Methods and compositions for treating sleep apnea

Abstract

To provide methods and compositions for treating sleep apnea.SOLUTION: A pharmaceutical composition comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) substantially enantiomerically pure (R)-oxybutynin in a pharmaceutically acceptable carrier, for administration to a subject in need of treatment.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62 / 623,892, filed January 30, 2018. The disclosure of this prior application is considered part of the disclosure of this application and is incorporated herein by reference in its entirety.

[0002] Technical Field The present invention provides pharmaceutical compositions comprising (R)-oxybutynin and a norepinephrine reuptake inhibitor (NRI), and methods for treating sleep apnea comprising administering (R)-oxybutynin and a norepinephrine reuptake inhibitor (NRI). [Background technology]

[0003] background Obstructive sleep apnea (OSA) is a common disorder caused by the collapse of the pharyngeal airway during sleep. OSA can have serious health consequences. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Taranto-Montemurro et al., Sleep. 2017 Feb 1;40(2) Summary of the Invention [Problem to be solved by the invention]

[0005] It is an object of the present invention to provide methods and compositions for treating sleep apnea. [Means for solving the problem]

[0006] overview One aspect of the present invention provides a method of treating a subject having a condition associated with pharyngeal airway collapse, comprising administering to a subject in need thereof effective amounts of (i) a norepinephrine reuptake inhibitor (NRI) and (ii) substantially enantomerically pure (R)-oxybutynin.

[0007] Embodiments of this aspect of the invention may include one or more of the following optional features: In some embodiments, the NRI is a norepinephrine selective reuptake inhibitor (NSRI). In some embodiments, the NSRI is selected from the group consisting of amedalin, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine. In some embodiments, the NRI is selected from the group consisting of amitriptyline, amoxapine, bupropion, ciclazindol, desipramine, desvenlafaxine, dexmethilphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxin, maprotiline, and fluoxetine. The norepinephrine nonselective reuptake inhibitor (NNRI) is selected from the group consisting of protiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, protryptyline, radafaxine, tapentadol, teniloxazine, and venlafaxine. In some embodiments, the NRI is selected from the group consisting of atomoxetine and reboxetine. In some embodiments, the NRI is atomoxetine. In some embodiments, atomoxetine is administered at a dose of about 20 to about 100 mg (e.g., about 25 to about 75 mg). In some embodiments, the (R)-oxybutynin is in an immediate-release formulation. In some embodiments, the (R)-oxybutynin is in an extended-release formulation. In some embodiments, (R)-oxybutynin is administered in a dose of about 2 to about 15 mg. For example, (R)-oxybutynin can be in an immediate release formulation and can be administered in a dose of about 2.5 to about 10 mg.Alternatively, for example, (R)-oxybutynin may be in an extended-release formulation and administered at a dose of about 5 to about 15 mg. In some embodiments, the condition associated with pharyngeal airway collapse is sleep apnea or simple snoring. For example, the condition associated with pharyngeal airway collapse may be obstructive sleep apnea (OSA). In some embodiments, the subject is in a non-fully conscious state (e.g., sleep). In some embodiments, the NRI and (R)-oxybutynin are administered in a single composition. In some embodiments, the single composition is an oral dosage form (e.g., a syrup, pill, tablet, lozenge, capsule, or patch).

[0008] Another aspect of the present invention provides a pharmaceutical composition comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) substantially enantiomerically pure (R)-oxybutynin in a pharmaceutically acceptable carrier.

[0009] Embodiments of this aspect of the invention may include one or more of the following optional features: In some embodiments, the NRI is a norepinephrine selective reuptake inhibitor (NSRI). In some embodiments, the NSRI is selected from the group consisting of amedalin, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine. In some embodiments, the NRI is a norepinephrine nonselective reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, protriptyline, radafaxine, tapentadol, teniloxazine, and venlafaxine. In some embodiments, the NRI is selected from the group consisting of atomoxetine and reboxetine. In some embodiments, the NRI is atomoxetine. In some embodiments, atomoxetine is present in an amount of about 20 to about 100 mg (e.g., about 25 to about 75 mg). In some embodiments, the (R)-oxybutynin is in an immediate-release formulation. In some embodiments, the (R)-oxybutynin is in an extended-release formulation. In some embodiments, the (R)-oxybutynin is present in an amount of about 2 to about 15 mg. For example, the (R)-oxybutynin can be in an immediate-release formulation and can be present in an amount of about 2.5 to about 10 mg. Or, for example, the (R)-oxybutynin can be in an extended-release formulation and can be present in an amount of about 5 to about 15 mg. In some embodiments, the composition is for use in treating a subject having a condition associated with pharyngeal airway collapse. In some embodiments, the condition associated with pharyngeal airway collapse is sleep apnea or simple snoring. In some embodiments, the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA). In some embodiments, the subject is in a non-fully conscious state (e.g., sleeping).

