Methods and compositions for treating sleep apnea

Abstract

To provide methods for the treatment of Obstructive Sleep Apnea (OSA).SOLUTION: The present invention provides methods and compositions for the treatment of conditions associated with pharyngeal airway muscle collapse while the subject is in a non-fully conscious state, e.g., sleep apnea and simple snoring, comprising administration of (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a non myorelaxing hypnotic and / or 5-HT2A inverse agonist or antagonist.SELECTED DRAWING: None

Description

[Technical field]

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

[0002] Federally funded research or development This invention is funded by the National Institutes of Health. This work was funded with government support under grant numbers HL102321 and HL095491. The Government has certain rights in this invention.

[0003] The present invention relates to a condition in which a subject is in a partially conscious state and simultaneously has a pharyngeal airway collapse, e.g. The discovery of methods and compositions for the treatment of snoring and sleep apnea is due, at least in part, to Based on the above, norepinephrine reuptake inhibitors (NRIs) and nonmuscle relaxant hypnotics or 5 -Including administration of HT2A inverse agonists or antagonists. [Background technology]

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

[0005] The present disclosure relates to the administration of noradrenergic agonists and non-muscle relaxant hypnotics to a sleeping person. It increases pharyngeal muscle activity in patients with OSA, for example, reducing snoring and sleep apnea. Based on reducing the severity of inhalation.

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

[0007] In some embodiments, the NRI is a norepinephrine selective reuptake inhibitor (NS RI), such as atomoxetine, CP-39,332, daledalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine, selected from the group consisting of amedalin, and is an NSR I.

[0008] In some embodiments, the NRI is a norepinephrine non-selective reuptake inhibitor (N NRI), such as 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, selected from the group consisting of and is an NNR

[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; t razodone; diphenhydramine; suvorexant; tasimelteon; ramelteon; ago melatonin; doxepin; zaleplon; doxylamine; sodium oxybate; or t iagabine.

[0012] In some embodiments, the 5-HT2A inverse agonist is AC-90179, ketanserin neurotanserin, eplivanserin, pimavanserin, or volinanserin; alternatively, the 5-HT2A antagonist is trazodone, mirtazapine, ketanserin, clozap ine, olanzapine, quetiapine, risperidone, iloperidone, perospirone, asena pine, nefazodone, MDL-100,907, cyproheptadine, pizotifen, LY -367,265, 2-alkyl-4-aryl-tetrahydropyrimidazepine, haloper idol, chlorpromazine, hydroxyzine (Atarax), 5-MeO-NBpB rT, or niaprazine. In some embodiments, the 5-HT2A antagonist is ke​ It is tandospirone, iloperidone, perospirone, risperidone or nefazodone.

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

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

[0015] In some embodiments, the non-muscle relaxant sleeping pill or 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 dose of, for example, 2 to 10 mg therein.

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

[0019] In some embodiments, the disease or disorder is obstructive sleep apnea (e.g., 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, troche, or capsule.

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

[0026] (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, are also provided herein.

[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, escitalopram, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine. In some embodiments, the NRI is amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dextromethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phentermine, phendimetrazine, protriptyline, lada​​​​​​​​ Faxine, tapentadol (Nucynta), teniloxazine (Lucelan, M etatone) and venlafaxine, a norepinephrine non- selective reuptake inhibitor (NNRI).

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

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

[0031] In some embodiments, the non - muscle - relaxant sleep aid is zolpidem. In some embodiments it is in an immediate - release formulation at a dosage of, for example, 2 - 10 mg. In some embodiments it is in a sustained - release formulation at a dosage of, for example, 5 - 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, clozap ine, olanzapine, quetiapine, risperidone, iloperidone, perospirone, asena pine, nefazodone, MDL-100,907, cyproheptadine, pizotifen, LY -367,265, 2-alkyl-4-aryl-tetrahydropyrimidoazepine, haloper idol, chlorpromazine, hydroxyzine (Atarax), 5-MeO-NBpB rT, or niaprazine. In some embodiments, the 5-HT2A antagonist is ke tanserin, 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 20-40 mg or 30-40 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]

[0036] In some embodiments, the incomplete state of consciousness is sleep.

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

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

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

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

[0040] Further provided herein is a kit for use, for example, in the methods described herein, for treating a subject having a condition characterized by an incomplete state of consciousness and concomitant pharyngeal airway collapse, comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a non- depolarizing sleep medication and / or a 5-HT2A inverse agonist or antagonist. 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 enable separate dosing, 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 are well known in the art. Other suitable known methods and materials can also be used. The materials, methods, and examples are merely illustrative and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references cited herein are hereby incorporated 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, resulting in airflow stoppage. As shown in FIG. 1, as indicated by an increase in the amplitude of the fluctuations in esophageal pressure, ventilation efforts continue and increase in an attempt to overcome the occlusion. The movements of the thorax and abdomen are in opposite directions as a result of the diaphragm contracting against the occluded airway, with the abdominal wall expanding and the chest wall caving in inward. When the effort to breathe increases, it is led from sleep to arousal and visualized by EEG (FIG. 1), as a result, the airway is opened and normal breathing resumes. The lack of airflow during apnea also causes hypoxia indicated by a decrease in oxyhemoglobin saturation (FIG. 1). The severity is generally measured using the apnea-hypopnea index (AHI), which is apnea (at least 10 seconds and hypopnea (a decrease in airflow by at least 30% for at least 10 seconds) per hour of sleep.

