Method and composition for treating sleep apnea

Abstract

To provide a method and a composition for treating a subject having an incomplete conscious state and, at the same time, a symptom accompanied by collapse of pharyngeal airway muscles, which is, sleep apnea and snoring for example.SOLUTION: A method for treating a subject having an incomplete conscious state and, at the same time, a symptom accompanied by collapse of pharyngeal airway muscles includes administering an effective dose of (i) norepinephrine reuptake inhibitor (NRI) and (ii) muscarinic receptor antagonist to a subject who needs the treatment.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Priority claims This application is a continuation of U.S. patent application Ser. No. 62 / 491,504 filed April 28, 2017, and Ser. No. 2016 / 0109994 filed April 28, 2017. This application claims the benefit of U.S. Patent Application No. 62 / 558,814, filed September 14, 2017. The entire disclosure of the foregoing is incorporated herein by reference.

[0002] Federally funded research or development This invention is based on the findings of the National Institutes of Health Government support under grant number HL095491 awarded by the National Institute of Health The Government has certain rights in this invention.

[0003] The present invention relates to a condition involving pharyngeal airway collapse while a subject is in a partially conscious state, such as snoring. Based at least in part on the discovery of methods and compositions for treating sleep apnea, This includes the administration of nephrin reuptake inhibitors (NRIs) and muscarinic receptor antagonists. nothing. [Background technology]

[0004] Obstructive sleep apnea (OSA) is a common disorder caused by the collapse of the pharyngeal airway during sleep. harm 1 OSA can have serious health consequences. Summary of the Invention [Means for solving the problem]

[0005] The present disclosure provides a method for the treatment of muscular atrophy by administration of noradrenergic and antimuscarinic drugs. Therefore, pharyngeal muscle activity increases during human sleep and snoring occurs in, for example, OSA patients. and based on the surprising discovery that sleep apnea severity can be reduced.

[0006] Therefore, subjects with symptoms involving pharyngeal airway collapse while in a partially conscious state are A method of treating an inflammatory bowel disease is provided, which comprises administering to a subject in need thereof an effective amount of (i) (i) epinephrine reuptake inhibitors (NRIs) and (ii) muscarinic receptor antagonists This includes administering a sto.

[0007] In some embodiments, the NRI is a norepinephrine selective reuptake inhibitor (NS RI), such as Amedalin, Atomoxetine, CP-39,332, Daredalin, Eddy Voxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram an NSRI selected from the group consisting of thiamin, talsupram, tandamycin, and viloxazine; be.

[0008] In some embodiments, the NRI is a norepinephrine nonselective reuptake inhibitor (N NRI), e.g., amitriptyline, amoxapine, bupropion, cyclazindol , desipramine, desvenlafaxine, dextromethylphenidate, diethylpropional Pion, doxepin, duloxetine, imipramine, levomilnacipran, manifaki Synth, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline Chirin, phendimetrazine, phenmetrazine, protriptyline, radafaxine, NN selected from the group consisting of tapentadol, teniloxazine, and venlafaxine It is RI.

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

[0010] In some embodiments, the NRI is atomoxetine, and in certain embodiments The dosage of atomoxetine is 20 to 100 mg, for example, 25 to 75 mg.

[0011] In some embodiments, the muscarinic receptor antagonist is an M2 receptor agonist. Examples of antihistamines include atropine, propantheline, bethanechol, solifenacin, and dali Consists of fenacin, tolterodine, fesoterodine, trospium, and oxybutynin The compound is selected from the group consisting of:

[0012] In some embodiments, the muscarinic receptor antagonist is anisotropine, benzamidine, or benzodiazepine. dzutropin, biperiden, clidinium, cyclimine, dicyclomine, diphemanil, Difenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropanol mepenzolate, methixene, methscopolamine, oxyphencyclamine, oxaliplatin Cyphenonium, procyclidine, scopolamine, tridihexethyl and trihexyphen Nijiru is selected from the group consisting of.

[0013] In some embodiments, the muscarinic receptor antagonist is in an immediate release dosage form. .

[0014] In some embodiments, the muscarinic receptor antagonist is in a sustained release dosage form.

[0015] In some embodiments, the muscarinic receptor antagonist is oxybutynin. , and in certain embodiments, the dosage of oxybutynin is 2 to 15 mg.

[0016] In some embodiments, oxybutynin is administered immediately, e.g., in a dose of 2.5 to 10 mg. Take the dosage form.

[0017] In some embodiments, oxybutynin is provided in a sustained release dosage form, e.g., at a dose of 5-15 mg. Take.

[0018] In some embodiments, the disease or disorder is obstructive sleep apnea (e.g., AHI > 1 0 events / hour) or simple snoring.

[0019] In some embodiments, the state of incomplete consciousness is sleep.

[0020] In some embodiments, the NRI and the muscarinic receptor antagonist are combined in a single composition. It is administered in a substance.

[0021] In some embodiments, the single composition is in an oral dosage form.

[0022] In some embodiments, the oral dosage form is a syrup, pill, tablet, lozenge, or is a capsule formulation.

[0023] In some embodiments, the single composition is in the form of a transdermal dosage form, such as a patch.

[0024] (i) norepinephrine reuptake inhibitors (NRIs), (ii) muscarinic receptor agonists Also described herein are pharmaceutical compositions comprising an antagonist, and (iii) a pharmaceutically acceptable carrier. It is provided at.

[0025] In some embodiments, the NRI is a norepinephrine selective reuptake inhibitor (NS RI), such as Amedalin, Atomoxetine, CP-39,332, and Daredalin , edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, It is selected from the group consisting of talopram, talsupram, tandamin, and viloxazine. In some embodiments, the NRI is amitriptyline, amoxapine, bupropion, Cyclazindol, desipramine, desvenlafaxine, dextromethylphenidate diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran Ran, manifaxin, maprotiline, methylphenidate, milnacipran, nefazo Don, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, Radafaxine, tapentadol (Nucynta), teniloxazine (Lucelan) Norepinephrine selected from the group consisting of: Metatone, and venlafaxine It is a nonselective reuptake inhibitor (NNRI).

[0026] In some embodiments, the NRI is selected from the group consisting of atomoxetine and reboxetine. be selected.

[0027] In some embodiments, the NRI is atomoxetine, and in particular embodiments, The dosage of atomoxetine is 20 to 100 mg.

