WO2013028909A1

WO2013028909A1 - Combination therapy for the treatment of sleep-related breathing disorders

Info

Publication number: WO2013028909A1
Application number: PCT/US2012/052139
Authority: WO
Inventors: Gregory Stein; Robert Spence
Original assignee: Sova Pharmaceuticals, Inc.
Priority date: 2011-08-25
Filing date: 2012-08-23
Publication date: 2013-02-28

Abstract

Provided herein are methods for treatment of sleep-related breathing disorders comprising administration of a dopamine-2 receptor antagonist and a sympathomimetic agent to an individual suffering from or suspected to be suffering from a sleep-related breathing disorder.

Description

COMBINATION THERAPY FOR THE TREATMENT OF SLEEP-RELATED BREATHING

DISORDERS

CROSS-REFERENCE

[0001] This application claims the benefit of U.S. provisional application Ser. No. 61/527,513, filed August 25, 2011, which is incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0001] Sleep-related breathing disorders (SRBDs) alter sleep duration and architecture, and, if repetitive, result in daytime symptoms, signs, or organ system dysfunction.

SUMMARY OF THE INVENTION

[0002] Provided herein, in some embodiments, are compositions comprising a combination of a dopamine-2 receptor (D2) antagonist and a sympathomimetic agent for use in treatment of SRBDs. In some embodiments, SRBDs are associated with mood disorders, cognitive disorders, hypertension, heart failure, stroke, arrhythmias, myocardial ischemia and infarction, pulmonary arterial hypertension and/or early stage renal disease resulting in increased mortality.

[0003] Provided herein, in some embodiments, are compositions comprising a combination of a D2 antagonist and a sympathomimetic agent for use in treatment of snoring and pathologies related to snoring. In certain embodiments, snoring (e.g., severe snoring) is associated with obstructive sleep apnea (OSA), central sleep apnea (CSA), obstructive sleep apnea syndrome (OSAS), upper airway resistance syndrome (UARS), obesity hypoventilation syndrome, and/or Cheyne- Stokes breathing.

[0004] In one aspect provided herein are methods for treatment of SRBDs in an individual in need thereof comprising administration of a composition comprising a D2 antagonist, or a pharmaceutically acceptable salt thereof, and a sympathomimetic agent, or a pharmaceutically acceptable salt thereof, to the individual in need thereof; provided that the composition does not comprise a free base of domperidone. Also described herein is the use of a combination of a D2 antagonist and a sympathomimetic agent for manufacture of a medicament for the treatment of SRBDs.

[0005] In some embodiments of the methods described above, the sleep-related breathing disorder is severe snoring. In some embodiments of the methods described herein the severe snoring is associated with OSA, CSA, OSA, OSAS, UARS, obesity hypoventilation syndrome, or Cheyne-Stokes breathing.

[0006] In some embodiments of the methods described above, the D2 antagonist is selected from

acepromazine, amisulpride, amoxapine, azaperone, benperidol, bromopride, butaclamol, clomipramine, chlorpromazine, chlorprothixene, clopenthixol, droperidol, eticlopride, flupenthixol, fluphenazine, fluspirilene, haloperidol, iodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, metopimazine, nafadotride, nemonapride, penfluridol, perazine, perphenazine, pimozide, prochlorperazine, promazine, raclopride, remoxipride, risperidone, spiperone, spiroxatrine, stepholidine, sulpiride, sultopride,

tetrahydropalmatine, thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, and ziprasidone, or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments of the methods described above, the D2 antagonist does not have central nervous system effects.

[0008] In some embodiments of the methods described above, the D2 antagonist is metopimazine, or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments of the methods described above, the sympathomimetic agent is selected from cyclopentamine, phenylephrine, phenylpropanolamine, mephentermine, midodrine, methoxamine, metaraminol, oxymetazoline, tetryzoline, xylometazoline, naphazoline, tramazoline, metizoline, tuaminoheptane, fenoxazoline, tymazoline, epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine,

methamphetamine, methylphenidate, lisdexamfetamine, cocaine, cathinone, cathine, methcathinone, benzylpiperazine, methylenedioxypyrovalerone, 4-methylaminorex, pemoline, phenmetrazine, and

propylhexedrine, or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments of the methods described above, the sympathomimetic agent is ephedrine or pseudoephedrine, or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments of the methods described above, the D2 antagonist is administered in a dose of between about 1 mg/day to about 300 mg/day. In some embodiments of the methods described above, the D2 antagonist is administered in a dose of between about 1 mg/day to about 60 mg/day.

[0012] In some embodiments of the methods described above, the sympathomimetic agent is administered in a dose of between about 15 mg/day to about 240 mg/day. In some embodiments of the methods described above, the sympathomimetic agent is administered in a dose of between about 60 mg/day to about 120 mg/day.

[0013] In some embodiments of the methods described above, the D2 antagonist is orally administered in an immediate release form. In some embodiments of the methods described above, the D2 antagonist is orally administered in a controlled release form.

[0014] In some embodiments of the methods described above, the sympathomimetic agent is orally administered in an immediate release form. In some embodiments of the methods described above, the sympathomimetic agent is orally administered in a controlled release form.

[0015] In some embodiments of the methods described above, the individual is orally administered a unit dosage form that contains both the D2 antagonist and the sympathomimetic agent. In some embodiments, a D2 antagonist tablet and a sympathomimetic agent tablet are over-encapsulated to provide a single capsule dosage form.

[0016] In some embodiments of the methods described above, the D2 antagonist is metopimazine, or a pharmaceutically acceptable salt thereof, and the sympathomimetic agent is pseudoephedrine, or a

pharmaceutically acceptable salt thereof. [0017] In some embodiments of the methods described above, the D2 antagonist dosage reduces the C_max of the D2 antagonist to minimize peak concentration side effects of the D2 antagonist.

[0018] In some embodiments of the methods described above, the individual has an apnea hypopnea index (AHI) of > 5. In some embodiments of the methods described above, the individual has an AHI of >15. In some embodiments of the methods described above, the individual has an AHI of >30. In some embodiments of the methods described above, the individual has an AHI of > 5 and < 30. In some embodiments of the methods described above, the individual has an AHI of > 5 and < 15. In some embodiments of the methods described above, the individual has an AHI of < 30. In some embodiments of the methods described above, the individual has an AHI of < 15. In some embodiments of the methods described above, the individual has a respiratory disturbance index (RDI) of > 5. In some embodiments of the methods described above, the individual has an RDI of > 10. In some embodiments of the methods described above, the individual has an RDI of > 15. In some embodiments of the methods described above, the individual has an RDI of > 5 and < 15. In some embodiments of the methods described above, the individual has an RDI of > 5 and < 10. In some embodiments of the methods described above, the individual has an RDI of > 10 and < 15. In some embodiments of the methods described above, the individual has an oxygen desaturation index (ODI) of > 5. In some embodiments of the methods described above, the individual has an ODI of > 10. In some embodiments of the methods described above, the individual has an ODI of > 15. In some embodiments of the methods described above, the individual has an ODI of > 5 and < 15. In some embodiments of the methods described above, the individual has an ODI of > 5 and < 10. In some embodiments of the methods described above, the individual has an ODI of > 10 and < 15. In some embodiments of the methods described above, the individual has an ODI of < 15. In some embodiments of the methods described above, the individual has a body mass index (BMI) of < 35. In some embodiments of the methods described above, the individual has a BMI of < 35. In some embodiments of the methods described above, the individual has a BMI of < 30. In some embodiments of the methods described above, the individual has a BMI of >35.

[0019] In another aspect, provided herein are methods for treatment of snoring in an individual in need thereof comprising administration of a composition comprising

(i) a first agent selected from acepromazine, amisulpride, amoxapine, azaperone, benperidol, bromopride, butaclamol, clomipramine, chlorpromazine, chlorprothixene, clopenthixol, droperidol, eticlopride, flupenthixol, fluphenazine, fluspirilene, haloperidol, iodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, metopimazine, nafadotride, nemonapride, penfluridol, perazine, perphenazine, pimozide, prochlorperazine, promazine, raclopride, remoxipride, risperidone, spiperone, spiroxatrine, stepholidine, sulpiride, sultopride, tetrahydropalmatine, thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, and ziprasidone, or a pharmaceutically acceptable salt thereof; and

(ii) a second agent selected from cyclopentamine, phenylephrine, phenylpropanolamine,

mephentermine, midodrine, methoxamine, metaraminol, oxymetazoline, tetryzoline, xylometazoline, naphazoline, tramazoline, metizoline, tuaminoheptane, fenoxazoline, tymazoline, epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine, methamphetamine, methylphenidate, lisdexamfetamine, cocaine, cathinone, cathine, methcathinone, benzylpiperazine, methylenedioxypyrovalerone, 4-methylaminorex, pemoline, phenmetrazine, and propylhexedrine, or a pharmaceutically acceptable salt thereof.