[0045] As the effort to breathe increases, it is led from sleep to arousal and visualized by EEG (FIG. 1), as a result, the airway is opened and normal breathing resumes. The lack of airflow during apnea also causes hypoxia indicated by a decrease in oxyhemoglobin saturation (FIG. 1). The severity is generally measured using the apnea-hypopnea index (AHI), which is apnea (at least 10 seconds The average of apnea (cessation of breathing) and hypopnea (decrease in airflow and oxygen saturation) per hour of sleep is combined. For example, see 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. It is estimated that 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 due to the increasing rates of aging and obesity. OSA is associated with major comorbidities and economic costs, such as hypertension, diabetes, cardiovascular disease, motor vehicle accidents, workplace accidents, and fatigue / productivity loss . For example, see Young et al., WMJ 2009; 108:246; Peppard et al., Am J Epidemiol 2013;177:1006

[0047] Current major treatments (Engleman and Wild, Sleep Med Rev 2003;7:81-99; Kribbs et al. , The American review of respiratory disease 1993;147:887-95) are continuous positive airway pressure (CPAP). CPAP is effective in virtually all patients, and approximately 85% of diagnosed patients are treated, but compliance is low. Patients find CPAP uncomfortable and j. Often intolerable; at least 30% (up to 80%) of patients usually do not 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%), neither of which appears to be effective in the general population. So far, pharmacological treatment has not been shown to be effective.

[0048] The search for drugs that activate pharyngeal muscles in humans during sleep is not promising; agents 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; Sa ngal 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). See also 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 (Tarant o-Montemurro et al. Eur Respir J 2016; 48:1340-135) have been tested in all patients with OSA, similar to 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 e t 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, since the patients' oxygen saturation and daytime sleepiness improved, it is 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 that in 10 patients with moderate or In patients with severe OSA, protriptyline 20 mg for 14 days was administered to They found that the NREM AHI did not change as a function of time, but that there was a large interindividual variability in the response. Finally, in a 4-week open-label crossover study of 9 patients, Nzel et al. (Chest 1991; 100:416-421) reported a statistically significant AHI of 42% above baseline. Taken together, these results suggest that protriptyline may have a yet to be identified These results suggest that it may be useful in a subgroup of OSA patients who need to be monitored for a long time.

[0050] Desipramine, another tricyclic drug, was administered as a placebo overnight dose, similar to protriptyline. It was tested in a controlled, double-blind, crossover study. However, 14 patients were studied. There have been mixed results regarding AHI reduction in 6, see above). The effect on OSA severity was not significant as a group, Compared to placebo, patients showed less airway collapse with desipramine. Post-hoc analysis demonstrated that the subgroup of patients with minimal muscle compensation responded best to treatment. In addition, studies conducted on healthy controls showed that desipramine increased genioglossus muscle activity during sleep and reduced upper airway collapse.

[0051] Atomoxetine, a selective norepinephrine reuptake inhibitor, is available from Bart-San Gal et al. (2008, see above) conducted a prospective study of 15 patients with mild OSA. The drug did not improve AHI, but it did significantly improve daytime sleepiness. As shown herein, atomoxetine administered alone reduced moderate to severe cerebrovascular events in 9 patients. did not improve OSA severity in a sample of OSA patients (Taranto-Montemurro et al. al. Am J Respir Crit Care Med 2019; 199:1267-1276).

[0052] Animals in the last 10 years 1、2 and humans 3 Research on the central nervous system Withdrawal of noradrenergic drugs plays a major role in determining the relaxation of upper airway dilator muscle tone during sleep. Recent translation work done in the inventors' lab has shown that it plays an important role. The authors reported that noradrenergic drugs such as desipramine have been shown to increase the oocyte secretion during sleep in humans. Increases genioglossus activity 3 , which may reduce upper airway collapse 4 However, His team and others have shown that noradrenergic drugs taken alone do not reduce O Protriptyline has been shown to be unable to reduce the severity of SA. 5、6 , De Cypramine 4 , and atomoxetine 7 has been tested in patients with OSA, It was not successful in reducing HI. Nevertheless, a study performed overnight in our laboratory In a randomized, double-blind, crossover study, atomoxetine was compared with antimuscarinic opioids. When administered in combination with cyclosporine, it was more effective than placebo in 20 unselected patients. 63% reduction in OSA severity compared with 8 Initially, oxybutynin was used as a treatment for The reason for combining it with the muscarinic receptor-mediated inhibitory mechanism is to contrast it with the muscarinic receptor-mediated inhibitory mechanism. Yes, according to the group of Richard Horner 9 the muscarinic receptor is responsible for the expression of the main suppression of genioglossus muscle activity during REM sleep. However, the inhibitory role of the muscarinic receptor is not supported in all animal experiments; for example, Kubi n et al. showed that in an anesthetized rat model, the suppression of genioglossus muscle activity related to REM sleep could be fully explained by the combined blockade of two excitatory inputs, noradrenergic and serotonergic

[0053] 10、11 .