[0010] Another aspect of the present invention provides a norepinephrine reuptake inhibitor (NRI) and substantially enantiomerically pure (R)-oxybutynin for use in treating a subject having a condition associated with pharyngeal airway collapse.

[0011] Another aspect of the present invention provides a kit comprising a norepinephrine reuptake inhibitor (NRI) and substantially enantiomerically pure (R)-oxybutynin. In some embodiments, the kit is for use in treating a subject having a condition associated with pharyngeal airway collapse.

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention belongs.Methods and materials are described herein for use in the present invention, and other suitable methods and materials known in the art can also be used.Materials, methods and examples are illustrative only and are not intended to be limiting.All publications, patent applications, patents, sequences, database entries and other references mentioned herein are incorporated by reference in their entirety.In the case of conflict, the present specification, including definitions, will control.

[0013] Other features and advantages of the invention will be apparent from the following detailed description and drawings, and from the claims.

[0014] That is, the gist of the present invention relates to the following. Item 1 A pharmaceutical composition comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) substantially enantiomerically pure (R)-oxybutynin in a pharmaceutically acceptable carrier. [Effects of the Invention]

[0015] The present invention may provide methods and compositions for treating sleep apnea. [Brief explanation of the drawings]

[0016] BRIEF DESCRIPTION OF THE DRAWINGS The following drawings are provided by way of example and are not intended to limit the scope of the claimed invention. [Figure 1] Figure 1 is a graphical illustration of obstructive apnea. The top channel shows the electroencephalogram (EEG) pattern of sleep, the next channel shows airflow. The next three channels show ventilatory effort due to chest and abdominal movement and changes in esophageal pressure, all of which reflect contractions of respiratory muscles. The final channel shows oxyhemoglobin saturation. DETAILED DESCRIPTION OF THE INVENTION

[0017] Detailed Description 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 can collapse, causing airflow to stop. As shown in Figure 1, ventilatory efforts continue, increasing attempts to overcome the obstruction indicated by increasing esophageal pressure changes. The thoracic and abdominal movements are in opposite directions, with the abdominal wall expanding outward and the thoracic wall collapsing inward as a result of diaphragmatic contraction against the obstructed airway.

[0018] Increased breathing effort results in arousal from sleep, which can be visualized on EEG (Figure 1), with the airway opening and resumption of normal breathing. The lack of airflow during apnea also causes hypoxia, indicated by a drop in oxyhemoglobin saturation (Figure 1). Severity is commonly measured using the apnea-hypopnea index (AHI), which combines the average number of apneas (cessation of breathing for at least 10 seconds) and hypopneas (drops in airflow and oxygen saturation) occurring per hour of sleep (Ruehland et al., The new AASM criteria for scoring hypopneas: Impact on the apnea hypopnea index. SLEEP 2009;32(2):150-157).

[0019] When strict definitions of OSA are used (AHI >15 events per hour or AHI >5 events per hour with daytime sleepiness), the estimated prevalence is approximately 15% in men and 5% in women. An estimated 30 million individuals in the United States have OSA, of which approximately 6 million are diagnosed. The prevalence of OSA in the United States appears to be increasing due to aging and increasing rates of obesity. OSA is associated with major comorbidities and economic costs, e.g., hypertension, diabetes, cardiovascular disease, motor vehicle accidents, workplace accidents, and fatigue / loss of productivity. (Young et al., WMJ 2009; 108:246; Peppard et al., Am J Epidemiol 2013; 177:1006.)