[0020] Also described herein is the use of a combination of

(i) a first agent selected from acepromazine, amisulpride, amoxapine, azaperone, benperidol, bromopride, butaclamol, clomipramine, chlorpromazine, chlorprothixene, clopenthixol, droperidol, eticlopride, flupenthixol, fluphenazine, fluspirilene, haloperidol, lodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, metopimazine, nafadotride, nemonapride, penfluridol, perazine, perphenazine, pimozide, prochlorperazine, promazine, raclopride, remoxipride, risperidone, spiperone, spiroxatrine, stepholidine, sulpiride, sultopride, tetrahydropalmatine, thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, and ziprasidone, or a pharmaceutically acceptable salt thereof; and

mephentermine, midodrine, methoxamine, metaraminol, oxymetazoline, tetryzoline, xylometazoline, naphazoline, tramazoline, metizoline, tuaminoheptane, fenoxazoline, tymazoline, epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine, methamphetamine, methylphenidate, lisdexamfetamine, cocaine, cathinone, cathine, methcathinone, benzylpiperazine, methylenedioxypyrovalerone, 4-methylaminorex, pemoline, phenmetrazine, and propylhexedrine, or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment of snoring.

[0021] In some embodiments of the methods described above, the snoring is severe snoring.

[0022] In some embodiments of the methods described above, the severe snoring is associated with obstructive sleep apnea (OSA), central sleep apnea (CSA), obstructive sleep apnea syndrome (OSAS), upper airway resistance syndrome (UARS), obesity hypoventilation syndrome, or Cheyne-Stokes breathing.

[0023] In some embodiments of the methods described above, the first agent is metopimazine, or a

pharmaceutically acceptable salt thereof. In some embodiments of the methods described above, the first agent is metopimazine and the second agent is pseudoephedrine, or a pharmaceutically acceptable salt thereof. In some embodiments of the methods described above, the first agent is metopimazine and the second agent is ephedrine, or a pharmaceutically acceptable salt thereof. In some embodiments of the methods described above, the first agent is metopimazine and the second agent is phenylephrine, or a pharmaceutically acceptable salt thereof.

[0024] In another aspect, provided herein are methods for treatment of obstructive sleep apnea syndrome

(OSAS) in an individual in need thereof comprising administration of a composition comprising

[0025] Also described herein is the use of a combination of

mephentermine, midodrine, methoxamine, metaraminol, oxymetazoline, tetryzoline, xylometazoline, naphazoline, tramazoline, metizoline, tuaminoheptane, fenoxazoline, tymazoline, epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine, methamphetamine, methylphenidate, lisdexamfetamine, cocaine, cathinone, cathine, methcathinone, benzylpiperazine, methylenedioxypyrovalerone, 4-methylaminorex, pemoline, phenmetrazine, and propylhexedrine, or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment of obstructive sleep apnea syndrome (OSAS).

[0026] In some embodiments of the methods described above, the first agent is metopimazine, or a

[0027] Provided herein is a pharmaceutical composition comprising metopimazine, or a pharmaceutically acceptable salt thereof, and pseudoephedrine, or a pharmaceutically acceptable salt thereof.

[0028] Provided herein is a pharmaceutical composition comprising metopimazine, or a pharmaceutically acceptable salt thereof, and ephedrine, or a pharmaceutically acceptable salt thereof.

[0029] Provided herein is a pharmaceutical composition comprising metopimazine, or a pharmaceutically acceptable salt thereof, and phenylephrine, or a pharmaceutically acceptable salt thereof. [0030] In some embodiments, for any methods or compositions described above, the pseudoephedrine or a pharmaceutically acceptable salt thereof, is pseudoephedrine. In some embodiments, for any methods or compositions described above, the pseudoephedrine or a pharmaceutically acceptable salt thereof, is pseudoephedrine HC1. In some embodiments, for any methods or compositions described above, the pseudoephedrine or a pharmaceutically acceptable salt thereof, is pseudoephedrine sulfate. In some embodiments, for any methods or compositions described above, the phenylephrine or a pharmaceutically acceptable salt thereof, is phenylephrine. In some embodiments, for any methods or compositions described above, the phenylephrine or a pharmaceutically acceptable salt thereof, is phenylephrine HC1. In some embodiments, for any methods or compositions described above, the phenylephrine or a pharmaceutically acceptable salt thereof, is phenylephrine tannate.

[0031] Further provided herein are kits for sleep -related breathing disorder therapy in an individual in need thereof, wherein the kit comprises:

a plurality of a first unit dosage form comprising a D2 antagonist; and

a plurality of a second unit dosage form comprising a sympathomimetic agent;

wherein the D2 antagonist dosage is in a form that minimizes peak concentration side effects of the D2 antagonist.

INCORPORATION BY REFERENCE

[0032] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0034] Figure 1 illustrates an overview of study design, as described in Example 1. When subjects are recruited into the trial they are randomized to one of two cohorts.

DETAILED DESCRIPTION OF THE INVENTION

[0035] Sleep related breathing disorders represent a continuum starting with mild or moderate snoring, and spanning other disorders including severe snoring, snoring with partial airway obstruction, or apneas when the airway obstruction is complete. Mild or moderate snoring is often harmless and, in most cases, is not associated with OSA. However, loud habitual snoring causes sleep disturbances and waking episodes. When snoring is severe, in some cases, it is associated with other pathologies. In other words, the snoring is pathological snoring. In many cases, pathological snoring is associated with mild OSA (AHI > 5 and < 15). Increased airway obstruction worsens sleep apnea. OSA often leads to a number of morbidities and is associated with greater mortality when other factors, such as age and BMI, have also been accounted for. Specifically, sleep apnea is associated with a range of cardiovascular and metabolic conditions that include diabetes, hypertension, heart failure, stroke, arrhythmias, myocardial ischemia and infarction, pulmonary arterial hypertension and early stage renal disease. See Somers, V. K. et al., Circulation 2008; 118:1080-111.

[0036] Furthermore, in some instances, when subjects have a BMI greater than 30, apneas may become moderate and then progress to severe. Berger and colleagues (Berger, G., et al., The European respiratory journal : Official journal of the European Society for Clinical Respiratory Physiology 2009;33:338-45), following a population of patients who exhibited primary snoring and mild, moderate and severe OSA for 5 years showed that progression from snoring to mild and moderate apneas was associated with an increased BMI. In some other instances, moderate or severe OSA occur in subjects having a body mass index less than 30.

[0037] Census data from the US, Europe, Japan, China and India show that the prevalence of snoring, both with and without mild OSA, is very high. In the US, habitual snorers either without OSA or with mild OSA represent approximately 72% of the population. Europe also has a similarly high prevalence in this group. Although not as high, Japan, China and India also have a high prevalence of snoring (>40%). In addition to the disturbance snoring causes to sleeping partners, objective studies comparing snoring and all-cause mortality show a clear association. In some embodiments, snoring is considered non-pathological when the intensity is less than 40 dB and has a steady frequency. In some embodiments snoring is loud (e.g., > 50 dB) and irregular and is considered severe snoring. In some embodiments, when snoring exceeds, for example, 70 dB, it can lead to arousals and awakenings and is considered pathological snoring. Pathological snoring can also be associated with OSA, CSA, OSAS, UARS, obesity hypoventilation syndrome, and/or Cheyne-Stokes breathing and the like. Severe and/or pathological snoring affects the quality of life for patients as well as family members of patients.