[0053] A second possible mechanism that acts with the combination of atomoxetine and oxybutynin is that oxybutynin can act as a sleep aid by increasing the arousal threshold and enhancing sleep, thus being in contrast to the arousal-promoting effect of atomoxetine. Previous 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 also consistent with this hypothesis 1 4 .

[0054] If the respiratory arousal threshold is low (easily awakened in response to upper airway obstruction), the neuromuscular compensation of the upper airway is limited, which can cause many people to develop sleep-related hypopnea and apnea. During obstructive apnea / hypopnea, when ventilation during sleep decreases, the ventilation drive that can increase the upper airway resistance by activating the pharyngeal muscles and hardening the upper airway increases, and the accumulation of Co 2 occurs. However, if the respiratory arousal threshold is low, this important compensatory mechanism can be suppressed. Thus , arousal is a life-saving mechanism for people with a high arousal threshold to protect themselves from sleep apnea, but for patients with a low arousal threshold, premature arousal can repeatedly occur, potentially perpetuating the cycle of upper airway collapse and leading to instability. Therefore, in patients taking arousal-activating drugs such as atomoxetine that induce a low arousal threshold , preventing arousal with a pharmaceutical having a specific profile may result in more stable breathing and less OSA. , preventing arousal with a pharmaceutical 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 adrenergic stimulants (amphetamine) in the central nervous system and induces low-frequency and high-amplitude brain waves typical of non-REM sleep . Even when activating the pharyngeal muscles 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), 15 it may be insufficient for the treatment of OSA. The simultaneous administration of a strong sedative with a strong activator of upper airway dilators such as atomoxetine may pharmacologically resolve OSA in many patients. The simultaneous administration of a strong sedative with a strong activator of upper airway dilators such as atomoxetine may pharmacologically resolve OSA in many patients. The simultaneous administration of a strong sedative with a strong activator of upper airway

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

[0057] Atomoxetine was probably involved in reducing the arousal threshold (easier to wake up) due to its adrenergic activity. However, when atomoxetine was co - administered with oxybutynin, the decrease in arousal threshold due to the combination was not statistically significant, being 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 could 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, C arberry et al. have 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 or absence of OSA. Among the sleeping pills tested, zolpidem improved the arousal threshold by about 30% compared to placebo and, unexpectedly, also tripled the median responsiveness of the genioglossus muscle (p = 0.03) 16 .

[0059] As described herein, drugs such as tiagabine or gabapentin for sleep depth (and Drugs that specifically increase slow-wave sleep (SWS) may be useful in the resolution of OSA. The inventors administered tiagabine, an anti-epileptic drug, to 14 OSA subjects, and this did not worsen the AHI or oxygen saturation during sleep in these patients. The EEG showed a 16% increase in slow-wave activity, suggesting that the drug gently increased sleep depth. Pharmacologically increasing slow-wave sleep (SWS) is an ideal mechanism for treating OSA by raising the arousal threshold, especially 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 during SWS. 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 may enable higher activation of the upper airway dilator muscles. Furthermore, recently, the inventors showed that the time during which the activity of the genioglossus muscle remained elevated above the baseline value after inducing reflex activation of the genioglossus muscle by transient upper airway occlusion during sleep and then removing the occlusion stimulus (also called post-emission, see Figure 5) was twice as long during SWS as during 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. Therefore, drugs such as gabapentin, which increase SWS by 20 - 60% as described herein, are ideal candidates for the treatment of OSA in combination with atomoxetine. 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) is an ideal mechanism for treating OSA by raising the arousal threshold, especially 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 during 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 may enable higher activation of the upper airway dilator muscles. Furthermore, recently, the inventors showed that the time during which the activity of the genioglossus muscle remained elevated above the baseline value after inducing reflex activation of the genioglossus muscle by transient upper airway occlusion during sleep and then removing the occlusion stimulus (also called post-emission, see Figure 5) was twice as long during SWS as during 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 Therefore, drugs such as gabapentin, which increase SWS by 20 - 60% as described herein, are ideal candidates for the treatment of OSA in combination with atomoxetine. 20、2 1 ​​​​​​​​​​

[0060] Brainstem serotonin neurons are important for eliciting both cortical and respiratory motor responses to hypercapnia. Serotonin neuron-deficient mice have impaired hypercapnic ventilatory responses (HCVR) and are unable to wake from sleep in response to Co . 26 2 Buchanan showed that stimulation of the 5-HT2A receptor can 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 27 showed that administration of 100 mg of trazodone (a 5-HT2A antagonist) before bedtime to eight patients with OSA increased the arousal threshold in response to hypercapnia, allowing them to tolerate higher CO2 levels without awakening. Eckert et al 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 showed that in 15 randomly selected patients with OSA, 100 mg of trazodone reduced AHI by 26%. 28 Other sleep and sedative medications (zolpidem, zopiclone, eszopiclone, temazepam, tiagabine) have been previously tested in OSA patients to raise the arousal threshold. These sedatives act by activating the GABA receptor rather than targeting the 5-HT2A receptor and by reducing the overall excitability of the central nervous system, atomoxetine 29 30

[0061] ​​​​​​​​​​​​​ and used in combination with other adrenergic agents to reduce the severity of OSA It is possible.