[0028] In some embodiments, the muscarinic receptor antagonist is an M2 antagonist. Examples of such antihistamines include atropine, propantheline, bethanechol, solifenacin, and darifenol. Consists of phenacin, tolterodine, fesoterodine, trospium, and oxybutynin is selected from the group.

[0029] In some embodiments, the muscarinic receptor antagonist component of the pharmaceutical composition is Nisotropine, benztropine, biperiden, clidinium, cyclimine, dicyclomine , difemanil, difenidol, ethopropazine, glycopyrrolate, hexocycline um, isopropamide, mepenzolate, methixene, methscopolamine, oxyphen Cyclimine, oxyphenonium, procyclidine, scopolamine, tridihexethyl and and trihexyphenidyl. In some embodiments, the muscari receptor antagonist is in an immediate release dosage form. The agonist receptor antagonist is in a sustained release dosage form.

[0030] In some embodiments, the muscarinic receptor antagonist is oxybutynin. In some embodiments, oxybutynin is provided as an immediate release formulation, e.g., in a dose of 2.5 to 10 mg. In some embodiments, oxybutynin is administered in a sustained dose of, for example, 5 to 15 mg. It takes a fixed release form.

[0031] For use in treating subjects with conditions associated with pharyngeal airway collapse while the subject is partially conscious Also provided are compositions described herein that treat a disease or disorder. In some embodiments, the disease or disorder is obstructive sleep apnea or simple snoring. I have sleep apnea.

[0032] In some embodiments, the state of incomplete consciousness is sleep.

[0033] In some embodiments, the NRI and the muscarinic receptor antagonist are combined in a single composition. It is administered in a substance.

[0034] In some embodiments, the single composition is in an oral dosage form.

[0035] In some embodiments, the oral dosage form is a pill, tablet, lozenge, or capsule. is.

[0036] For use in treating subjects with conditions associated with pharyngeal airway collapse while the subject is in a partially conscious state. Norepinephrine reuptake inhibitors (NRIs) and muscarinic receptor antagonists are used Agonists are also provided.

[0037] Additionally, for example, a subject may have symptoms associated with pharyngeal airway collapse while in a partially conscious state. Norepinephrine, for example, as used in the methods described herein, to treat a subject suffering from Kits containing a reuptake inhibitor (NRI) and a muscarinic receptor antagonist are also available. The kits provided herein include a pharmaceutically acceptable salt or carrier of: The individual pharmaceutical compositions may comprise any of the individual active agents claimed herein, The kit may include (a) separate or common bottles or packets, potentially allowing for separate dosing; and (b) optionally, a set of kit instructions.

[0038] Unless otherwise specified, all technical and scientific terms used herein are defined by the The term "method and material" has the same meaning as commonly understood by a person skilled in the art to which the invention pertains. The materials may be prepared by any of the methods described herein for use in the present invention; or by other suitable methods known in the art. The materials, methods, and examples are merely illustrative and not restrictive. All publications, patent applications, patents, and related documents mentioned herein are not intended to be limiting. , sequences, database entries, and other references are incorporated herein by reference in their entireties. In case of conflict, the present specification, including definitions, will control.

[0039] Other features and advantages of the invention will become apparent from the following detailed description and drawings, as well as from the claims. It will be obvious. [Brief explanation of the drawings]

[0040] [Figure 1] Obstructive apnea is illustrated. The top channel shows the electroencephalogram (EEG) pattern of sleep. The next channel represents airflow. The next three channels show ventilatory effort through thoracic and abdominal movement and changes in esophageal pressure, all of which represent contraction of the respiratory muscles. The final channel shows oxyhemoglobin saturation. [Figure 2A-2B] Decrease in pharyngeal muscle activity from wakefulness to sleep in the presence of placebo (2A). In contrast, atomoxetine plus oxybutynin keeps pharyngeal muscle activity close to wakefulness values ​​during sleep (2B). [Figure 3A-3B] Participants received treatment (atomoxetine 80 mg + oxybutynin 5 mg) or placebo in random order 30 minutes before sleep. Results showed that the combination of atomoxetine and oxybutynin reduced the apnea-hypopnea index (AHI) from 31 [10-54] to 8 [2-18] (3A). Data are expressed as median [25th-75th percentile]. When the analysis of OSA severity was limited to the 15 subjects with an AHI > 10 events / hour, the effect of the atomoxetine / oxybutynin combination was even greater (-78% AHI compared with placebo) (3B). [Figure 4] The combination of atomoxetine and oxybutynin increased ventilation during sleep. Ventilation was calculated as % of normal ventilation with normal ventilatory drive for placebo and drug nights. [Figure 5] Patients with OSA improved their overnight minimum oxygen blood level from 84 [79-92] on placebo to 94 [89-95] during the atomoxetine / oxybutynin night. [Figures 6A-6B]For subjects with an AHI > 10, total sleep time (6A) and sleep efficiency (6B) were also improved on atomoxetine / oxybutynin nights compared to placebo. [Figure 7] Only the combination of atomoxetine and oxybutynin showed a significant reduction in AHI compared to placebo; atomoxetine or oxybutynin alone did not show any improvement in AHI. [Figure 8] In subjects with mild to moderate upper airway collapse, atomoxetine and fesoterodine were as effective as atomoxetine and oxybutynin in reducing AHI. [Figure 9] In six subjects not treated with CPAP, administration of a combination of atomoxetine and oxybutynin (atomoxetine 80 mg / oxybutynin 5 mg) reduced AHI by 63% after 1 week. [Figures 10A-10B] (10A) Group data showing the effect of atomoxetine plus oxybutynin (ato-oxy) on genioglossus reactivity. The shaded area represents the interquartile range of the slope. The horizontal error bars illustrate the interquartile range of the Pes baseline; the baseline value (EMGGG = 100%) is offset vertically to facilitate visualization of the error bars. (10B) Example raw data are shown to provide context. The signals show an increase in Pes swing during sleep with a concomitant increase in genioglossus activity. EMGGG: genioglossus electromyography; mta: mean movement time; Pes: esophageal pressure. DETAILED DESCRIPTION OF THE INVENTION

[0041] In humans, the pharyngeal airway region has no bony or cartilaginous support and is held open by muscles. When these muscles relax during sleep, the pharynx collapses, resulting in airflow obstruction. As shown in Figure 1, the esophageal pressure may increase as the patient attempts to overcome the obstruction. The respiratory effort continues and increases. The movement of the thorax and abdomen forces the diaphragm against the obstructed airway. Contraction results in opposite directions, with the abdominal wall expanding outward and the chest wall expanding inward. To collapse.