[0038] Rich et al (Otolaryngo logy-head and neck surgery: Official Journal of American Academy of

Otolaryngology-Head and Neck Surgery 2011) compared snoring, as measured using the SNAP test device (a home sleep testing device), with the Social Security Death Master file. They showed that, for patients without

OSA and with a BMI < 30, increased snoring was associated with an age- and sex -adjusted rise in mortality (OR

= 1.16; 95% CI, 1.01-1.32; P = .034). For all patients, increasing nonpalatal snoring was associated with rising morality (OR = 1.21; 95% CI, 1.09-1.35;P< .001) after adjustment for age, sex, BMI, and AHI. Therefore, due to the high number of habitual snorers in the population, a higher mortality rate may be expected in this population.

Accordingly, any treatment for snoring would be expected to reduce both morbidity and mortality.

[0039] The available treatments for patients suffering from OSA are: continuous positive airway pressure

(CPAP), bilevel ventilation, and adaptive servoventilation (ASV). However, such treatments do not treat the causes of OSA. In addition, two drugs, Provigil and Nuvigil, are approved for the daytime somnolence often seen in OSA patients. These drugs treat a subset of the symptoms of OSAS, but do not reduce apneas and therefore would not be expected to improve the longer-term morbidities. Acetazolamide is labeled for use in acute mountain sickness but not for the larger OSA population. The device treatments, such as CPAP, though effective, are not well tolerated by many patients and not used consistently by others. In such cases, the patients often require more invasive treatments to reduce their apneas. Furthermore, patients with snoring and mild OSA are less likely to be motivated to use CPAP and other devices.

[0040] Thus, severe snoring and mild OSA represent the first steps in a progression to pathological snoring, including severe OSAS. In addition to poor quality of life, OSAS is associated with a number of serious health issues as well as increased mortality. A pharmaceutical substitute or complement to the current therapies would enable a larger number of patients to be treated, at the very least, for snoring and mild apneas.

[0041] Accordingly, provided herein, in some embodiments, are compositions and methods for treatment of snoring. In other embodiments, provided herein are compositions and methods for treatment of mild to moderate snoring that is not associated with apneas. In further embodiments, provided herein are compositions and methods for treatment of severe snoring associated with other pathologies (e.g., OSAS, UARS and the like) as described herein. In yet further embodiments, provided herein are compositions and methods for treatment of pathological snoring and related conditions associated with pathological snoring (e.g., OSAS, UARS and the like) as described herein. In some further embodiments, provided herein are compositions and methods for treatment of SRBDs as described herein.

Definitions

[0042] Sleep-related breathing disorder (SRBD) refers to an abnormal respiratory pattern (e.g., apneas, hypopneas, or respiratory effort-related arousals) during sleep. SRBD alters sleep duration and architecture, and, if repetitive, results in daytime symptoms, signs, or organ system dysfunction. In some embodiments, a SRBD is mild to moderate snoring. In other embodiments, a SRBD is severe snoring. In some embodiments, severe snoring is associated with other pathologies as described herein. In some embodiments, SRBD includes OSA, OSAS, CSA, mixed apnea, hypopnea, hypercapnia, hypocapnia, central sleep apnea syndrome (CSAS), idiopathic central sleep apnea (ICSA), Cheyne-Stokes breathing-central sleep apnea (CSB-CSA), UARS, obesity hypoventilation syndrome, alveolar hypoventilation syndromes, congenital central hypoventilation syndrome (CCHS ), high altitude periodic breathing, CSA due to a medical condition, CSA due to a drug or substance (e.g., opioid-induced CSA), chronic mountain sickness, and/or SRBDs associated with neurologic conditions or neuromuscular conditions.

[0043] As used herein, the term "treatment", "treat", or "treating" in some embodiments includes achieving a therapeutic benefit. Therapeutic benefit is meant to include eradication or amelioration of the underlying disorder or condition being treated. For example, therapeutic benefit includes alleviation or partial and/or complete halting of the SRBD. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological or psychological symptoms associated with the underlying condition such that an improvement is observed in the patient, notwithstanding the fact that the patient is still affected by the condition. For example, in an individual suffering from sleep apnea, therapeutic benefit includes alleviation or partial and/or complete halting of sleep fragmentation, or reduction in frequency of arousals or awakenings or reduction in incidence of awakenings. In some embodiments, "treatment" provides prophylactic benefit including prevention of a condition, retarding the progress of a condition, or decreasing the likelihood of occurrence of a condition. As used herein, in other embodiments, "treat", "treating" or "treatment" includes prophylaxis, e.g., when treatment prevents the occurrence of sleep apnea in a snorer.

[0044] As used herein "free base" of an active agent means a non-salt form of the parent compound.

Control of respiratory activity

[0045] Ventilatory control disturbances can be associated with the manifestation of SRBDs. Specialized chemical receptors, called chemoreceptors, are located in several areas outside the brain. They are especially important for detecting changes in the partial pressure of oxygen in the blood, although they also respond to changes in the partial pressure of carbon dioxide as well as hydrogen ion concentrations. The peripheral chemoreceptors cause afferent signals to the respiratory center in the brain to increase respiratory activity. Most of the chemoreceptors are in the carotid bodies. The carotid bodies are located bilaterally at the bifurcation of the common carotid artery. Their afferent nerve fibers pass through Hering's nerves to the glossopharyngeal nerves and then to the dorsal respiratory area of the medulla. Additionally, the aortic bodies are located along the arch of the aorta; their afferent nerve fibers pass through the vagus nerve, also to the dorsal medullary respiratory area. Each of the chemoreceptor bodies receives its blood supply through an artery that originates directly from an adjacent arterial trunk (Hall JE. Textbook of Medical Physiology: Elsevier, 2011).

[0046] Cells of the carotid body express the dopamine-2 receptor. The activation of these receptors by dopamine inhibits the activity of the carotid body, which reduces impulses along the afferent carotid sinus nerve. This leads to a reduction in respiratory rate and/or tidal volume. Thus, antagonists of the dopamine-2 receptor will reverse the inhibitory activity of dopamine and act as respiratory stimulants. It has also been shown that inhibition of carotid sinus nerve firing leads to inhibited activity of the phrenic, recurrent laryngeal and hypoglossal nerves, with the latter being most inhibited. Also, two respiratory stimulants, isoproterenol and lobeline, increased the activity of all three nerves with the hypoglossal nerve being the most stimulated (van Lunteren, E., et al., Journal of applied physiology: respiratory, environmental and exercise physiology 1984; 56:737-45.). Activation of the hypoglossal and recurrent laryngeal nerves may, in addition to increasing the muscle tone of the tongue, increase the tone of the genioglosus and posterior cricoarytenoid muscles, respectively, thereby increasing upper airway patency. Conditions which preferentially decrease upper airway muscle activity would favor airway closure, and this could lead to OSA. Therefore, a D2 antagonist would also increase upper airway patency, thereby alleviating symptoms of sleep apneas.

[0047] D2 antagonists have been used in the clinic as antipsychotics and for the treatment of gastroespophageal reflux disease (GERD) and emesis. The dopamine-2 receptor is expressed both centrally and peripherally, such as in the carotid body, which is a peripheral chemoreceptor that is important in the regulation of respiration. D2 antagonists that can cross the blood brain barrier, such as clozapine, cause a range of central nervous system

(CNS) effects, including adverse effects like extrapyramidal side effects. As used herein, a D2 antagonist that

"does not have central nervous system effects" is, in one embodiment, an agent that does not cross the blood brain barrier (BBB). In another embodiment, a D2 antagonist that does not have central nervous system effects crosses the blood brain barrier but undergoes rapid efflux (e.g., by the P -glycoprotein efflux pump of the BBB) and does not cause any effects on the central nervous system.

[0048] Contemplated within the scope of embodiments presented herein is the mitigation of central nervous systems effects and control of breathing by use of D2 antagonists that do not cross the blood brain barrier, so that only the beneficial peripheral effects are seen. Two D2 antagonists, domperidone and metopimazine, have been shown not to cross the blood brain barrier (Jolliet, P., et al., Pharmacol Res. 2007; 56:11-7). Contemplated within the scope of embodiments presented herein are sympathomimetic agents and/or respiratory stimulants that avoid any concerns regarding effects on the CNS.

[0049] Accordingly, provided herein are methods for treatment of SRBDs comprising administration of a respiratory stimulant (e.g., a D2 antagonist) that does not cross the blood brain barrier and/or cause

extrapyramidal side-effects and/or cause any CNS effects, thereby reducing airway blockage that is associated with snoring and/or mild OS A.