[0062] In a physiological study involving 21 subjects with or without OSA, 10 mg of zol pidem 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 zopiclo n have been studied in OSA patients to measure their effect on the arousal threshold. Eckert et al 3 4 showed that eszopiclone increased the arousal threshold by approximately 30% in an overnight crossover study involving 17 OSA patients . Group data did not show an overall significant reduction in AHI , but those with a low baseline arousal threshold (8 / 17) had a 43% reduction in AHI . Carter et al 35 administered 7.5 mg of zopiclone overnight (n = 12 ) and showed that the arousal threshold increased by 20% compared to placebo, but there was no significant change in AHI . A subsequent parallel-group comparison study of zopiclone (n = 14) versus placebo (n = 16) in the same group showed a non-significant reduction between the two groups in AHI after 30 days of treatment (-25% from baseline and -15% from placebo) . 36 . In a four-group comparison study by Carberry and co-researchers 33 , 7.5 mg of zopiclone significantly increased the arousal threshold compared to placebo in a group of 21 healthy subjects and O SA patients (however, AHI did not change).

[0063] Treatment method The methods described herein include methods for the treatment of disorders associated with pharyngeal airway muscle collapse during sleep including. In some embodiments, the disorder is obstructive sleep apnea (OSA) (defined as an AHI of 1 0 events or more per hour) or simple snoring. Generally, such methods administer 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, which are known in the art and / or described herein, to a subject in whom such treatment is necessary or has been determined to be necessary .

[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 interruptions in breathing (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, administration of a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non-muscle relaxant sleep aid and / or a 5-HT2A inverse agonist or antagonist for the treatment of a subject having a condition associated with pharyngeal airway collapse while being in an incomplete state of consciousness such as OSA reduces the AHI . In some embodiments, a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non-muscle relaxant sleep aid and / or a 5-HT2A inverse agonist or antagonist for the treatment of a subject having a condition associated with pharyngeal airway collapse while being in an incomplete state of consciousness such as OSA ​​​​​​​​By administering an antagonist, the AHI is reduced by 50% or more. In some embodiments, For the treatment of a subject having a condition with pharyngeal airway collapse while being in an incomplete state of consciousness such as OSA a therapeutically effective amount of a norepinephrine reuptake inhibitor, a non-muscle relaxant sleep aid and / or by administering 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 condition with pharyngeal airway collapse while being in an incomplete state of consciousness such as OSA a therapeutically effective amount of a norepinephrine reuptake inhibitor, a non-muscle relaxant sleep aid and / or a 5-HT2A inverse agonist or antagonist increases ventilation. In still other embodiments, for the treatment of a subject having a condition with pharyngeal airway collapse while being in an incomplete state of consciousness such as OSA a therapeutically effective amount of a norepinephrine reuptake inhibitor, a non-muscle relaxant sleep aid and / or a 5-HT2A inverse agonist or antagonist increases the oxygen blood level. In yet another embodiment, for the treatment of a subject having a condition with pharyngeal airway collapse while being in an incomplete state of consciousness such as OSA a therapeutically effective amount of a norepinephrine reuptake inhibitor, a non-muscle relaxant sleep aid and / or a 5-HT2A inverse agonist or antagonist increases the total sleep time, decreases the AHI, increases the oxygen addition, decreases the sleep fragmentation, increases the total sleep time, and / or improves the subjective sleep quality. In still another embodiment, for the treatment of a subject having a condition with pharyngeal airway collapse while being in an incomplete state of consciousness such as OSA a therapeutically effective amount of a norepinephrine reuptake inhibitor, a non-muscle relaxant sleep aid and / or a 5-HT2A inverse agonist or antagonist administered by increases the total sleep time, decreases the AHI, increases the oxygen addition, decreases the sleep fragmentation, increases the total sleep time, and / or improves the subjective sleep quality. The therapeutically effective amount of the norepinephrine reuptake inhibitor and the non-muscle relaxant sleep aid can be administered simultaneously or separately, in one or multiple

