or capsule. [Invention 42] The composition according to any one of Inventions 25 to 41, for use in the treatment of a subject having a state of incomplete consciousness and at the same time accompanied by pharyngeal airway collapse. [Invention 43] The composition for use according to Invention 42, wherein the disease or disorder is sleep apnea or simple snoring. [Invention 44] The composition for use according to Invention 43, wherein the disease or disorder is obstructive sleep apnea. [Invention 45] The composition for use according to Invention 42, wherein the incomplete consciousness state is sleep. [Invention 46] For use in the treatment of a subject having a state of incomplete consciousness and at the same time accompanied by pharyngeal airway collapse, a norepinephrine reuptake inhibitor (NRI) and a non-muscle relaxant sleeping pill and / or a 5-HT2A inverse agonist or antagonist. [Invention 47] A kit comprising a norepinephrine reuptake inhibitor (NRI) and a non-muscle relaxant sleeping pill and / or a 5-HT2A inverse agonist or antagonist. [Invention 48] A kit according to Invention 47 for use in the treatment of a subject having a state of incomplete consciousness and at the same time accompanied by pharyngeal airway collapse.

Claims

1. A pharmaceutical composition for treating a disease or disorder accompanied by pharyngeal airway collapse, comprising atomoxetine, wherein the pharmaceutical composition is administered in combination with pimavanserin.

2. The pharmaceutical composition according to claim 1, wherein the atomoxetine is administered at a dose of 20 to 100 mg.

3. The pharmaceutical composition according to claim 2, wherein the atomoxetine is administered at a dose of 25 to 75 mg.

4. The pharmaceutical composition according to claim 1, wherein the pimavanserin is in an immediate-release formulation.

5. The pharmaceutical composition according to claim 1, wherein the pimavanserin is in a sustained-release formulation.

6. The pharmaceutical composition according to claim 1, wherein the pimavanserin is administered at a dose of 20 to 40 mg, preferably 34 mg.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the disease or disorder accompanied by pharyngeal airway collapse is obstructive sleep apnea or simple snoring.

8. The pharmaceutical composition according to claim 7, wherein the disease or disorder accompanied by pharyngeal airway collapse is obstructive sleep apnea.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutical composition is in an oral dosage form.

10. The pharmaceutical composition according to claim 9, wherein the oral dosage form is a syrup, pill, tablet, lozenge, or capsule.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the atomoxetine and the pimavanserin are used to be administered simultaneously.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the atomoxetine and the pimavanserin are formulated into a single composition.

13. The pharmaceutical composition according to claim 12, wherein the single composition comprises the atomoxetine, the pimavanserin, and a pharmaceutically acceptable carrier.

14.

14. A pharmaceutical composition for treating a disease or disorder accompanied by pharyngeal airway collapse, comprising pimavanserin, wherein the pharmaceutical composition is administered in combination with atomoxetine.

15. The pharmaceutical composition according to claim 14, wherein the atomoxetine is administered at a dose of 20 to 100 mg.

16. The pharmaceutical composition according to claim 15, wherein the atomoxetine is administered at a dose of 25 to 75 mg.

17. The pharmaceutical composition according to claim 14, wherein the pimavanserin is in an immediate-release formulation.

18. The pharmaceutical composition according to claim 14, wherein the pimavanserin is in a sustained-release formulation.

19. The pharmaceutical composition according to claim 14, wherein the pimavanserin is administered at a dose of 20 to 40 mg, preferably 34 mg.

20. The pharmaceutical composition according to any one of claims 14 to 19, wherein the disease or disorder accompanied by pharyngeal airway collapse is obstructive sleep apnea or simple snoring.

21. The pharmaceutical composition according to claim 20, wherein the disease or disorder accompanied by pharyngeal airway collapse is obstructive sleep apnea.

22. The pharmaceutical composition according to any one of claims 14 to 21, wherein the pharmaceutical composition is in an oral administration form.

23. The pharmaceutical composition according to claim 22, wherein the oral administration form is a syrup, pill, tablet, lozenge, or capsule.

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