[0050] Nasal congestion has been associated with an increased risk for snoring (Young, T., Archives of internal medicine 2001 ; 161 :1514-9). Sympathomimetic agents such as catecholamines, adrenalin and noradrenaline, which mimic the effects of the sympathetic nervous system, have been used as nasal and sinus decongestants. For example, pseudoephedrine is a commonly used nasal decongestant.

[0051] Accordingly, provided herein are methods for treatment of SRBDs comprising administration of a combination of a sympathomimetic agent and a D2 antagonist that does not cross the blood brain barrier to an individual in need thereof. Accordingly provided herein are methods for treatment of pathological snoring and related conditions comprising administration of a combination of a sympathomimetic agent and a D2 antagonist that does not cross the blood brain barrier to an individual in need thereof.

D2 antagonists

[0052] A dopamine antagonist blocks dopamine receptors by receptor antagonism. There are five known types of dopamine receptors in the human body; they are found in the brain, peripheral nervous system, blood vessels, and the kidney. A number of antipsychotic drugs are D2 antagonists. Contemplated for use in the methods of treatment described herein are D2 antagonists. Examples include, but are not limited to, acepromazine, amisulpride, amoxapine, azaperone, benperidol, bromopride, butaclamol, clomipramine, chlorpromazine, chlorprothixene, clopenthixol, droperidol, domperidone, eticlopride, flupenthixol, fluphenazine, fluspirilene, haloperidol, iodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, metopimazine, nafadotride, nemonapride, penfluridol, perazine, perphenazine, pimozide, prochlorperazine, promazine, raclopride, remoxipride, risperidone, spiperone, spiroxatrine, stepholidine, sulpiride, sultopride,

tetrahydropalmatine, thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, ziprasidone, or pharmaceutically acceptable salts thereof, or combinations thereof. In specific embodiments of the methods such D2 antagonists are administered in dose amounts that reduce and/or minimize and/or do not cause extrapyramidal side-effects. In some of such embodiments, the D2 antagonists are administered in a dosage form that allows for drug release over a period of time such that Cmax in the plasma does not exceed levels that would cause extrapyramidal side-effects. In some embodiments, D2 antagonists suitable for methods of treatment described herein are peripheral antagonists, i.e., they do not cross the blood brain barrier.

Sympathomimetic agents

[0053] Sympathomimetic agents mimic the effects of the sympathetic nervous system. Examples include catecholamines, epinephrine (adrenaline), norepinephrine (noradrenaline), dopamine, and the like.

Contemplated for use in the methods of treatment described herein are sympathomimetic agents such as cyclopentamine, phenylephrine, phenylpropanolamine, mephentermine, midodrine, methoxamine, metaraminol, oxymetazoline, tetryzoline, xylometazoline, naphazoline, tramazoline, metizoline, tuaminoheptane, fenoxazoline, tymazoline, epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine,

methamphetamine, methylphenidate, lisdexamfetamine, cocaine, cathinone, cathine, methcathinone, benzylpiperazine, methylenedioxypyrovalerone, 4-methylaminorex, pemoline, phenmetrazine, propylhexedrine, or pharmaceutically acceptable salts thereof, or combinations thereof.

Combination of D2 antagonists and sympathomimetic agents

[0054] Provided herein, in some embodiments are combinations of active agents suitable for compositions and methods for treatment of sleep related breathing disorders described herein comprising a combination of a non- centrally active D2 antagonist and a sympathomimetic agent.

[0055] (A) In some embodiments, a combination of active agents suitable for compositions and methods for treatment of sleep related breathing disorders described herein comprises a combination of

[0056] (1) a D2 antagonist selected from acepromazine, amisulpride, amoxapine, azaperone, benperidol, bromopride, butaclamol, clomipramine, chlorpromazine, chlorprothixene, clopenthixol, droperidol, domperidone maleate, eticlopride, flupenthixol, fluphenazine, fluspirilene, haloperidol, iodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, metopimazine, nafadotride, nemonapride, penfluridol, perazine, perphenazine, pimozide, prochlorperazine, promazine, raclopride, remoxipride, risperidone, spiperone, spiroxatrine, stepholidine, sulpiride, sultopride, tetrahydropalmatine, thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, and ziprasidone, or pharmaceutically acceptable salts thereof, or combinations thereof; and

[0057] (2) a sympathomimetic agent selected from cyclopentamine, phenylephrine, phenylpropanolamine, mephentermine, midodrine, methoxamine, metaraminol, oxymetazoline, tetryzoline, xylometazoline, naphazoline, tramazoline, metizoline, tuaminoheptane, fenoxazoline, tymazoline, epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine, methamphetamine, methylphenidate, lisdexamfetamine, cocaine, cathinone, cathine, methcathinone, benzylpiperazine, methylenedioxypyrovalerone, 4-methylaminorex, pemoline, phenmetrazine, and propylhexedrine, or pharmaceutically acceptable salts thereof, or combinations thereof; [0058] £B In some embodiments, a combination of active agents suitable for compositions and methods for treatment of sleep related breathing disorders described herein comprises a combination of

[0059] (1) a D2 antagonist selected from acepromazine, amoxapine, bromapride, butaclamol, clomipramine, chlorpromazine, chlorprothixene, droperidol, eticlopride, flupenthixol, fluphenazine, fluspirilene,

iodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, metopimazine, nafadotride, nemonapride, penfluridol, perazine, perphenazine, pimozide, prochlorperazine, promazine, raclopride, remoxipride, risperidone, spiperone, spiroxatrine, sulpiride, sultopride, tetrahydropalmatine, thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, and ziprasidone, or

pharmaceutically acceptable salts thereof, or combinations thereof; and

[0060] (2) a sympathomimetic agent selected from cyclopentamine, phenylephrine, phenylpropanolamine, mephentermine, midodrine, methoxamine, metaraminol, oxymetazoline, tetryzoline, xylometazoline, naphazoline, tramazoline, metizoline, tuaminoheptane, fenoxazoline, tymazoline, epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine, methamphetamine, methylphenidate, lisdexamfetamine, cocaine, cathinone, cathine, methcathinone, benzylpiperazine, methylenedioxypyrovalerone, 4-methylaminorex, pemoline, phenmetrazine, and propylhexedrine, or pharmaceutically acceptable salts thereof, or combinations thereof.

[0061] £C} In some embodiments, a combination of active agents suitable for compositions and methods for treatment of sleep related breathing disorders described herein comprises a combination of

[0062] (1) a D2 antagonist selected from amoxapine, bromapride, chlorpromazine, chlorprothixene, droperidol, eticlopride, flupenthixol, fluphenazine, fluspirilene, iodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, metopimazine, prochlorperazine, promazine, raclopride, remoxipride, risperidone, sulpiride, sultopride, tetrahydropalmatine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, and ziprasidone, or pharmaceutically acceptable salts thereof, or combinations thereof; and

[0063] (2) a sympathomimetic agent selected from cyclopentamine, phenylephrine, phenylpropanolamine, mephentermine, midodrine, methoxamine, metaraminol, oxymetazoline, tetryzoline, xylometazoline, naphazoline, tramazoline, metizoline, tuaminoheptane, fenoxazoline, tymazoline, epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine, methamphetamine, methylphenidate, lisdexamfetamine, cocaine, cathinone, cathine, methcathinone, benzylpiperazine, methylenedioxypyrovalerone, 4-methylaminorex, pemoline, phenmetrazine, and propylhexedrine, or pharmaceutically acceptable salts thereof, or combinations thereof.

[0064] £D In some embodiments, a combination of active agents suitable for compositions and methods for treatment of sleep related breathing disorders described herein comprises a combination of

[0065] (1) a D2 antagonist selected from chlorpromazine, levomepromazine, metoclopramide, metopimazine, prochlorperazine, promazine, raclopride, remoxipride, risperidone, sulpiride, sultopride, and ziprasidone, or pharmaceutically acceptable salts thereof, or combinations thereof; and [0066] (2) a sympathomimetic agent selected from cyclopentamine, phenylephrine, phenylpropanolamine, mephentermine, midodrine, methoxamine, metaraminol, oxymetazoline, tetryzoline, xylometazoline, naphazoline, tramazoline, metizoline, tuaminoheptane, fenoxazoline, tymazoline, epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine, methamphetamine, methylphenidate, lisdexamfetamine, cocaine, cathinone, cathine, methcathinone, benzylpiperazine, methylenedioxypyrovalerone, 4-methylaminorex, pemoline, phenmetrazine, and propylhexedrine, or pharmaceutically acceptable salts thereof, or combinations thereof.