[0020] The current primary treatment is continuous positive airway pressure (CPAP). CPAP is effective for virtually all patients, with approximately 85% of diagnosed patients prescribed CPAP, but compliance is low. Patients find CPAP uncomfortable and sometimes intolerable, and at least 30% (up to 80%) of patients are non-adherent and therefore untreated (Weaver, Proc Am Thorac Soc. 2008 Feb 15; 5(2): 173-178). Other treatment modalities with variable success rates include oral appliances (10%) and surgery (5%), neither of which may be effective in all of the general population. To date, no pharmacological treatment has been shown to be effective.

[0021] Research into medications to activate pharyngeal muscles in sleeping humans has been disappointing; drugs such as serotonin reuptake inhibitors, tricyclic antidepressants, and sedatives have all been tested in humans and shown to be ineffective in reducing OSA severity. For example, Proia and Hudgel, Chest. 1991 Aug;100(2):416-21;Brownell et al., N Engl J Med 1982, 307:1037-1042;Sangal et al., Sleep Med. 2008 Jul;9(5):506-10. Epub 2007 Sep 27;Marshall et al. p. 2008 Jun;31(6):824-31;Eckert et al., Clin Sci (Lond). 2011 Jun;120(12);505-14;Taranto-Montemurro et al., Sleep. See 2017 Feb 1;40(2).

[0022] Treatment method The method described herein comprises the method for treating disorders related to the collapse of pharyngeal airway muscles during sleep.In some embodiments, the disorder is obstructive sleep apnea (OSA) or simple snoring.Generally, the method comprises administering a therapeutically effective amount of norepinephrine reuptake inhibitor and substantially enantiomerically pure (R)-oxybutynin to the subject who needs or is determined to need such treatment, as known in the art and / or described herein.

[0023] In this context, "treat" refers to improving at least one symptom of disorders related to pharyngeal airway collapse.Sometimes, pharyngeal airway collapse during sleep leads to snoring and / or breathing interruptions (apnea or hypopnea), awakening from sleep and reduced oxygen enrichment (hypoxemia), so treatment can reduce snoring, apnea / hypopnea, sleep fragmentation and hypoxemia.Administering a therapeutically effective amount of the compound described herein for treating a subject with OSA results in a reduction in AHI.

[0024] An effective amount can be administered in one or more administrations, applications, or doses. The composition can be administered from once or more times per day to once or more times per week, for example, once every other day. In some embodiments, the composition is administered daily. Those skilled in the art will understand that certain factors, including but not limited to, the severity of the disease or disorder, previous treatment, the general health and / or age of the subject, and other diseases present, can affect the dosage and timing required to effectively treat a subject. Furthermore, treatment of a subject with a therapeutically effective amount of the therapeutic compound described herein can include a single treatment or a series of treatments.

[0025] The dosage, toxicity, and therapeutic efficacy of therapeutic compounds (i.e., NRI and (R)-oxybutynin in a single composition or in separate compositions) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50 / ED50.

[0026] Data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage of such compounds is preferably within a range of circulating concentrations that includes the ED50 with little or no toxicity. The dosage can vary within this range depending on the dosage form used and the route of administration utilized. For any compound used in the methods of the present invention, a therapeutically effective dose can be initially estimated from cell culture assays. Doses can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves half-maximal inhibition of symptoms), as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Plasma levels can be measured, for example, by high-performance liquid chromatography.

[0027] In some embodiments, the method comprises administering a 20-100 mg dose of atomoxetine (or an equivalent dose of another NRI) and a 2-15 mg dose of (R)-oxybutynin. In some embodiments, the method comprises administering 75 mg atomoxetine / 6 mg (R)-oxybutynin; 75 mg atomoxetine / 5 mg (R)-oxybutynin; 75 mg atomoxetine / 4.5 mg (R)-oxybutynin; 50 mg atomoxetine / 4 mg (R)-oxybutynin; or 25 mg atomoxetine / 3 mg (R)-oxybutynin, e.g., 15-60, e.g., 15-25, 20-30, or 20-45 minutes before bedtime.

[0028] Pharmaceutical Compositions and Methods of Administration The methods described herein involve the use of pharmaceutical compositions containing a norepinephrine reuptake inhibitor and a substantially enantiomerically pure (R)-oxybutynin as active ingredients. The norepinephrine reuptake inhibitor and (R)-oxybutynin can be administered in a single composition or in separate compositions.