[0042] Increased respiratory effort leads to a sleep-wake state that can be visualized on EEG (Figure 1). 1), which results in the airway opening and normal breathing resuming. This also results in hypoxia, indicated by a decrease in oxyhemoglobin saturation (Figure 1). It is generally measured using the Apnea Hypopnea Index (AHI), which is the number of apneas (at least 1 0 seconds of breathing cessation) and hypopnea (reduced airflow and oxygen saturation) per hour of sleep For example, Ruehland et al., The ne w AASM criteria for scoring hypopneas:Im pact on the apnea hypopnea index.SLEEP 2 See 009;32(2):150-157.

[0043] If a strict definition of OSA is used (AHI ≥ 15 events / hour or AHI ≥ 15 events / hour during daytime sleep), ≥5 events / hour), the estimated prevalence is approximately 15% in men and 5% in women. An estimated 30 million people in the United States have OSA, of which approximately 6 million are diagnosed. The prevalence of OSA in Japan is thought to be increasing due to an aging population and rising rates of obesity. Major complications and economic costs include: hypertension, diabetes, cardiovascular disease, car accidents, Associated with workplace accidents and fatigue / reduced productivity. For example, Young et al. .,WMJ 2009;108:246;Peppard et al.,Am JE See pidemiol 2013;177:1006.

[0044] Treatment according to the present invention 2、3 is continuous positive airway pressure (CPAP). It is effective in virtually all patients, treating approximately 85% of diagnosed patients, but compliance is Patients often find CPAP painful and intolerable; 30% (up to 80%) of all braces are worn inconsistently and therefore untreated (Weave r,Proc Am Thorac Soc.2008 Feb 15;5(2):17 3-178) Other treatment modalities with varying success rates include oral appliances (10%) and manual surgery (5%), but neither is likely to be effective across the general population. However, pharmacological treatment has not been shown to be effective.

[0045] Studies of drugs activating pharyngeal muscles in humans during sleep are disappointing: serotonin reuptake. Drugs such as receptor blockers, tricyclic antidepressants, and sedatives have all been tested in humans, have not been shown to be effective in reducing OSA severity. Hudgel,Chest.1991 Aug;100(2):416-21;Brow nell et al.,N Engl J Med 1982,307:1037-1 042;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 See Feb 1;40(2).

[0046] Surprisingly, the present inventors have found that administration of noradrenergic and antimuscarinic drugs administration increases pharyngeal muscle activity in humans during sleep and reduces snoring in OSA patients. and found that sleep apnea severity can be reduced.

[0047] Treatment method The methods described herein include methods of treating disorders involving collapse of pharyngeal airway muscles during sleep. In some embodiments, the condition is obstructive sleep apnea (OSA) (AHI≧10 The term "snoring" is used to refer to a condition where snoring is present, defined as a "period of time" or "event / time" (e.g., a "period of time"). Generally, the method is used to refer to a condition where such treatment is necessary. For subjects that are or have been determined to be necessary, and a therapeutically effective amount of a norepinephrine reuptake inhibitor and an antimuscarinic agent as described in the document. This includes administering.

[0048] As used in this context, "treatment" means the treatment of at least one symptom of a disease associated with pharyngeal airway collapse. Often, pharyngeal airway collapse during sleep can cause snoring and / or breathing problems. This results in interruptions in sleep (apnea or hypopnea), arousals from sleep, and reduced oxygenation; Treatment may result in one or more of the following: snoring, apnea / hypopnea, sleep fragmentation, and hypoxemia. can be reduced by several.

[0049] Surprisingly, subjects may be in a state of incomplete consciousness, such as OSA, while also experiencing pharyngeal airway collapse. -Therapeutically effective amounts of norepinephrine reuptake inhibition for treating subjects with conditions associated with Administration of the agent and the antimuscarinic agent reduces AHI. In this case, the subject is in a state of incomplete consciousness such as OSA, and at the same time, the subject is in a state of pharyngeal airway collapse. A therapeutically effective amount of a norepinephrine reuptake inhibitor and an anti-inflammatory drug for treating a subject having Administration of the sculinomimetic reduces AHI by 50% or more. In this case, the subject is in a state of incomplete consciousness such as OSA, and at the same time, the subject is in a state of pharyngeal airway collapse. A therapeutically effective amount of a norepinephrine reuptake inhibitor and an anti-inflammatory drug for treating a subject having Administration of the sculinomimetic reduces AHI by 75% or more. In this study, the subject was in a state of incomplete consciousness, such as OSA, and was also in a state of pharyngeal airway collapse. and a therapeutically effective amount of a norepinephrine reuptake inhibitor for treating a subject having a Administration of an antimuscarinic agent increases ventilation. The subject has a condition that is accompanied by pharyngeal airway collapse while also being in a state of partial consciousness, such as OSA. Therapeutically effective amounts of a norepinephrine reuptake inhibitor and an antimuscari agent for treating a subject Administration of the agonist increases blood oxygen levels. The subject has a condition that is accompanied by pharyngeal airway collapse while also being in a state of partial consciousness, such as OSA. Therapeutically effective amounts of a norepinephrine reuptake inhibitor and an antimuscari agent for treating a subject Administration of agonist-like agents improved total sleep time, reduced AHI, increased oxygenation, Sleep fragmentation is reduced, total sleep time is increased, and / or subjective sleep quality is improved.

[0050] The effective amounts of the norepinephrine reuptake inhibitor and the antimuscarinic agent may be administered in one or more doses. Several administrations, applications or doses may be administered simultaneously or separately. In some cases, a combination of, for example, a norepinephrine reuptake inhibitor and an antimuscarinic agent is administered as a single dosage form. as a capsule, tablet or liquid containing both the steroid-like agent and the antihistamine-like agent, or as separate dosage forms, e.g. For example, one is a capsule, tablet, or liquid containing a norepinephrine reuptake inhibitor. The other is a capsule, tablet, or liquid containing an antimuscarinic agent. A luteinizing agent, an epinephrine reuptake inhibitor, and an antimuscarinic agent can be formulated. a norepinephrine reuptake inhibitor and an antimuscarinic agent simultaneously, or Separately, administered one or more times daily to one or more times weekly; e.g., once every other day In some embodiments, a norepinephrine reuptake inhibitor and an anti-muscarinic The cullinomimetic is administered daily. Those skilled in the art will appreciate that the administration of cullinomimetic depends on, but is not limited to, the severity of the disease or disorder. the severity of the condition, previous treatments, the subject's general health and / or age, and other diseases present. Certain factors may influence the dosage and timing required to effectively treat a subject. It will be understood that treatment of a subject with a therapeutically effective amount of a therapeutic compound as described herein will further be contemplated. Treatment can include a single treatment or a series of treatments.