[0066] doses, applications or dosages. Administered simultaneously ​In such cases, a norepinephrine reuptake inhibitor and a non-muscle relaxant sleep aid and / or a 5- HT2A inverse agonist or antagonist can be formulated as a single dosage form, e.g., a capsule, tablet, or liquid containing both a norepinephrine reuptake inhibitor and a non-muscle relaxant sleep aid, or as separate dosage forms, e.g., one being a capsule, tablet, or liquid containing a norepinephrine reuptake inhibitor and the other being a capsule, tablet, or liquid containing a non-muscle relaxant sleep aid and / or a 5-HT2A inverse agonist or antagonist. The norepinephrine reuptake inhibitor and the non-muscle relaxant sleep aid and / or the 5-HT2A inverse agonist or antagonist can each be administered simultaneously or separately, once a day or multiple times a day, or once a week or multiple times a week; for example, it can be administered once every other day. In some embodiments, the norepinephrine reuptake inhibitor and the non-muscle relaxant sleep aid and / or the 5-HT2A inverse agonist or antagonist are administered daily. In some embodiments, the drug 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. Those skilled in the art will understand that certain factors, including but not limited to the severity of the disease or disorder, previous treatments, the overall health status and / or age of the subject, and the presence of other diseases, etc., can affect the dosage and timing required to effectively treat the subject. Furthermore, the treatment of the subject with a therapeutically effective amount of the therapeutic compound described herein can include a single treatment or a series of treatments. The therapeutic composition (i.e., the NRI in a single composition or in separate compositions,

[0067] along with the non-muscle relaxant sleep aid and / or the 5-HT2A inverse agonist or antagonist, if any) and the dosage of a non-muscle relaxant sleeping pill and / or a 5-HT2A inverse agonist or antagonist), Toxicity and therapeutic efficacy are 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 dosage 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 the dosage range for use in humans. The dosage of such a compound is preferably 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 to be used and the route of administration utilized. A therapeutically effective dosage can be initially estimated from cell culture assays. The dosage can be formulated in an animal model to achieve a plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves maximum half-suppression of symptoms) determined in cell culture. Using such information, a dosage useful in humans can be more accurately determined. Plasma levels can be measured, for example, by high performance liquid chromatography.

[0069] In some embodiments, such a method comprises administering a dosage of atomoxetine of 20 - 100 mg ( or an equivalent dosage of another NRI) and zolpidem, for example, a dosage of extended release zolpidem of 2 - 12.5 mg (or an equivalent dosage of another non-muscle relaxant sleeping pill). In some embodiments, such a method comprises 80 mg atomoxetine / 12.5 mg zolpidem; 75 mg atomoxetine / 10 mg zolpidem; 75 mg atom oxetine / 8 mg zolpidem; 50 mg atomoxetine / 6 mg zolpidem; or 2 5 mg atomoxetine / 4 mg zolpidem. In other embodiments , such methods include administering a dose of 20 - 100 mg of atomoxetine (or an equivalent dose of another NRI) and a dose of 2 - 12 mg of zolpidem (or an equivalent dose of another non - muscle - relaxant sleep medication) 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 - 10 minutes before bedtime.

[0070] In further embodiments, such methods include administering atomoxetine / zol pidem 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 - 10 minutes before bedtime.

[0071] In some embodiments, gabapentin, e.g., 600 mg of gabapentin, is used instead of zolpidem. In some embodiments, pimavanserin, e.g., 20 - 40 mg, e.g., 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 norepinephrine reuptake inhibitor and a non-muscle relaxant sleep agent and / or a 5-HT2A inverse agonist or antagonist as an active ingredient. A norepinephrine reuptake inhibitor and a non-muscle relaxant sleep agent 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 agent and / or a 5-HT2A inverse agonist or antagonist, and do not include administering other active ingredients, i.e., the norepinephrine reuptake inhibitor and a non-muscle relaxant sleep agent and / or a 5-HT2A inverse agonist or antagonist are the only active agents. 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-221 6684), escitalopram, lortalamine (LM-1404), nisoxetine (LY -94,939), reboxetine (Edronax, Vestra), talopram (Lu

[0073] 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), mapro tiline, mazindol, mirtazapine, nortriptyline, protriptyline, reboxetine, sertraline, trimipramine, venlafaxine; and the pharmaceutically acceptable salts thereof. Examples of non-muscle relaxant sleep agents include benzodiazepines such as alprazolam, chlordiazepoxide, clonazepam, diazepam, estazolam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam; non-benzodiazepine hypnotics such as zolpidem, zaleplon, eszopiclone; and the pharmaceutically acceptable salts thereof. Chlorine, methylphenidate, milnacipran, nefazodone, nortriptyline, phen dimetrazine, fenmetrazine, protriptyline, ladafaxine (GW-353 ,162), tapentadol (Nucynta), teniloxazine (Lucelan, M etatone) and venlafaxine.

[0074] Examples of suitable non-muscle relaxant sleeping pills include, but are not limited to, benzodiazepine sleeping pills, for example, temazepam, brotizolam, flurazepam, nitrazepam or triazolam ; or non-benzodiazepine sleeping pills, such as cyclopyrrolone sleeping pills, 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 Jou rnal 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 , 162), tapentadol (Nucynta), teniloxazine (Lucelan, M etatone) and venlafaxine. ,265, 2-alkyl-4-aryl tetrahydropyrimidoazepine, haloperidol , chlorpromazine, hydroxyzine (Atarax), 5-MeO-NBpBrT, and niaprazine are included. 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-muscle relaxant sleeping pill 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 and absorption delaying agents, etc., which are compatible with pharmaceutical administration. Optionally, 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, for example, Remington: The Science and Practice of Pharmacy, 21st ed., 2005; and the books in the ser ies Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, oral compositions generally contain an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound may be incorporated with excipients and administered in the form of a pill, tablet, bolus, or capsule. It can be used in the form of lozenges or capsules, for example gelatin capsules. Oral compositions may also be prepared using liquid carriers. Pharmaceutically compatible binding agents, and Tablets, pills, capsules, trotters, and / or adjuvant substances may be included as part of the composition. The binders may be any of the following ingredients or compounds of a similar nature: binders, such as microcrystalline cellulose. , tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, glidants such as magnesium stearate or sterotes; glidants such as colloids a sweetening agent, such as sucrose or saccharin; or a flavoring agent, such as For example, peppermint, methyl salicylate, or orange flavoring may be included.