[0029] Exemplary norepinephrine reuptake inhibitors (NRIs) include the selective NRIs amedalin (UK-3540-1), atomoxetine (Strattera), CP-39,332, daredalin (UK-3557-15), edivoxetine (LY-2216684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY-94,939), reboxetine (Edronax, Vestra), talopram (Lu 3-010), talsupram (Lu 5-005), tandamin (AY-23,946), viloxazine (Vivalan); nonselective NRIs include amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxin (GW-320,659), maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, radafaxine (GW-353,162), tapentadol (Nucynta), teniloxazine (Lucelan, Metatone), and venlafaxine.

[0030] In some embodiments, the norepinephrine reuptake inhibitor is atomoxetine.

[0031] (R)-oxybutynin is an antimuscarinic drug. The drug is the (R)-enantiomer of oxybutynin. As described herein, a composition comprising substantially enantiomerically pure (R)-oxybutynin contains an enantiomeric excess of (R)-oxybutynin relative to the enantiomer of (R)-oxybutynin (i.e., (S)-oxybutynin). The enantiomeric excess of the substantially enantiomerically pure (R)-oxybutynin can be ≧80%, ≧90%, ≧95%, ≧98%, ≧99%, ≧99.5%, ≧99.8%, or ≧99.9%.

[0032] Pharmaceutical compositions typically contain a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" includes saline, solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonicity agents, and absorption delaying agents that are compatible with pharmaceutical administration. Supplementary active compounds, such as hypnotics such as zolpidem, eszopiclone, benzodiazepines, gabapentin, tiagabine, and xyrem, can also be incorporated into the composition. In some embodiments, patients with OSA have a low awakening threshold that can be exacerbated by the administration of norepinephrine inhibitors. In such embodiments, where patients have a low awakening threshold that is caused or exacerbated by the use of one or more norepinephrine inhibitors (e.g., atomoxetine), hypnotics can be used as supplementary active compounds to increase the awakening threshold of patients with OSA, pharyngeal airway collapse, or a combination thereof. In some embodiments, the patient's awakening threshold can be measured by polysomnography (PSG). In some embodiments, the pharmaceutical composition comprises one or more norepinephrine reuptake inhibitors, substantially enantiomerically pure (R)-oxybutynin, and a hypnotic. In some embodiments, a method for treating a subject with a condition associated with pharyngeal airway collapse is provided, comprising administering to the subject in need of treatment an effective amount of (i) a norepinephrine reuptake inhibitor (NRI); (ii) substantially enantiomerically pure (R)-oxybutynin; and (iii) a hypnotic. The features of the compositions and methods described herein can be used in any combination with the embodiment incorporating a hypnotic.

[0033] In some embodiments, the method comprises administering atomoxetine at a dose of 20-100 mg (or an equivalent dose of another NRI), (R)-oxybutynin at a dose of 2-15 mg, and zolpidem at a dose of 0.5-15 mg (or an equivalent dose of another hypnotic). In some embodiments, the method comprises administering 75 mg atomoxetine / 6 mg (R)-oxybutynin / 10 mg zolpidem; 75 mg atomoxetine / 5 mg (R)-oxybutynin / 10 mg zolpidem; 75 mg atomoxetine / 4.5 mg (R)-oxybutynin / 5 mg zolpidem; 50 mg atomoxetine / 4 mg (R)-oxybutynin / 3.5 mg zolpidem; or 25 mg atomoxetine / 3 mg (R)-oxybutynin / 1.75 mg zolpidem, e.g., 15 to 60, e.g., 15 to 25, 20 to 30, or 20 to 45 minutes before sleep time. In some embodiments, the hypnotic is present in an amount of about 0.5 to about 15 mg, about 0.5 to about 10 mg, about 0.5 to about 5 mg, about 0.5 to about 3.5 mg, or about 0.5 to about 1.75 mg. In some embodiments, the norepinephrine reuptake inhibitor (NRI), the substantially enantiomerically pure (R)-oxybutynin, and the hypnotic are administered in a single composition for oral administration, for example, in the form of a syrup, pill, tablet, capsule, or patch.

[0034] A pharmaceutical composition is typically formulated to be compatible with its intended route of administration, such as systemic oral or transdermal administration.

[0035] Methods for formulating suitable pharmaceutical compositions are known in the art, see, for example, Remington: The Science and Practice of Pharmacy, 21st edition, 2005; and Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, oral compositions generally contain an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, active compound(s) can be combined with excipients and used in the form of pills, tablets, lozenges or capsules, for example, gelatin capsules. Oral compositions can also be prepared using liquid carriers. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, primogel or corn starch; a lubricant such as magnesium stearate or sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.