[0051] Therapeutic compounds (i.e., NRI and Mus in a single composition or in separate compositions) The dosage, toxicity, and therapeutic efficacy of the phospholipase C1 receptor antagonists were determined in cell culture or experimental animals. Standard pharmaceutical procedures for substances can determine, for example, the LD50 (the dose that is lethal to 50% of the population) and This can be determined by determining the ED50 (the dose that is therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which is defined as the LD50 / ED50 ratio. It can be expressed as:

[0052] The data obtained from cell culture assays and animal studies are used to define a range of dosage for use in humans. The dosage of such compounds is preferably at most toxic levels. The dosage ranges from circulating concentrations that include the ED50 with no toxicity or toxicity. Therapeutically effective doses may vary within this range depending on the dosage form used and the route of administration utilized. The dose can be initially estimated from cell culture assays. IC5 determined in cell culture Circulating plasma concentrations including 0 (i.e., the concentration of test compound that achieves 50% maximal inhibition of symptoms). A dose can be formulated in animal models to achieve this range. This allows for more accurate determination of useful doses in humans. For example, it can be measured by high performance liquid chromatography.

[0053] In some embodiments, the method includes administering atomoxetine at a dose of 20-100 mg (or Other NRIs, equivalent doses) and oxybutynin 2-15 mg doses (or other This includes administering a dose of a scalin receptor antagonist (or an equivalent dose thereof). In an embodiment, the method comprises administering 80 mg atomoxetine / 5 mg oxybutynin; mg atomoxetine / 5mg oxybutynin; 75mg atomoxetine / 6mg oxybutynin oxybutynin; 50 mg atomoxetine / 4 mg oxybutynin; or 25 mg atomoxetine In another embodiment, the method comprises administering 3 mg oxybutynin per 100 mg of sleep time. A dose of 20-100 mg of atomoxetine (or equivalent of other NRIs) within 1 hour dose) and oxybutynin 2-15 mg dose (or other muscarinic receptor antagonists) In some embodiments, the method includes administering a dose of the compound (a dose of the compound equivalent to that of the compound). 15-60 minutes before sleep time, e.g., 20-45 minutes, 15-25 minutes, or 20-30 minutes before sleep time 80mg atomoxetine / 5mg oxybutynin; 75mg atomoxetine / 5mg Oxybutynin; 75 mg atomoxetine / 6 mg oxybutynin; 50 mg atomoxetine 25 mg atomoxetine / 4 mg oxybutynin; or 25 mg atomoxetine / 3 mg oxybutynin This includes giving.

[0054] In a further embodiment, the method comprises administering atomoxetine / oxygen in a weight ratio of 12.5:1. In another embodiment, the method comprises administering butynin to a patient 15 to 20 minutes after sleep. 60 minutes, e.g., 20 to 45 minutes, 15 to 25 minutes, or 20 to 30 minutes before the dose of atomoxetine / oxybutynin in a weight ratio of 12.5:1.

[0055] Pharmaceutical compositions and methods of administration The methods described herein include administering to a subject a norepinephrine reuptake inhibitor and an antimuscarinic agent. The present invention relates to the use of pharmaceutical compositions containing the drug as an active ingredient. The steroid and antimuscarinic agents may be administered in a single composition or in separate compositions. In some embodiments, the method includes administering to a subject a norepinephrine reuptake inhibitor and It contains an antimuscarinic agent and no other active ingredients, meaning it prevents norepinephrine reuptake. Import inhibitors and antimuscarinic agents are the only agonists.

[0056] Exemplary norepinephrine reuptake inhibitors (NRIs) include selective NRIs, e.g., Amedalin (UK-3540-1), atomoxetine (Strattera), CP- 39,332, Daredalin (UK-3557-15), Edivoxetine (LY-221 6684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY -94,939), reboxetine (Edronax, Vestra), talopram (Lu 3-010), Talsprum (Lu 5-005), Tandamine (AY-23,946 ), viloxazine (Vivalan); and non-selective NRIs such as amitriptyline, Amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine , dextromethylphenidate, diethylpropion, doxepin, duloxetine, Imipramine, levomilnacipran, manifaxin (GW-320,659), mapro tyline, methylphenidate, milnacipran, nefazodone, nortriptyline, phenytoin Dimetrazine, phenmetrazine, protriptyline, radafaxine (GW-353 ,162), tapentadol (Nucynta), teniloxazine (Lucelan, M etatone) and venlafaxine.

[0057] Suitable examples of antimuscarinic agents include, but are not limited to, atropine, propanediol, Phosphorus, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine Other examples include benzodiazepines, trospium, and oxybutynin, which have activity at the M2 receptor. Typical antimuscarinic agents include anisotropine, benztropine, biperiden, Clidinium, cyclimine, dicyclomine, diphemanil, difenidol, ethopropanol Glycopyrrolate, Hexocyclium, Isopropamide, Mepenzolate, Methionine Xene, methscopolamine, oxyphencyclimine, oxyphenonium, procyclimine Examples of antihistamines include scopolamine, tridihexethyl, and trihexyphenidyl.

[0058] In some embodiments, the norepinephrine reuptake inhibitor is atomoxetine In some embodiments, the antimuscarinic agent is oxybutynin (e.g., N-desoxybutynin). ethyloxybutynin).

[0059] A pharmaceutical composition typically contains a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means a saline, solvent, dispersion, or the like that is compatible with pharmaceutical administration. These include media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. Active compounds such as zolpidem, eszopiclone, benzodiazepines, gabapentin Hypnotics such as thiagavine, thiamin, and xylem may also be incorporated into the composition.

[0060] A pharmaceutical composition is typically formulated to be compatible with its intended route of administration. Examples include systemic oral or transdermal administration.