[0067] (E In some embodiments, a combination of active agents suitable for compositions and methods for treatment of sleep related breathing disorders described herein comprises a combination of

[0068] (1) a D2 antagonist selected from acepromazine, amisulpride, amoxapine, azaperone, benperidol, bromopride, butaclamol, clomipramine, chlorpromazine, chlorprothixene, clopenthixol, droperidol, domperidone maleate, eticlopride, flupenthixol, fluphenazine, fluspirilene, haloperidol, iodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, metopimazine, nafadotride, nemonapride, penfluridol, perazine, perphenazine, pimozide, prochlorperazine, promazine, raclopride, remoxipride, risperidone, spiperone, spiroxatrine, stepholidine, sulpiride, sultopride, tetrahydropalmatine, thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, and ziprasidone, or pharmaceutically acceptable salts thereof, or combinations thereof; and

[0069] (2) a sympathomimetic agent selected from cyclopentamine, phenylephrine, xylometazoline, naphazoline, tramazoline, metizoline, fenoxazoline, epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine, methamphetamine, methylphenidate, lisdexamfetamine, cocaine, cathinone, cathine,

methcathinone, benzylpiperazine, methylenedioxypyrovalerone, pemoline, phenmetrazine, and propylhexedrine, or pharmaceutically acceptable salts thereof, or combinations thereof.

[0070] £F) In some embodiments, a combination of active agents suitable for compositions and methods for treatment of sleep related breathing disorders described herein comprises a combination of

[0071] (1) a D2 antagonist selected from acepromazine, amisulpride, amoxapine, azaperone, benperidol, bromopride, butaclamol, clomipramine, chlorpromazine, chlorprothixene, clopenthixol, droperidol, domperidone maleate, eticlopride, flupenthixol, fluphenazine, fluspirilene, haloperidol, iodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, metopimazine, nafadotride, nemonapride, penfluridol, perazine, perphenazine, pimozide, prochlorperazine, promazine, raclopride, remoxipride, risperidone, spiperone, spiroxatrine, stepholidine, sulpiride, sultopride, tetrahydropalmatine, thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, and ziprasidone, or pharmaceutically acceptable salts thereof, or combinations thereof; and

[0072] (2) a sympathomimetic agent selected from cyclopentamine, phenylephrine, xylometazoline, naphazoline, tramazoline, metizoline, fenoxazoline, epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine, methamphetamine, methylphenidate, lisdexamfetamine, cocaine, benzylpiperazine, methylenedioxypyrovalerone, pemoline, phenmetrazine, and propylhexedrine, or pharmaceutically acceptable salts thereof, or combinations thereof.

[0073] {GQ In some embodiments, a combination of active agents suitable for compositions and methods for treatment of sleep related breathing disorders described herein comprises a combination of

[0074] (1) a D2 antagonist selected from acepromazine, amisulpride, amoxapine, azaperone, benperidol, bromopride, butaclamol, clomipramine, chlorpromazine, chlorprothixene, clopenthixol, droperidol, domperidone maleate, eticlopride, flupenthixol, fluphenazine, fluspirilene, haloperidol, iodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, metopimazine, nafadotride, nemonapride, penfluridol, perazine, perphenazine, pimozide, prochlorperazine, promazine, raclopride, remoxipride, risperidone, spiperone, spiroxatrine, stepholidine, sulpiride, sultopride, tetrahydropalmatine, thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, and ziprasidone, or pharmaceutically acceptable salts thereof, or combinations thereof; and

[0075] (2) a sympathomimetic agent selected from epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine, methamphetamine, methylphenidate, lisdexamfetamine, cocaine, benzylpiperazine, and propylhexedrine, or pharmaceutically acceptable salts thereof, or combinations thereof.

[0076] (H) In some embodiments, a combination of active agents suitable for compositions and methods for treatment of sleep related breathing disorders described herein comprises a combination of

[0077] (1) a D2 antagonist selected from acepromazine, amisulpride, amoxapine, azaperone, benperidol, bromopride, butaclamol, clomipramine, chlorpromazine, chlorprothixene, clopenthixol, droperidol, domperidone maleate, eticlopride, flupenthixol, fluphenazine, fluspirilene, haloperidol, iodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, metopimazine, nafadotride, nemonapride, penfluridol, perazine, perphenazine, pimozide, prochlorperazine, promazine, raclopride, remoxipride, risperidone, spiperone, spiroxatrine, stepholidine, sulpiride, sultopride, tetrahydropalmatine, thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, and ziprasidone, or pharmaceutically acceptable salts thereof, or combinations thereof; and

[0078] (2) a sympathomimetic agent selected from epinephrine, ephedrine, pseudoephedrine, and dopamine, or pharmaceutically acceptable salts thereof, or combinations thereof.

[0079] (I) In some embodiments, a combination of active agents suitable for compositions and methods for treatment of sleep related breathing disorders described herein comprises a combination of

[0080] (1) a D2 antagonist selected from acepromazine, amoxapine, bromapride, butaclamol, clomipramine, chlorpromazine, chlorprothixene, droperidol, eticlopride, flupenthixol, fluphenazine, fluspirilene,

iodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, metopimazine, nafadotride, nemonapride, penfluridol, perazine, perphenazine, pimozide, prochlorperazine, promazine, raclopride, remoxipride, risperidone, spiperone, spiroxatrine, sulpiride, sultopride, tetrahydropalmatine, thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, and ziprasidone, or pharmaceutically acceptable salts thereof, or combinations thereof; and [0081] (2) a sympathomimetic agent selected from cyclopentamine, phenylephrine, xylometazoline, naphazoline, tramazoline, metizoline, fenoxazoline, epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine, methamphetamine, methylphenidate, lisdexamfetamine, cocaine, cathinone, cathine,

[0082] £J) In some embodiments, a combination of active agents suitable for compositions and methods for treatment of sleep related breathing disorders described herein comprises a combination of

[0083] (1) a D2 antagonist selected from amoxapine, bromapride, chlorpromazine, chlorprothixene, droperidol, eticlopride, flupenthixol, fluphenazine, fluspirilene, iodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, metopimazine, prochlorperazine, promazine, raclopride, remoxipride, risperidone, sulpiride, sultopride, tetrahydropalmatine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, and ziprasidone, or pharmaceutically acceptable salts thereof, or combinations thereof; and

[0084] (2) a sympathomimetic agent selected from cyclopentamine, phenylephrine, xylometazoline, naphazoline, tramazoline, metizoline, fenoxazoline, epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine, methamphetamine, methylphenidate, lisdexamfetamine, cocaine, benzylpiperazine,

methylenedioxypyrovalerone, pemoline, phenmetrazine, and propylhexedrine, or pharmaceutically acceptable salts thereof, or combinations thereof.

[0085] (K) In some embodiments, a combination of active agents suitable for compositions and methods for treatment of sleep related breathing disorders described herein comprises a combination of

[0086] (1) a D2 antagonist selected from chlorpromazine, levomepromazine, metoclopramide, metopimazine, prochlorperazine, promazine, raclopride, remoxipride, risperidone, sulpiride, sultopride, and ziprasidone, or pharmaceutically acceptable salts thereof, or combinations thereof; and

[0087] (2) a sympathomimetic agent selected from phenylephrine, epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine, methamphetamine, methylphenidate, lisdexamfetamine, cocaine, benzylpiperazine, and propylhexedrine, or pharmaceutically acceptable salts thereof, or combinations thereof.

[0088] £L} In some embodiments, a combination of active agents suitable for compositions and methods for treatment of sleep related breathing disorders described herein comprises a combination of

[0089] (1) a D2 antagonist selected from chlorpromazine, levomepromazine, metopimazine, promazine, and domeperidone maleate, or pharmaceutically acceptable salts thereof, or combinations thereof; and

[0090] (2) a sympathomimetic agent selected from phenylephrine, epinephrine, ephedrine, pseudoephedrine, and dopamine, or pharmaceutically acceptable salts thereof, or combinations thereof.