[0080] One or both of the compounds described herein (i.e., norepinephrine reuptake inhibitors) Systemic administration of hypnotics (hypnotic agents and / or non-muscle relaxants) can be achieved, for example, by patch, gel, or It may also be applied to the skin by transdermal means, using a lotion, or thin film. In this regard, a penetrant suitable for penetrating the epidermal barrier can be used in the formulation. Agents are generally known in the art. For example, for transdermal administration, The active compound can be formulated into an ointment, an ointment preparation, a gel preparation, or a cream preparation as follows. Gels and / or lotions 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 and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Such formulations can be prepared using standard techniques or can be obtained commercially, for example, from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared, 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.

[0083]

[0084]

Examples

[0083] The present invention is further illustrated in the following examples, but does not limit the scope of the present invention as described in the claims.

[0084] [Example 1] In a preliminary investigation, a respiratory airflow meter attached to an oro-nasal mask for measuring ventilation, and nine patients wearing an esophageal catheter for estimating the arousal threshold were subjected to sleep tests 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), but when administered alone, atomoxetine and oxybutynin did not improve the non-REM and REM-specific AHI as hypothesized initially. 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, whereas 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 , but this is likely due to adrenergic activity. However, when atomoxetine was administered with oxybutynin, the decrease in arousal threshold due to the combination was not statistically significant at 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

[0085] atomoxetine. Furthermore, after inducing reflex activation of the genioglossus muscle during a transient upper airway obstruction during sleep and then removing the occlusion stimulus (also called The square was twice as long as non-REM2 sleep. These data are the neural memory of the upper airway dilator muscles There is a form of, and during SWS in OSA, it may help to selectively stiffen the pharynx and stabilize breathing by suggesting that there is a possibility 19 .

[0086] [Example 2] Pilot study Subjects OSA subjects with a wide range of apnea severities (higher than 10 - 60 / hour) were tested by a double-blind controlled, placebo-controlled, crossover study. To conduct these experiments, since we did not want to delay treatment , treated OSA patients were enrolled. These people are otherwise healthy (excluding well-controlled hypertension, diabetes, or hyperlipidemia ), do not have active medical problems, and are not taking medications that could affect respiration or muscle control . The subjects are aged 21 - 70 years. 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 polysomnogram (PSG) recording. Sleep stages and wakefulness are measured by electrodes (EEG, EOG, EKG, submental EMG) attached to the scalp, face, chin , and chest. Adhesive EMG electrodes are placed on the anterior tibialis muscle to detect leg movements . A respiratory effort belt is worn around the chest and abdomen to measure respiratory movements. Oxygen saturation is continuously measured by a pulse oximetry probe attached to the fingertip. Snoring is detected by a small microphone placed above the suprasternal notch . Body position is recorded by a sensor attached to the chest belt . All of these devices are standard for diagnostic PSG and there is no discomfort​ No. To measure the airflow, a standard CPAP mask is worn over the mouth and nose and secured with straps. The mask allows for measurement of the respiratory airflow (inspiratory flow by a respiratory airflow meter that can integrate the produced tidal volume), and the carbon dioxide level (PCO₂) in exhaled air can be monitored using a calibrated infrared CO₂ analyzer (capnograph / oximeter monitor). 2 2

[0088] Protocol The inventors randomly administered to OSA patients to test the effect of the research treatment on the severity of OSA. 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 a baseline sleep polysomnogram, a sleep study was conducted in the laboratory on the third day of treatment, randomly over a period of about one week. Two tablets of placebo or the combination were administered 15 minutes before lights out. 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 Apneas, hypopneas, arousals, and sleep stages are scored by a Registered Polysomnographic Technologist (RPSGT) who is blinded to the treatment assignment, using the standard guidelines of the American Academy of Sleep Medicine. 22 ​​​​​​​​​​​​is defined as having a flow rate decrease of 30% or more from the reference value, continuing for at least 10 seconds, and accompanied by desaturation of oxyhemoglobin of 3% or more upon awakening from sleep or is accompanied by desaturation of oxyhemoglobin of 3% or more. The nocturnal phenotypic traits (Vpassive, Vactive, arousal threshold, loop gain) using placebo and drugs are automatically calculated from the sleep polysomnogram using an algorithm developed and validated in the inventors' laboratory. 23、24 .