[0061] Methods for formulating suitable pharmaceutical compositions are known in the art and are described, for example, in Remin gton:The Science and Practice of Pharmac y, 21st ed., 2005; and the books in the serie s Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs(Dek 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 formulated into pills, tablets, or other pharmaceutical preparations. The composition may be used in the form of tablets, lozenges, or capsules, for example gelatin capsules. Oral compositions can also be prepared using a liquid carrier, pharmaceutically compatible binders, and Tablets, pills, capsules, trowels, etc. may be included as part of the composition. The adhesive may contain the following ingredients or compounds of a similar nature: binders, e.g., microcrystalline cellulose, gum lagarose or gelatin; excipients such as starch or lactose, alginic acid, Disintegrants such as Primogel or corn starch; stearic acid Lubricants such as magnesium or sterotes; colloidal silicon dioxide a flow agent such as sucrose or saccharin; a sweetener such as peppermint, salicylic acid, or the like; methyl phosphate, or a flavoring agent such as orange flavoring.

[0062] One or both of the compounds described herein (i.e., norepinephrine reuptake inhibitors) Systemic administration of steroids (inhibitors and / or muscarinic receptor antagonists) is suitable for application to the skin. and by transdermal means, for example, using patches, gels, lotions, or films. For transdermal administration, penetrants appropriate to the epidermal barrier to be permeated should be used in the formulation. Such penetrants are generally known in the art. For example, for transdermal administration: As commonly known in the art, ointments, salves, gels, etc. The active compound can be formulated into a gel, lotion, or cream. The dose may be provided in individual sachets or via a metered dose pump applied daily; Cohn et al.,Ther Adv Urol.2016 Apr;8(2 ):83-90.

[0063] In one embodiment, the therapeutic compound is administered in a variety of dosage forms, including implants and microencapsulated delivery systems. These drugs are manufactured with carriers that protect the therapeutic compound from rapid elimination from the body, such as sustained-release formulations. Ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester Biodegradable, biocompatible polymers such as esters and polylactic acid can be used. can be prepared using standard techniques or can be manufactured by, for example, Alza Corporation Commercially available from ion and Nova Pharmaceuticals, Inc. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. For example, according to the method known to those skilled in the art as described in U.S. Pat. No. 4,522,811. These can be manufactured by

[0064] The composition may be packaged in a container, pack, or device together with instructions for administration or use in the methods described herein. The dispenser may contain a pharmaceutical composition. [Example]

[0065] The invention is further described in the following examples, but the invention as defined in the claims It does not limit the scope of

[0066] Example 1. Pilot Study The effects of antimuscarinic drugs, o- and o-steroids, on genioglossus muscle activity were investigated in three healthy human subjects. selective noradrenergic reuptake inhibitor, Atmo, in conjunction with xibutynin 5 mg The effect of xetine 80 mg was measured in a pilot study.

[0067] Figures 2A-B show the results of three individuals who received a combination of atomoxetine and oxybutynin. The data are shown in Figure 2A, which is the night of placebo administration. The graph in the first column shows the mean (relative mean) mean (relative mean) of the 24-hour period during restful wakefulness. Genioglossus muscle activity (EMG GG , quantified as a percentage of maximum Each circle represents the peak EMG of one breath. GG and the pressure is proportional to the epiglottis pressure. The graphs in the second column were obtained during stable NREM sleep. EMG during nighttime sleep GG Note the variable but apparent decrease in activity In contrast, when these same three individuals were given atomoxetine plus oxybutynin, , sleep-related decreases in pharyngeal muscle activity were partially or completely prevented (Figure 2B).

[0068] The data suggest that the tested drugs significantly reduced E during NREM sleep compared to placebo. MG GG These drugs are known to induce REM sleep. In subjects, EMG GG Activity was maintained at 49% of the wakefulness level in REM sleep, which suggests that the drug is effective at this stage as well.

[0069] Example 2. Crossover study This was followed by a placebo-controlled, double-blind, placebo-controlled study in 20 human patients with obstructive sleep apnea (OSA). A randomized, crossover study was conducted. Patients received treatment (atomoxa) in random order 30 minutes before sleep. Patients received either Atomoxine 80 mg + Oxybutynin 5 mg or placebo. The combination of oxybutynin and acetaminophen reduced the apnea-hypopnea index (AHI) by 31. The data showed a decrease from 0-54 to 8 [2-18]. Data are expressed as median values. [25th-75th percentile] (Figure 3A). During the study, five subjects received placebo on the night of The analysis of OSA severity showed that AHI > When limited to 15 subjects with 10 events / hour, the atomoxetine / oxybutynin combination The combined effect was even greater (78% reduction in AHI compared with placebo) (Figure 3B). All OSA patients showed improvement in OSA severity.

[0070] In these subjects, the combination of atomoxetine and oxybutynin Genioglossus muscle reactivity was increased, with ventilatory drive increasing by 0.1 to 0.3% max / min compared to placebo This corresponds to an increase in ventilatory drive with each cmH2O increase (measured as esophageal pressure). The genioglossus muscle showed more than two times the number of times with the drug compared to placebo. This increased upper airway muscle activity may contribute to the sleep This is thought to be the reason for the decrease in AHI and increase in ventilation during this period (Figure 4).

[0071] Oxygen levels (SaO2) also increased on the nights the drug was administered due to improved ventilation. The minimum SaO2 ranged from 84% [79-92] with placebo to 94% [8 The oxygen desaturation index (ODI) was 9.9-96 (Fig. 5), and the oxygen desaturation index (ODI) was 9.9-96 (Fig. 5). It changed from 13 [6-34] to 3 [0-8] with drug administration.

[0072] Furthermore, as shown in Figure 6A-B, for subjects with an AHI > 10, compared with placebo On nights when atomoxetine / oxybutynin was administered, total sleep time and sleep efficiency also decreased. It has improved.

[0073] Seven patients with OSA were also studied for two nights, with the two drugs administered alone (not in combination). As shown in Figure 7, only the combination of atomoxetine and oxybutynin was significantly superior to placebo. A significant reduction in AHI was observed compared with the control group, whereas the control group showed no significant reduction in AHI compared with the control group. Butynin did not improve AHI.

[0074] Example 3. Fesoterodine Studies Is it possible to use other antimuscarinic drugs instead of oxybutynin? To determine whether fesoterodine (a newer, sustained-release antimuscarinic agent) 4 mg in combination with atomoxetine 80 mg used (sleep ventilation with normal effort was greater than 50% of normal breathing ventilation with placebo) In this subgroup of patients, fesoterodine was superior to oxybutynin in reducing AHI. was equally effective.