[0091] In some embodiments, for any of the combinations described above in {A) - £L , the pseudoephedrine or a pharmaceutically acceptable salt thereof, is pseudoephedrine. In some embodiments, for any of the combinations described above in {A) - £L}, the pseudoephedrine or a pharmaceutically acceptable salt thereof, is pseudoephedrine HC1. In some embodiments, for any of the combinations described above in {A) - £L}, the pseudoephedrine or a pharmaceutically acceptable salt thereof, is pseudoephedrine sulfate. In some embodiments, for any of the combinations described above in (A) - {L}, the phenylephrine or a

pharmaceutically acceptable salt thereof, is phenylephrine. In some embodiments, for any of the combinations described above in {A) - £L}, the phenylephrine or a pharmaceutically acceptable salt thereof, is phenylephrine HC1. In some embodiments, for any of the combinations described above in {A) - £L}, the phenylephrine or a pharmaceutically acceptable salt thereof, is phenylephrine tannate.

[0092] In further embodiments, for any of the combinations described above in {A) - £L}, the combination is suitable for compositions and methods for treatment of snoring. In further embodiments, for any of the combinations described above in (A) - {L}, the combination is suitable for compositions and methods for treatment of severe snoring. In further embodiments, for any of the combinations described above in (A) - (L). the combination is suitable for compositions and methods for treatment of pathological snoring. In further embodiments, for any of the combinations described above in {A) - £L}, the combination is suitable for compositions and methods for treatment of OSA and/or OSAS. In further embodiments, for any of the combinations described above in {A) - £L}, the combination is suitable for compositions and methods for treatment of any one or more of CSA, mixed apnea, hypopnea, hypercapnia, hypocapnia, CSAS, ICSA, -CSB- CSA, UARS, obesity hypoventilation syndrome , alveolar hypoventilation syndromes, CCHS, high altitude periodic breathing, CSA due to a medical condition, CSA due to a drug or substance (e.g., opioid-induced CSA), chronic mountain sickness, and/or SRBDs associated with neurologic conditions or neuromuscular conditions.

[0093] In specific embodiments, provided herein are methods for treatment of SRBDs comprising the administration of a combination of metopimazine, or a pharmaceutically acceptable salt thereof, and pseudoephedrine, or a pharmaceutically acceptable salt thereof, to an individual in need thereof. In specific embodiments, provided herein are methods for treatment of SRBDs comprising the administration of a combination of domperidone maleate, and pseudoephedrine, or a pharmaceutically acceptable salt thereof, to an individual in need thereof. Provided herein are compositions comprising metopimazine, or a pharmaceutically acceptable salt thereof, and pseudoephedrine, or a pharmaceutically acceptable salt thereof, for use in treatment of SRBDs. Provided herein are compositions comprising domperidone maleate, and pseudoephedrine, or a pharmaceutically acceptable salt thereof, for use in treatment of SRBDs.

[0094] In specific embodiments, provided herein are methods for treatment of snoring comprising the administration of a combination of metopimazine, or a pharmaceutically acceptable salt thereof, and pseudoephedrine, or a pharmaceutically acceptable salt thereof, to an individual in need thereof. In specific embodiments, provided herein are methods for treatment of snoring comprising the administration of a combination of domperidone maleate, and pseudoephedrine, or a pharmaceutically acceptable salt thereof, to an individual in need thereof. Provided herein are compositions comprising metopimazine, or a pharmaceutically acceptable salt thereof, and pseudoephedrine, or a pharmaceutically acceptable salt thereof, for use in treatment of snoring. Provided herein are compositions comprising domperidone maleate, and pseudoephedrine, or a pharmaceutically acceptable salt thereof, for use in treatment of snoring. [0095] In specific embodiments, provided herein are methods for treatment of pathological snoring comprising the administration of a combination of metopimazine, or a pharmaceutically acceptable salt thereof, and pseudoephedrine, or a pharmaceutically acceptable salt thereof, to an individual in need thereof. In specific embodiments, provided herein are methods for treatment of pathological snoring comprising the administration of a combination of domperidone maleate, and pseudoephedrine, or a pharmaceutically acceptable salt thereof, to an individual in need thereof. Provided herein are compositions comprising metopimazine, or a

pharmaceutically acceptable salt thereof, and pseudoephedrine, or a pharmaceutically acceptable salt thereof, for use in treatment of pathological snoring. Provided herein are compositions comprising domperidone maleate, and pseudoephedrine, or a pharmaceutically acceptable salt thereof, for use in treatment of pathological snoring.

[0096] In some embodiments of any of the methods and compositions described herein, the pseudoephedrine is a pseudoephedrine HC1 salt, or a pseudoephedrine sulfate salt.

[0097] In some embodiments of the compositions and methods described above, the D2 antagonist and sympathomimetic agent are administered to an individual prior to bedtime. In some embodiments of the compositions and methods described above, the D2 antagonist and sympathomimetic agent are administered to an individual simultaneously. In some embodiments of the compositions and methods described above, the D2 antagonist and sympathomimetic agent are administered to an individual sequentially. In some embodiments of the compositions and methods described above, the D2 antagonist and sympathomimetic agent are administered to an individual as a single unit dose. In some embodiments of the compositions and methods described above, the D2 antagonist and sympathomimetic agent are administered to an individual as separate dosage

formulations.

[0098] In some of the embodiments described above an individual suffering from a SRBD is administered between about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg, and about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg of a D2 antagonist per day and between about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, and about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 240 mg, about 250 mg, about 300 mg, or about 500 mg, of a sympathomimetic agent per day.

[0099] In some of the embodiments described above an individual suffering from a SRBD is administered between about 1 mg to about 60 mg of a D2 antagonist per day and between about 15 mg to about 240 mg of a sympathomimetic agent per day. In some of the embodiments described above an individual suffering from a SRBD is administered between about 1 mg to about 40 mg of a D2 antagonist per day and between about 15 mg to about 240 mg of a sympathomimetic agent per day. In some of the embodiments described above an individual suffering from a SRBD is administered between about 5 mg to about 70 mg of a D2 antagonist per day and between about 15 mg to about 240 mg of a sympathomimetic agent per day. In some of the embodiments described above an individual suffering from a SRBD is administered between about 10 mg to about 80 mg of a D2 antagonist per day and between about 15 mg to about 240 mg of a sympathomimetic agent per day. [00100] In some of the embodiments described above an individual suffering from a SRBD is administered between about 1 mg to about 80 mg of a D2 antagonist per day and between about 5 mg to about 240 mg of a sympathomimetic agent per day. In some of the embodiments described above an individual suffering from a SRBD is administered between about 1 mg to about 80 mg of a D2 antagonist per day and between about 25 mg to about 300 mg of a sympathomimetic agent per day. In some of the embodiments described above an individual suffering from a SRBD is administered between about 1 mg to about 80 mg of a D2 antagonist per day and between about 50 mg to about 350 mg of a sympathomimetic agent per day.

Pharmaceutical compositions

[00101] Pharmaceutical compositions are formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Eahston, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[00102] A pharmaceutical composition, as used herein, refers to a mixture of an agent that modulates the activity of a carotid body with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the D2 antagonist and/or the sympathomimetic agent. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of a D2 antagonist and/or a sympathomimetic agent are administered in a pharmaceutical composition to a mammal having a condition, disease, or disorder to be treated. Preferably, the mammal is a human. A therapeutically effective amount varies depending on the severity and stage of the condition, the age and relative health of an individual, the potency of a D2 antagonist and/or a sympathomimetic agent used and other factors. The D2 antagonist and/or a sympathomimetic agent are optionally used with one or more further therapeutic agents as components of mixtures.

[00103] The pharmaceutical formulations described herein are optionally administered to an individual by multiple administration routes, including but not limited to, oral (solid or liquid formulations), buccal, sublingual, nasal or rectal administration routes. In specific embodiments, the pharmaceutical formulations described herein are optionally administered to an individual orally.

[00104] In some embodiments, pharmaceutical formulations described herein are optionally administered as controlled release (e.g., sustained release, immediate release, intermediate release, pulsed release) formulations. One or both active agents (a D2 antagonist and/or a sympathomimetic agent) are administered as controlled release formulations.

[00105] The methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of a D2 antagonist and/or a sympathomimetic agent having the same type of activity. In some situations, D2 antagonists and/or a sympathomimetic agents exist as tautomers. All tautomers are included within the scope of the compounds presented herein. Additionally, such agents exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of D2 antagonists and/or sympathomimetic agents presented herein are also considered to be disclosed herein.