[0091] The main result of the test is the change in AHI. One-way analysis of variance followed by post hoc analysis is used to compare between treatment groups, compare each treatment group with the placebo, and p < 0 .025 is considered statistically significant to correct for multiple comparisons. Individual studies of 4 times (reference value + 3 test nights) are necessary.

[0092] Hypothesized results The tested combinations are evaluated for a significant decrease in the severity of OSA (AHI), an increase in oxygen level (SaO 2 ), and a decrease in exhaustion (Vpassive and Vactive) in both non-REM and REM sleep. The results determine whether a combination 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 of the nights using placebo and drugs will provide information on the mechanism of action of these combinations.

[0093] [Example 3] Alternative sleeping pills ​Whether other non - muscle - relaxant sleeping agents can be used instead of zolpidem or gabapentin To determine this, additional tests using zopiclone, eszopiclone, trazodone, or diphenhydr amine are performed in subjects with mild to moderate upper airway collapsibility (ventilation during sleep with normal effort was more than 50% of the placebo's resting ventilation) in combination with 80 mg of atomoxetine. The effects on the severity of OSA (AHI), oxygen level (SaO (SaO 2 ), and airway collapsibility (Vpassive and Vactive) are evaluated during both non - REM sleep 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 pimav anserin 34 mg to 5 patients to block the EEG 2 arousal response to CO associated with 80 mg of atomoxetine and measured the effects of this combination on the severity of OSA, arousal threshold, and collapsibility. These doses were each selected based on prescribing information, as they are the usual effective doses for attention - deficit disorder and hallucinations in patients with Parkinson's disease. Also, patients were fitted with a nose - mouth mask, and 4 / 5 patients were fitted with an esophageal catheter and genioglossus and masseter muscle intramuscular electrodes. 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 collapsibility (Vpassive ) by 63

[28] % 1d during quiet breathing (p = 0.07), increased the arousal threshold by 32

[20] % (Figure 6), and ​ The activity of the genioglossus muscle was increased by 110

[0244] %. As described above, pimavanserin In previous tests, it was administered together with atomoxetine, an arousal-promoting drug that reduced the arousal threshold by about 18% compared to placebo in OSA patients. Therefore, the effect on the arousal threshold is noteworthy. This means that pimavanserin can substantially increase the respiratory arousal threshold by about 50%. was administered together with atomoxetine, an arousal-promoting drug that reduced the arousal threshold by about 18% compared to placebo in OSA patients. Therefore, the effect on the arousal threshold is noteworthy. This means that pimavanserin can substantially increase the respiratory arousal threshold by about 50%. was administered together with atomoxetine, an arousal-promoting drug that reduced the arousal threshold by about 18% compared to placebo in OSA patients. Therefore, the effect on the arousal threshold is noteworthy. This means that pimavanserin can substantially increase the respiratory arousal threshold by about 50%. was administered together with atomoxetine, an arousal-promoting drug that reduced the arousal threshold by about 18% compared to placebo in OSA patients. Therefore, the effect on the arousal threshold is noteworthy. This means that pimavanserin can substantially increase the respiratory arousal threshold by about 50%.

[0095] References

[0096]

Table 1-1

[0097]

Table 1-2

[0098]

Table 1-3

[0099]

Table 1-4

[0100] Other Embodiments Although the present invention has been described in conjunction with its detailed description, it should be understood that the foregoing description is intended to illustrate, but not limit, the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. Although the present invention has been described in conjunction with its detailed description, it should be understood that the foregoing description is intended to illustrate, but not limit, the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. Although the present invention has been described in conjunction with its detailed description, it should be understood that the foregoing description is intended to illustrate, but not limit, the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. Although the present invention has been described in conjunction with its detailed description, it should be understood that the foregoing description is intended to illustrate, but not limit, 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

1. A pharmaceutical composition for treating a disease or disorder associated with pharyngeal airway collapse, said pharmaceutical composition comprising a norepinephrine reuptake inhibitor (NRI), said pharmaceutical composition being used to be administered in combination with a non-muscle relaxant hypnotic.

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

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

4. The pharmaceutical composition of claim 1, wherein the NRI is a norepinephrine nonselective reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxin, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, radafaxine, tapentadol, teniloxazine, and venlafaxine.

5. The pharmaceutical composition of claim 1, wherein the NRI is selected from the group consisting of atomoxetine and reboxetine.

6. The pharmaceutical composition described in claim 5, wherein the NRI is atomoxetine.

7. The pharmaceutical composition described in claim 6, wherein the atomoxetine is administered at a dose of 20 to 100 mg.

8. The pharmaceutical composition of claim 1, wherein the NRI is viloxazine.

9. The pharmaceutical composition described in claim 1, wherein the non-muscle relaxant hypnotic is a benzodiazepine hypnotic, preferably temazepam, brotizolam, flurazepam, nitrazepam, or triazolam.