[0036] Systemic administration of one or both of the compounds described herein (i.e., one or both of the norepinephrine reuptake inhibitor and the substantially enantiomerically pure (R)-oxybutynin) can also be achieved by transdermal means, for example, using a patch, gel, or lotion applied to the skin. For transdermal administration, a penetrant suitable for penetrating the epithelial barrier can be used in the formulation. Such penetrants are generally known in the art. For example, for transdermal administration, the active compound can be formulated into an ointment, salve, gel, or cream, as generally known in the art. Gels and / or lotions can be provided in individual sachets or via a daily metered dose pump; see, for example, Cohn et al., Ther Adv Urol. 2016 Apr; 8(2): 83-90.

[0037] In one embodiment, the therapeutic compound is prepared with a carrier that protects the therapeutic compound from rapid elimination from the body, such as a controlled-release formulation, including implants and microencapsulated delivery systems.Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used.Such formulations can be prepared using standard techniques or commercially available from, for example, Alza Corporation and Nova Pharmaceuticals, Inc.Liposomal suspensions can also be used as pharmaceutically acceptable carriers.These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0038] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration or use in the methods described herein. [Example]

[0039] Example The present invention is further described in the following examples, which do not limit the scope of the claimed invention.

[0040] Example 1. Pilot study The effect of the antimuscarinic drug (R)-oxybutynin 5 mg in combination with the selective noradrenergic reuptake inhibitor atomoxetine 80 mg on genioglossus muscle activity in healthy human individuals is measured in a pilot study.

[0041] The first group of patients will receive a combination of atomoxetine 80 mg and (R)-oxybutynin 5 mg. The second group of patients will receive a placebo. Genioglossus activity (EMG GG , quantified as a percentage of maximum) is measured during gentle awakening. GG is measured and plotted against the corresponding epiglottic pressure. GG is measured during stable NREM sleep.

[0042] Variable but distinct EMG during placebo night sleep GG It is expected that there will be a decrease in activity and, in contrast, if patients are given atomoxetine plus (R)-oxybutynin, the sleep-related decrease in pharyngeal muscle activity will be partially or completely prevented.

[0043] Compared with placebo, the test drug produced significantly higher EMG during NREM sleep. GG For subjects who exhibit REM sleep when administered a test drug, the drug is also expected to be effective during REM sleep.

[0044] Example 2. Crossover study A placebo-controlled, double-blind, randomized crossover study will be conducted in human patients with OSA. Participants will receive treatment (atomoxetine 80 mg + (R)-oxybutynin 5 mg) or placebo 30 minutes before sleep in a randomized order. The combination of atomoxetine and (R)-oxybutynin is expected to reduce the apnea-hypopnea index, and all patients are expected to experience an improvement in OSA severity. Additional benefits expected include increased genioglossus muscle responsiveness to increased ventilatory drive, improved upper airway muscle activity, improved ventilation, improved oxygen levels (SaO2), increased total sleep time, and improved sleep efficiency.

[0045] reference [Table 1-1] [Table 1-2] [Table 1-3]

[0046] Other Aspects While the present invention will be described in conjunction with its detailed description, it is understood that the foregoing description is intended to be illustrative and not limiting of the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