[00106] In some embodiments, pharmaceutically acceptable salts are obtained by reacting an active agent (e.g., a

D2 antagonist and/or a sympathomimetic agent) with acids. Pharmaceutically acceptable salts are also obtained by reacting an active agent (e.g., a D2 antagonist and/or a sympathomimetic agent) with a base. In some embodiments, an active agent (e.g., a D2 antagonist and/or a sympathomimetic agent) is used as a

pharmaceutically acceptable salt. The type of pharmaceutical acceptable salt, includes, but is not limited to: (1) an acid addition salt, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid to form a salt such as, for example, a hydrochloric acid salt, a hydrobromic acid salt, a sulfuric acid salt, a phosphoric acid salt, a metaphosphoric acid salt, and the like; or with an organic acid to form a salt, such as, for example, an acetic acid salt, a propionic acid salt, a hexanoic acid salt, a

cyclopentanepropionic acid salt, a glycolic acid salt, a pyruvic acid salt, a lactic acid salt, a malonic acid salt, a succinic acid salt, a malic acid salt, a maleic acid salt, a fumaric acid salt, a trifluoroacetic acid salt, a tartaric acid salt, a citric acid salt, a benzoic acid salt, a cinnamic acid salt, a mandelic acid salt, a methanesulfonic acid salt, an ethanesulfonic acid salt, a 1,2-ethanedisulfonic acid salt, a 2-hydroxyethanesulfonic acid salt, a benzenesulfonic acid salt, a toluenesulfonic acid salt, a 2-naphthalenesulfonic acid salt, a glucoheptonic acid salt, a 3-phenylpropionic acid salt, a trimethylacetic acid salt, a lauryl sulfuric acid salt, a gluconic acid salt, a glutamic acid salt, a salicylic acid salt, a stearic acid salt, a muconic acid salt, a butyric acid salt, a phenylacetic acid salt, a phenylbutyric acid salt, a valproic acid salt, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, or aluminum salt. In some cases, an active agent (e.g., a D2 antagonist and/or a sympathomimetic agent) is reacted with an organic base to form a salt, such as, but not limited to, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, a tromethamine salt, a N-methylglucamine salt, a dicyclohexylamine salt, a tris(hydroxymethyl)methylamine salt. In other cases, an active agent (e.g., a D2 antagonist and/or a sympathomimetic agent) form salts with amino acids such as, but not limited to, an arginine salt, a lysine salt, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. In certain embodiments, the compounds presented herein possess one or more stereocenters and each center independently exists in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns. In some embodiments, an active agent (e.g., a D2 antagonist and/or a sympathomimetic agent) is used as a single enantiomer. In some embodiments, an active agent (e.g., a D2 antagonist and/or a sympathomimetic agent) is used as a racemic mixture.

[00107] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structures presented herein, as well as active metabolites of these compounds having the same type of activity. In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In specific embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In other embodiments, the compounds described herein exist in unsolvated form.

[00108] In some embodiments, the compositions described herein include solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.

[00109] "Carrier materials" include any commonly used excipients in pharmaceutics and should be selected on the basis of compatibility with compounds disclosed herein, such as, a D2 antagonist and/or a sympathomimetic agent, and the release profile properties of the desired dosage form. Exemplary carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like.

[00110] Moreover, the pharmaceutical compositions described herein, which include a D2 antagonist and/or a sympathomimetic agent, are formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, powders suitable for reconstitution, and the like. For oral ingestion by a patient to be treated, dosage forms include and are not limited to effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, pills, capsules, solutions, gels, syrups, elixirs, suspensions or the like. In some embodiments, a formulation comprising an agent that modulates the activity of a carotid body is a solid drug dispersion. A solid dispersion is a dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by the melting (or fusion), solvent, or melting- solvent methods. (Chiou and Riegelman, Journal of Pharmaceutical Sciences, 60, 1281 (1971)). The dispersion of one or more active agents in a solid diluent is achieved without mechanical mixing. Solid dispersions are also called solid-state dispersions. In some embodiments, any compound described herein is formulated as a spray dried dispersion (SDD). An SDD is a single phase amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution prepared by dissolving the drug and a polymer in a solvent (e.g., acetone, methanol or the like) and spray drying the solution. The solvent rapidly evaporates from droplets which rapidly solidifies the polymer and drug mixture trapping the drug in amorphous form as an amorphous molecular dispersion. In some embodiments, such amorphous dispersions are filled in capsules and/or constituted into oral powders for reconstitution. Solubility of an SDD comprising a drug is higher than the solubility of a crystalline form of a drug or a non-SDD amorphous form of a drug. In some embodiments of the methods described herein, an agent that modulates the activity of a carotid body is administered as SDD constituted into appropriate dosage forms described herein.

[00111] Pharmaceutical preparations for oral use are optionally obtained by mixing one or more solid excipient with a D2 antagonist and/or a sympathomimetic agent, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents are added, such as the cross linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[00112] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions are generally used, which optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments are optionally added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[00113] In some embodiments, the solid dosage forms disclosed herein are in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), solid dispersion, solid solution, pellets, or granules. In other embodiments, the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet. Additionally, pharmaceutical formulations of an agent that modulates the activity of a carotid body are optionally administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets.

[00114] In another aspect, dosage forms include microencapsulated formulations. In some embodiments, one or more other compatible materials are present in the microencapsulation material. Exemplary materials include, but are not limited to, pH modifiers, erosion facilitators, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[00115] Exemplary useful microencapsulation materials include, but are not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel® or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR,

Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A, hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such as Natrosol®, carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S100,

Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, cellulose acetate phthalate, sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials.

[00116] Liquid formulation dosage forms for oral administration are optionally aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002). In addition to an agent that modulates the activity of a carotid body, the liquid dosage forms optionally include additives, such as: (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative, (e) viscosity enhancing agents, (f) at least one sweetening agent, and (g) at least one flavoring agent. In some embodiments, the aqueous dispersions further includes a crystal-forming inhibitor.

[00117] In some embodiments, the pharmaceutical formulations described herein are self-emulsifying drug delivery systems (SEDDS). Emulsions are dispersions of one immiscible phase in another, usually in the form of droplets. Generally, emulsions are created by vigorous mechanical dispersion. SEDDS, as opposed to emulsions or microemulsions, spontaneously form emulsions when added to an excess of water without any external mechanical dispersion or agitation. An advantage of SEDDS is that only gentle mixing is required to distribute the droplets throughout the solution. Additionally, water or the aqueous phase is optionally added just prior to administration, which ensures stability of an unstable or hydrophobic active ingredient. Thus, the SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. In some embodiments, SEDDS provides improvements in the bioavailability of hydrophobic active ingredients. Methods of producing self-emulsifying dosage forms include, but are not limited to, for example, U.S. Pat. Nos.

5,858,401 , 6,667,048, and 6,960,563.

[00118] Buccal or sublingual formulations that comprise a D2 antagonist and/or a sympathomimetic agent include, but are not limited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136. In addition, the buccal dosage forms described herein optionally further include a bioerodible (hydrolysable) polymeric carrier that also serves to adhere the dosage form to the buccal mucosa. Buccal drug delivery avoids the disadvantages encountered with oral drug administration, e.g., slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract and/or first-pass inactivation in the liver. The bioerodible (hydrolysable) polymeric carrier generally comprises hydrophilic (water-soluble and water-swellable) polymers that adhere to the wet surface of the buccal mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and co, e.g., those known as "carbomers" (Carbopol®, which may be obtained from B.F. Goodrich, is one such polymer). Other components that can also be incorporated into the buccal or sublingual dosage forms described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives, and the like. For buccal or sublingual administration, the compositions optionally take the form of tablets, lozenges, or gels formulated in a conventional manner.

[00119] In some embodiments, a D2 antagonist and/or a sympathomimetic agent is also optionally formulated for nasal administration. Suitable intranasal formulations include those described in, for example, U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffering and other stabilizing and solubilizing agents are optionally present.

[00120] For administration by inhalation, the D2 antagonist and/or the sympathomimetic agent is optionally formulated as an aerosol, a mist or a powder. Pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit is determined by providing a valve to deliver a metered amount. Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the D2 antagonist and/or the

sympathomimetic agent and a suitable powder base such as lactose or starch.