[0075] In two patients with severe upper airway collapse (ventilation during sleep was less than 50% of normal ventilation), The atomoxetine / fesoterodine combination did not reduce AHI in In contrast, atomoxetine / oxybutynin reduced AHI.

[0076] Example 4. Prospective Study To evaluate the effect of the atomoxetine / oxybutynin combination, A prospective study was conducted over one week in six untreated patients. The patients had a baseline sleep study performed in the hospital; the drug (atomoxetine 80 mg / oxybutynin 5 mg) was administered at home for six nights, and on the seventh night, the patients returned to the hospital and repeated the sleep test after taking the drug. These studies were performed using a standard montage used in clinical polysomnography, including electroencephalogram, electrooculogram, flow measurement with a nasal cannula, and thermistor, abdominal belt and chest belt, bilateral genioglossus electromyogram recording and oxygen saturation. From the results shown in Figure 9, it was demonstrated that the AHI decreased by 63% "53 - 70" one week after treatment, suggesting that the effect of the drug persists until one week after treatment. In six untreated patients, a prospective study was conducted over one week. The patients had a baseline sleep study performed in the hospital; the drug (atomoxetine 80 mg / oxybutynin 5 mg) was administered at home for six nights, and on the seventh night, the patients returned to the hospital and repeated the sleep test after taking the drug. These studies were performed using a standard montage used in clinical polysomnography, including electroencephalogram, electrooculogram, flow measurement with a nasal cannula, and thermistor, abdominal belt and chest belt, bilateral genioglossus electromyogram recording and oxygen saturation. From the results shown in Figure , it was demonstrated that the AHI decreased by 63% "53 - 70" one week after treatment, suggesting that the effect of the drug persists until one week after treatment. In three patients, the inventors tested low-dose combinations, namely atomoxetine 80 mg in combination with oxybutynin 5 mg, atomoxetine 50 mg in combination with oxybutynin 4 mg, and atomoxetine 25 mg in combination with oxybutynin 3 mg. The AHI showed a dose-dependent decrease compared to placebo, suggesting that doses less than 80 / 5 mg may be effective in treating less severe diseases. For the purposes of the present invention, the inventors defined mild disease as 5 < AHI < 15 events / hour and moderate disease as 15 < AHI < 30 events / hour. In six untreated patients, a prospective study was conducted over one week. The patients had a baseline sleep study performed in the hospital; the drug (atomoxetine 80 mg / oxybutynin 5 mg) was administered at home for six nights, and on the seventh night, the patients returned to the hospital and repeated the sleep test after taking the drug. These studies were performed using a standard montage used in clinical polysomnography, including electroencephalogram, electrooculogram, flow measurement with a nasal cannula, and thermistor, abdominal belt and chest belt, bilateral genioglossus electromyogram recording and oxygen saturation.

[0077] In three patients, the inventors tested low-dose combinations, namely atomoxetine 80 mg in combination with oxybutynin 5 mg, atomoxetine 50 mg in combination with oxybutynin 4 mg, and atomoxetine 25 mg in combination with oxybutynin 3 mg. The AHI showed a dose-dependent decrease compared to placebo, suggesting that doses less than 80 / 5 mg may be effective in treating less severe diseases. For the purposes of the present invention, the inventors defined mild disease as 5 < AHI < 15 events / hour and moderate disease as 15 < AHI < 30 events / hour. In six untreated patients, a prospective study was conducted over one week. The patients had a baseline sleep study performed in the hospital; the drug (atomoxetine 80 mg / oxybutynin 5 mg) was administered at home for six nights, and on the seventh night, the patients returned to the hospital and repeated the sleep test after taking the drug. These studies were performed using a standard montage used in clinical polysomnography, including electroencephalogram, electrooculogram, flow measurement with a nasal cannula, and thermistor, abdominal belt and chest belt, bilateral genioglossus electromyogram recording and oxygen saturation. From the results shown in Figure , it was demonstrated that the AHI decreased by 63% "53 - 70" one week after treatment, suggesting that the effect of the drug persists until one week after treatment. In three patients, the inventors tested low-dose combinations, namely atomoxetine 80 mg in combination with oxybutynin 5 mg, atomoxetine 50 mg in combination with oxybutynin 4 mg, and atomoxetine 25 mg in combination with oxybutynin 3 mg.

[0078] To determine the effect of atomoxetine + oxybutynin (ato-oxy) on bilateral genioglossus reactivity, group data were obtained using bilateral genioglossus electromyogram recording in 16 of the 20 patients who participated in the first study. Muscle reactivity was spontaneous in non-REM sleep. In six untreated patients, a prospective study was conducted over one week. The patients had a baseline sleep study performed in the hospital; the drug (atomoxetine 80 mg / oxybutynin 5 mg) was administered at home for six nights, and on the seventh night, the patients returned to the hospital and repeated the sleep test after taking the drug. These studies were performed using a standard montage used in clinical polysomnography, including electroencephalogram, electrooculogram, flow measurement with a nasal cannula, and thermistor, abdominal belt and chest belt, bilateral genioglossus electromyogram recording and oxygen saturation. Changes in genioglossus electromyographic activity according to changes in esophageal pressure (Pes) amplitude during spontaneous breathing (baseline) The percentage of the line is shown (see Figure 10B for physiological context). Median response with cetethin-oxybutynin (solid slope) was significantly higher than with placebo (dashed slope). Note that the reactivity of β-glucan is greater than that of β-glucan. Figure 10B shows the reactivity of β-glucan in the presence of β-glucan. Exemplary raw data is shown. The signal shows an increase in the Pes amplitude during sleep as well as the genioglossus muscle activity. This indicates a spontaneous increase in muscle activity. Pay attention to the restoration of airflow accompanied by increased muscle activity. thing.