[0047] The present invention includes the following aspects. Item 1 A method of treating a subject having a condition associated with pharyngeal airway collapse, comprising administering to the subject in need thereof effective amounts of (i) a norepinephrine reuptake inhibitor (NRI) and (ii) substantially enantiomerically pure (R)-oxybutynin. Section 2 The method of paragraph 1, wherein the NRI is a norepinephrine selective reuptake inhibitor (NSRI). Section 3 Item 3. The method of item 2, wherein the NSRI is selected from the group consisting of amedalin, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine. Section 4 The method of paragraph 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, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, protriptyline, radafaxine, tapentadol, teniloxazine, and venlafaxine. Section 5 The method of paragraph 1, wherein the NRI is selected from the group consisting of atomoxetine and reboxetine. Section 6 Item 6. The method according to item 5, wherein the NRI is atomoxetine. Section 7 Item 7. The method according to Item 6, wherein atomoxetine is administered at a dose of about 20 to about 100 mg. Section 8 Item 8. The method according to Item 7, wherein atomoxetine is administered at a dose of about 25 to about 75 mg. Section 9 The method of paragraph 1, wherein the (R)-oxybutynin is an immediate release formulation. Item 10 The method of item 1, wherein the (R)-oxybutynin is in an extended release formulation. Section 11 Item 2. The method according to Item 1, wherein (R)-oxybutynin is administered at a dose of about 2 to about 15 mg. Item 12 Item 12. The method according to Item 11, wherein (R)-oxybutynin is an immediate release formulation and is administered at a dose of about 2.5 to about 10 mg. Item 13 Item 12. The method according to Item 11, wherein (R)-oxybutynin is an extended-release formulation and is administered at a dose of about 5 to about 15 mg. Item 14 Item 14. The method according to any one of Items 1 to 13, wherein the condition associated with pharyngeal airway collapse is sleep apnea or simple snoring. Item 15 Item 15. The method of paragraph 14, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA). Item 16 16. The method according to any one of items 1 to 15, wherein the subject is in a non-fully conscious state. Item 17 Item 17. The method of paragraph 16, wherein the non-fully conscious state is sleep. Section 18 18. The method of any one of items 1 to 17, wherein the NRI and (R)-oxybutynin are administered in a single composition. Section 19 Item 19. The method of paragraph 18, wherein the single composition is an oral dosage form. Section 20 20. The method of paragraph 19, wherein the oral administration form is a syrup, pill, tablet, lozenge, capsule or patch. Section 21 A pharmaceutical composition comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) substantially enantiomerically pure (R)-oxybutynin in a pharmaceutically acceptable carrier. Section 22 Item 22. The composition according to item 21, wherein the NRI is a norepinephrine selective reuptake inhibitor (NSRI). Section 23 Item 23. The composition according to Item 22, wherein the NSRI is selected from the group consisting of amedalin, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine. Section 24 Item 22. The composition of item 21, 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, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, protriptyline, radafaxine, tapentadol, teniloxazine, and venlafaxine. Section 25 Item 22. The composition of item 21, wherein the NRI is selected from the group consisting of atomoxetine and reboxetine. Section 26 Item 26. The composition according to item 25, wherein the NRI is atomoxetine. Section 27 Item 27. The composition of item 26, wherein atomoxetine is present in an amount of about 20 to about 100 mg. Section 28 Item 28. The composition of item 27, wherein atomoxetine is present in an amount of about 25 to about 75 mg. Section 29 Item 22. The composition according to Item 21, wherein (R)-oxybutynin is an immediate release formulation. Section 30 Item 22. The composition according to Item 21, wherein (R)-oxybutynin is in an extended release formulation. Section 31 Item 22. The composition of item 21, wherein (R)-oxybutynin is present in an amount of about 2 to about 15 mg. Section 32 Item 32. The composition of item 31, wherein (R)-oxybutynin is an immediate release formulation and is present in an amount of about 2.5 to about 10 mg. Item 33 Item 32. The composition of item 31, wherein (R)-oxybutynin is an extended release formulation and is present in an amount of about 5 to about 15 mg. Section 34 Item 34. The composition of any one of Items 21 to 33, for use in treating a subject having a condition associated with pharyngeal airway collapse. Section 35 Item 35. The composition according to Item 34, wherein the condition associated with pharyngeal airway collapse is sleep apnea or simple snoring. Section 36 Item 36. The composition according to Item 35, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA). Section 37 Item 37. The composition according to any one of items 34 to 36, wherein the subject is in a non-fully conscious state. Section 38 Item 38. The composition according to Item 37, wherein the non-fully conscious state is sleep. Section 39 A norepinephrine reuptake inhibitor (NRI) and substantially enantiomerically pure (R)-oxybutynin for use in treating a subject having a condition associated with pharyngeal airway collapse. Section 40 A kit comprising a norepinephrine reuptake inhibitor (NRI) and substantially enantiomerically pure (R)-oxybutynin. Section 41 41. The kit of paragraph 40 for use in treating a subject having a condition associated with pharyngeal airway collapse.

Claims

[Claim 1] A pharmaceutical composition comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) substantially enantiomerically pure (R)-oxybutynin in a pharmaceutically acceptable carrier.

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