10. The pharmaceutical composition of claim 1, wherein the non-muscle relaxant hypnotic is a non-benzodiazepine hypnotic, preferably a cyclopyrrolone hypnotic, more preferably selected from the group consisting of zolpidem, zopiclone and eszopiclone, gabapentin, trazodone, diphenhydramine, suvorexant, tasimelteon, ramelteon, agomelatine, doxepin, zaleplon, doxylamine, sodium oxybate, and tiagabine.

11. The pharmaceutical composition of claim 1, wherein the non-muscle relaxant hypnotic is in an immediate release formulation.

12. The pharmaceutical composition described in claim 1, wherein the non-muscle relaxant hypnotic is in a sustained release formulation.

13. The pharmaceutical composition described in claim 1, wherein the non-muscle relaxant hypnotic is zolpidem.

14. The pharmaceutical composition of claim 13, wherein the zolpidem is administered at a dose of 2 to 12.5 mg.

15. The pharmaceutical composition of claim 14, wherein the zolpidem is in an immediate release formulation at a dose of 2 to 10 mg or in a sustained release formulation at a dose of 5 to 12.5 mg.

16. The pharmaceutical composition described in claim 10, wherein the non-muscle relaxant hypnotic is trazodone.

17. A pharmaceutical composition described in any one of claims 1 to 16, wherein the disease or disorder is obstructive sleep apnea or simple snoring.

18. The pharmaceutical composition described in claim 17, wherein the disease or disorder is obstructive sleep apnea.

19. The pharmaceutical composition of claim 1, wherein the NRI and the non-muscle relaxant hypnotic are formulated into a single composition.

20. The pharmaceutical composition of claim 19, wherein the single composition is an oral dosage form containing a pharmaceutically acceptable carrier.

21. The pharmaceutical composition of claim 20, wherein the oral dosage form is a syrup, pill, tablet, lozenge, or capsule.

22. The pharmaceutical composition described in claim 1, wherein the NRI and the non-muscle relaxant hypnotic are administered simultaneously.

23. A pharmaceutical composition comprising (i) a norepinephrine reuptake inhibitor (NRI), (ii) a non-muscle relaxant hypnotic, and (iii) a pharmaceutically acceptable carrier.

24. The pharmaceutical composition of claim 23, wherein the NRI is a norepinephrine selective reuptake inhibitor (NSRI).

25. The pharmaceutical composition of claim 24, wherein the NSRI is selected from the group consisting of amidabutyric acid, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine.

26. The pharmaceutical composition of claim 23, wherein the NRI is a norepinephrine nonselective reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxin, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, radafaxine, tapentadol (Nucynta), teniloxazine (Lucelan, Metatone), and venlafaxine.

27. The pharmaceutical composition of claim 23, wherein the NRI is selected from the group consisting of atomoxetine and reboxetine.

28. The pharmaceutical composition of claim 23, wherein the NRI is atomoxetine.

29. The pharmaceutical composition of claim 23, wherein the NRI is viloxazine.

30. The pharmaceutical composition described in claim 23, wherein the non-muscle relaxant hypnotic is a benzodiazepine hypnotic, preferably temazepam, brotizolam, flurazepam, nitrazepam, or triazolam.

31. The pharmaceutical composition of claim 23, wherein the non-muscle relaxant hypnotic is a non-benzodiazepine hypnotic, preferably a cyclopyrrolone hypnotic, more preferably selected from the group consisting of zolpidem, zopiclone and eszopiclone, gabapentin, trazodone, diphenhydramine, suvorexant, tasimelteon, ramelteon, agomelatine, doxepin, zaleplon, doxylamine, sodium oxybate, and tiagabine.

32. The pharmaceutical composition of claim 23, wherein the non-muscle relaxant hypnotic is in an immediate release formulation.

33. The pharmaceutical composition described in claim 23, wherein the non-muscle relaxant hypnotic is in a sustained release formulation.

34. The pharmaceutical composition described in claim 23, wherein the non-muscle relaxant hypnotic is zolpidem.

35. The pharmaceutical composition of claim 34, wherein the zolpidem is in an immediate release formulation at a dose of 2 to 10 mg or in a sustained release formulation at a dose of 5 to 12.5 mg.

36. The pharmaceutical composition described in claim 23, wherein the non-muscle relaxant hypnotic is trazodone.

37. The pharmaceutical composition of claim 23, wherein the NRI and the non-muscle relaxant hypnotic are formulated into a single composition.

38. The pharmaceutical composition of claim 37, wherein the single composition is an oral dosage form.

39. The pharmaceutical composition of claim 38, wherein the oral dosage form is a pill, tablet, lozenge, or capsule.

40. A pharmaceutical composition according to any one of claims 23 to 39 for use in treating a disease or disorder associated with pharyngeal airway collapse.

41. A pharmaceutical composition for use according to claim 40, wherein the disease or disorder is sleep apnea or simple snoring.

42. A pharmaceutical composition for use according to claim 41, wherein the disease or disorder is obstructive sleep apnea.

43. A pharmaceutical composition for treating a disease or disorder associated with pharyngeal airway collapse, the pharmaceutical composition comprising a non-muscle relaxant hypnotic, the pharmaceutical composition being used to be administered in combination with a norepinephrine reuptake inhibitor (NRI).

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