[0079] References 1.Young T,Peppard PE,Gottlieb DJ.Epidemi theory of obstructive sleep apnea:a popul ation health perspective.Am J Respir Cri t Care Med 2002;165:1217-39. 2.Engleman HM,Wild MR.Improving CPAP use by patients with the sleep apnoea / hypop noea syndrome(SAHS).Sleep Med Rev 2003;7 :81-99. 3.Kribbs NB,Pack AI,Kline LR,et al.Objec tive measurement of patterns of nasal CP AP use by patients with obstructive slee p apnea.The American review of respirato ry disease 1993;147:887-95. 4.Chan E,Steenland HW,Liu H,Horner RL.En dogenous excitatory drive modulating res piratory muscle activity across sleep-wa ke states.American journal of respirator y and critical care medicine 2006;174:12 64-73. 5.Grace KP,Hughes SW,Horner RL.Identific ation of the mechanism mediating geniogl ossus muscle suppression in REM sleep.Am J Respir Crit Care Med 2013;187:311-9. 6.Kubin L,Davies RO,Pack AI.Control of U pper Airway Motoneurons During REM Sleep .News Physiol Sci 1998;13:91-7. 7.Sood S,Morrison JL,Liu H,Horner RL.Rol e of endogenous serotonin in modulating genioglossus muscle activity in awake an d sleeping rats.American journal of resp iratory and critical care medicine 2005; 172:1338-47. 8.Sood S,Raddatz E,Liu X,Liu H,Horner RL .Inhibition of serotonergic medullary ra phe obscurus neurons suppresses genioglo ssus and diaphragm activities in anesthe tized but not conscious rats.J Appl Phys iol(1985)2006;100:1807-21. 9.Fenik VB,Davies RO,Kubin L.REM sleep-l ike atonia of hypoglossal(XII)motoneuron s is caused by loss of noradrenergic and serotonergic inputs.Am J Respir Crit Ca re Med 2005;172:1322-30. 10.Sood S,Liu X,Liu H,Horner RL.Genioglo ssus muscle activity and serotonergic mo dulation ofHypoglossal motor output in o bese Zucker rats.J Appl Physiol(1985)200 7;102:2240-50. 11.Hanzel DA,Proia NG,Hudgel DW.Response of obstructive sleep apnea to fluoxetin e and protriptyline.Chest 1991;100:416-2 1. 12.Kraiczi H,Hedner J,Dahlof P,Ejnell H, Carlson J.Effect of serotonin uptake inh ibition on breathing during sleep and da ytime symptoms in obstructive sleep apne a.Sleep 1999;22:61-7. 13.Berry RB,Yamaura EM,Gill K,Reist C.Ac ute effects of paroxetine on genioglossu s activity in obstructive sleep apnea.Sl eep 1999;22:1087-92. 14.Lai YY,Kodama T,Siegel JM.Changes in monoamine release in the ventral horn an d hypoglossal nucleus linked to pontine inhibition of muscle tone:an in vivo mic rodialysis study.J Neurosci 2001;21:7384 -91. 15.Grace KP,Hughes SW,Shahabi S,Horner R L.K+ channel modulation causes genioglos sus inhibition in REM sleep and is a str ategy for reactivation.Respir Physiol Ne urobiol 2013;188:277-88. 16.Eckert DJ,White DP,Jordan AS,Malhotra A,Wellman A.Defining phenotypic causes of obstructive sleep apnea.Identificatio n of novel therapeutic targets.Am J Resp ir Crit Care Med 2013;188:996-1004. 17.Wellman A,Eckert DJ,Jordan AS,Edwards BA,Passaglia CL,Jackson AC,Gautam S,Owe ns RL,Malhotra A,White DP.A method for m easuring and modeling the physiological traits causing obstructive sleep apnea.J Appl Physiol 2011;110:1627-1637. 18.Wellman A,Edwards BA,Sands SA,Owens R L,Nemati S,Butler JP,Passaglia CL,Jackso n AC,Malhotra A,White DP.A simplified me thod for determining phenotypic traits i n patients with obstructive sleep apnea. 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Prospective study of the association bet ween sleep-disordered breathing and hype rtension.The New England journal of medi cine 2000;342:1378-1384. 24.Hung J,Whitford EG,Parsons RW,Hillman DR.Association of sleep apnoea with myo cardial infarction in men.Lancet 1990;33 6:261-264. 25.Wessendorf TE,Teschler H,Wang YM,Koni etzko N,Thilmann AF.Sleep-disordered bre athing among patients with first-ever st roke.J Neurol 2000;247:41-47. 26.Hoffstein V.Blood pressure,snoring,ob esity,and nocturnal hypoxaemia.Lancet 19 94;344:643-645. 27.Shahar E,Whitney CW,Redline S,Lee ET, Newman AB,Nieto FJ,O’Connor GT,Boland LL ,Schwartz JE,Samet JM.Sleep-disordered b reathing and cardiovascular disease:Cros s-sectional results of the sleep heart h ealth study.Am J Respir Crit Care Med 20 01;163:19-25. 28.Redline S,Strauss ME,Adams N,Winters M,Roebuck T,Spry K,Rosenberg C,Adams K.N europsychological function in mild sleep -disordered breathing.Sleep 1997;20:160- 167. 29.Findley LJ,Unverzagt ME,Suratt PM.Aut omobile accidents involving patients wit h obstructive sleep apnea.Am Rev Respir Dis 1988;138:337-340. 30.Edwards BA,Sands SA,Eckert DJ,White D P,Butler JP,Owens RL,Malhotra A,Wellman A.Acetazolamide improves loop gain but n ot the other physiological traits causin g obstructive sleep apnoea.J Physiol 201 2;590:1199-1211. 31.Wellman A,Malhotra A,Jordan AS,Steven son KE,Gautam S,White DP.Effect of oxyge n in obstructive sleep apnea:Role of loo p gain.Respir Physiol Neurobiol 2008;162 :144-151. 32.Lai YY,Kodama T,Siegel JM.Changes in monoamine release in the ventral horn an d hypoglossal nucleus linked to pontine inhibition of muscle tone:An in vivo mic rodialysis study.J Neurosci 2001;21:7384 -7391.

[0080] Other embodiments The present invention has been described in detail with reference to the accompanying specification, the foregoing specification being intended to be illustrative. and is intended to limit the scope of the invention, which is defined by the appended claims. It should be understood that other aspects, advantages, and modifications are within the scope of the following claims. It's in range.

Claims

1. Method for treating a subject who is partially conscious and has symptoms associated with pharyngeal airway collapse The method comprises administering to a subject in need thereof an effective amount of (i) a norepinephrine reuptake inhibitor (ii) administering an NRI and (iii) a muscarinic receptor antagonist. 。

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

1. The method according to claim 1.

3. The NSRI is amidabutyric acid, atomoxetine, CP-39,332, daladalin, ethoxycodone, thiazolin ... Divoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, taro Plum, Talsplum, Tandamine, and Viloxazine. The method according to item 2.

4. The NRI is amitriptyline, amoxapine, bupropion, cyclazindol, Desipramine, desvenlafaxine, dextromethylphenidate, diethylpropional On, doxepin, duloxetine, imipramine, levomilnacipran, magnifex methicillin, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline Phosphorus, phendimetrazine, phenmetrazine, protriptyline, radafaxine, nor- selected from the group consisting of pentadol, teniloxazine, and venlafaxine; 10. The method of claim 1, which is an epinephrine nonselective reuptake inhibitor (NNRI).

5. 12. The method of claim 1, wherein the NRI is selected from the group consisting of atomoxetine and reboxetine. The method described below.

6. 6. The method of claim 5, wherein the NRI is atomoxetine.

7. 7. The method of claim 6, wherein the atomoxetine is administered at a dose of 20 to 100 mg.

8. 8. The method of claim 7, wherein the atomoxetine is administered at a dose of 25 to 75 mg.

9. The muscarinic receptor antagonist is atropine, propantheline, bethanechol solifenacin, darifenacin, tolterodine, fesoterodine, trospium, 2. The method of claim 1, wherein the active ingredient is selected from the group consisting of: and oxybutynin.

10. The muscarinic receptor antagonist is anisotropine, benztropine, biperidin, Dane, Clidinium, Cyclimine, Dicyclomine, Difemanil, Difenidol, Etho Propazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate , methixene, methscopolamine, oxyphencyclimine, oxyphenonium, pro From the group consisting of cyclizine, scopolamine, tridihexethyl and trihexyphenidyl The method of claim 1 , wherein

11. 10. The method of claim 1, wherein the muscarinic receptor antagonist is in an immediate release dosage form. Law.

12. 10. The method of claim 1, wherein the muscarinic receptor antagonist is in a sustained release dosage form. 。

13. 13. Any of claims 1 to 12, wherein the muscarinic receptor antagonist is oxybutynin. The method according to any one of claims 1 to 4.

14. 14. The method of claim 13, wherein the oxybutynin is administered at a dose of 2 to 15 mg.

15. 10. The method of claim 1, wherein the oxybutynin is in an immediate release dosage form having a dose of 2.5 to 10 mg.

4. The method according to claim 4.

16. 15. The method according to claim 14, wherein the oxybutynin is in a sustained release dosage form having a dose of 5 to 15 mg. How to post.

17. Any of claims 1 to 16, wherein the disease or disorder is obstructive sleep apnea or simple snoring. The method according to any one of claims 1 to 4.

18. 18. The method of claim 17, wherein the disease or disorder is obstructive sleep apnea.

19. The method of claim 1 , wherein the state of incomplete consciousness is sleep.

20. The NRI and the muscarinic receptor antagonist are administered in the form of a single composition. The method of claim 1 .

21. 21. The method of claim 20, wherein the single composition is an oral dosage form.

22. 10. The oral dosage form of claim 9, wherein the oral dosage form is a syrup, a pill, a lozenge, or a capsule.

22. The method according to claim 21.

23. (i) norepinephrine reuptake inhibitors (NRIs), (ii) muscarinic receptor agonists A pharmaceutical composition comprising an antagonist and (iii) a pharmaceutically acceptable carrier.

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

3. The composition described in 3.

25. The NSRI is amidabutyric acid, atomoxetine, CP-39,332, daladalin, ethoxycodone, thiazolin ... Divoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, taro Plum, Talsplum, Tandamine, and Viloxazine. Item 25. The composition according to item 24.

26. The NRI is amitriptyline, amoxapine, bupropion, cyclazindol, Desipramine, desvenlafaxine, dextromethylphenidate, diethylpropional On, doxepin, duloxetine, imipramine, levomilnacipran, magnifex methicillin, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline Phosphorus, phendimetrazine, phenmetrazine, protriptyline, radafaxine, Pentadol (Nucynta), teniloxazine (Lucelan, Metatone ) and venlafaxine, 24. The composition of claim 23, which is a non-steroidal anti-inflammatory drug (NNRI).

27. 2. The NRI of claim 1, wherein the NRI is selected from the group consisting of atomoxetine and reboxetine.

3. The composition described in 3.

28. 28. The composition of claim 27, wherein the NRI is atomoxetine.

29. 29. The composition of claim 28, wherein the dosage of atomoxetine is 20 to 100 mg.

30. The muscarinic receptor antagonist is atropine, propantheline, bethanechol solifenacin, darifenacin, tolterodine, fesoterodine, trospium, and oxybutynin.

31. The muscarinic receptor antagonist component of the pharmaceutical composition is selected from the group consisting of anisotropine, benzylparaben, and benzodiazepine. dzutropin, biperiden, clidinium, cyclimine, dicyclomine, diphemanil, Difenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropanol mepenzolate, methixene, methscopolamine, oxyphencyclamine, oxaliplatin Cyphenonium, procyclidine, scopolamine, tridihexethyl and trihexyphen 24. The composition of claim 23, wherein the composition is selected from the group consisting of nijiru.

32. 24. The method of claim 23, wherein the muscarinic receptor antagonist is in an immediate release dosage form. composition.

33. 24. The composition of claim 23, wherein the muscarinic receptor antagonist is in a sustained release dosage form. Finished product.

34. 34. The method of claim 23, wherein the muscarinic receptor antagonist is oxybutynin. The composition described in any one of claims 1 to 4.

35. 3. The oxybutynin of claim 3, wherein the oxybutynin is in an immediate release dosage form having a dose of 2.5 to 10 mg.

4. The composition described in 4.

36. 35. The method of claim 34, wherein the oxybutynin is in a sustained release dosage form having a dose of 5 to 15 mg. The composition described above.

37. The NRI and the muscarinic receptor antagonist are formulated in a single composition. The composition of claim 23.

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

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

40. For use in treating subjects with symptoms associated with partial consciousness and pharyngeal airway collapse The composition according to any one of claims 23 to 39,

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

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

43. 41. The composition for use according to claim 40, wherein the state of impaired consciousness is sleep.

44. For use in treating subjects with symptoms associated with partial consciousness and pharyngeal airway collapse Norepinephrine reuptake inhibitors (NRIs) and muscarinic receptor antagonists Nist.

45. Norepinephrine reuptake inhibitors (NRIs) and muscarinic receptor antagonists A kit to prepare.

46. For use in treating subjects with symptoms associated with partial consciousness and pharyngeal airway collapse 42. The kit of claim 41 ,

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