[00121] In some embodiments, a D2 antagonist and/or a sympathomimetic agent is also optionally formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the

compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

Combination Formulations and Kits

[00122] In one aspect, contemplated within the scope of formulations described herein are single-pill co- formulations comprising a D2 antagonist and/or a sympathomimetic agent. In some embodiments, the two active agents in a single pill formulation have the same rate of release. In some embodiments, the two active agents in a single pill formulation each independently have a titrated dosage such that maximal therapeutic benefit is achieved by the combination treatment. In some embodiments, the two active agents in a single pill formulation each independently have a different rate of release, e.g., one agent undergoes immediate release and the second agent is released via controlled release over a period of time.

[00123] In addition, in some embodiments, the two drugs are co-packaged in a manner that would facilitate the taking of both drugs at the same time. The formulations also enable a modified release of one or the other drug or both drugs. In a specific embodiment, the combination product incorporates a modified release formulation that reduces the Cmax of the D2 antagonist to minimize peak concentration side effects.

[00124] Also provided herein are kits that comprise formulations for combination therapy as described herein. The disclosure also provides kits for preventing, treating or ameliorating the symptoms of a Sleep Related Breathing Disorder in a mammal. Such kits generally will comprise one or more of the active agent as disclosed herein, and instructions for using the kit.

[00125] In some embodiments, kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) including one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In other embodiments, the containers are formed from a variety of materials such as glass or plastic.

[00126] In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound or combination of active agents provided herein. In another embodiment, the pack for example contains metal or plastic foil, such as a blister pack.

[00127] In some embodiments, a combination product described herein comprising a D2 antagonist and a sympathomimetic agent is used for the treatment of habitual snoring and/or mild OSAS (e.g., AHI between 5- 15).

Examples of Methods of Dosing and Treatment Regimens

[00128] A combination of a D2 antagonist and a sympathomimetic agent is optionally used in the preparation of medicaments for the prophylactic and/or therapeutic treatment of a condition that would benefit, at least in part, from amelioration of symptoms. In addition, a method for treating any of the diseases or conditions described herein in an individual in need of such treatment, involves administration of pharmaceutical compositions containing a D2 antagonist and a sympathomimetic agent described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said individual.

[00129] In the case wherein the patient's condition does not improve, upon the doctor's discretion the treatment is optionally administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[00130] In certain embodiments, the administered dose of a D2 antagonist and a sympathomimetic agent is determined via a step-wise dose escalation wherein a patient's response to treatment is titrated to determine the optimal dose of each agent (e.g., a D2 antagonist and a sympathomimetic agent) for each individual patient. The titration is optionally carried out under observation in a sleep clinic and the dose is modified till the desired therapeutic effect is achieved. Measures found in polysomnography reports include the fraction of sleep time spent at each level of oxygen saturation (i.e., the percent time below an oxygen saturation of 90 percent) and/or the mean oxygen saturation. The former quantifies the cumulative exposure to hypoxemia, while the latter may be inversely associated with risk for cardiovascular disease and/or glucose intolerance and/or insulin sensitivity.

[00131] In some embodiments, as a patient is started on a regimen of a D2 antagonist and a sympathomimetic agent, the patient is also weaned off (e.g., step-wise decrease in dose) any other medication such as a respiratory stimulant, a sleep medication or the like.

[00132] In certain embodiments, the daily administered dose of a D2 antagonist and/or a sympathomimetic agent is a dose such that there are no side-effects that would otherwise occur at higher doses (e.g., extrapyramidal effects associated with certain D2 antagonists). Thus, in some embodiments, administration of a combination of a D2 antagonist and/or a sympathomimetic agent reduces or prevents occurrence of side-effects such as hemorrhagic shock, edema, myocardial infarction, stroke, inflammatory mononuclear cell infiltration, sepsis and/or metabolic inhibition even after long term and/or chronic usage. In some embodiments, the administered dose of a D2 antagonist and/or a sympathomimetic agent is a dose that regulates breathing during REM and/or NREM sleep.

[00133] In certain embodiments, the daily administered dose of a D2 antagonist is titrated such that the plasma C_max of the dopamine receptor antagonist is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%> or about 70%> below the C_max at which extrapyramidal effects associated with dopamine receptor antagonists occur, such that there are no side-effects that would otherwise occur at a higher doses. In certain embodiments, the daily administered dose of a D2 antagonist is titrated such that the plasma AUC of the dopamine receptor antagonist is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%> or about 70%> less than the AUC at which extrapyramidal effects associated with dopamine receptor antagonists occur, such that there are no side-effects that would otherwise occur at a higher doses.

[00134] In the case wherein the patient's status does improve, upon the doctor's discretion the administration of a combination of a D2 antagonist and/or a sympathomimetic agent is optionally given continuously;

alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[00135] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In some embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms. [00136] In some embodiments, the pharmaceutical compositions described herein are in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of a D2 antagonist and/or a sympathomimetic agent. In some embodiments, the unit dosage is in the form of a package containing discrete quantities of the formulation. Non- limiting examples are packaged tablets or capsules, and powders in vials or ampoules. In some embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

[00137] The daily dosages appropriate for a D2 antagonist and/or a sympathomimetic agent are from about 0.001 to 2.5 mg/kg of body weight. An indicated daily dosage in the larger mammal, including, but not limited to, humans, is in the range from about 0.1 mg to about 1000 mg, conveniently administered in divided doses, including, but not limited to, up to four times a day or in extended release form. Suitable unit dosage forms for oral administration include from about 0.1 to 500 mg active ingredient, from about 0.1 to 250 mg of active ingredient, or from about 0.1 to about 100 mg active ingredient. The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. Such dosages are optionally altered depending on a number of variables, not limited to the activity of a D2 antagonist and/or a sympathomimetic agent, the disease or condition to be treated, the mode of administration, the requirements of an individual, the severity of the disease or condition being treated, and the judgment of the practitioner.

[00138] In some embodiments, the combination of a D2 antagonist and a sympathomimetic agent is administered to a patient as a single dose once a day, prior to bedtime. In some of such embodiments, a patient suffering from pathological snoring and/or conditions related to pathological snoring described herein (e.g., any sleep related breathing disorder described above) is administered a combination of metopimazine, or a pharmaceutically acceptable salt thereof, and pseudoephedrine, or a pharmaceutically acceptable salt thereof.

[00139] Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of 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 the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50. Agents that exhibit high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosages for use in humans. The dosage of such agents (a D2 antagonist and/or a sympathomimetic agent) lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

EXAMPLES

Example 1: Effect of combination therapy using a D2 antagonist and a sympathomimetic drug for treatment of daytime symptoms associated with UARS and mild OSAS. [00140] This study will be a double-blind, randomized, placebo-controlled, two-phase crossover study of patients, stratified into those with mild OSAS and those with UARS.

[001411 Objectives: To assess the ability of a fixed dose combination of metopimazine plus pseudoephedrine (MET+PE) to improve daytime symptoms associated with UARS and mild OSAS. Primary improvements in daytime symptoms associated with UARS and mild OSAS will be assessed through a comparison in the patient's Epworth Sleepiness Scale (ESS) score at the end of drug treatment versus the ESS score at the end of the placebo period. A secondary objective of the study is to show improved nighttime oxygenation, as assessed by the ARES™ device, a validated, in-home PSG instrument.

[00142] Study Design: This is a double-blind, randomized, placebo controlled, two-phase crossover study of patients who snore, stratified into those with mild OSAS and those with UARS. The study will include a 3 -day baseline period, in which the nature and the severity of the patients' SRBD are determined. Once the patients' SRBD is classified and characterized, the subjects will be randomized into one of two study groups, which will receive either 60 mg pseudoephedrine and 15 mg metopimazine (treatment) or matching placebo for two weeks. After completion of the first treatment/placebo period, patients will undergo a 2 -week washout period followed by a second study period, in which they receive the other regimen (Figure 1). All patients will wear an ARES™ device every third night during the study periods.

[00143] Primary criteria for inclusion:

1. Patients must have the ability to give informed consent.

2. Must be able to read and speak English.

3. AHI <30 and a respiratory disturbance index (RDI) >10, as diagnosed by PSG within the 12 months prior to randomization.

4. Average nightly AHI of 5-30, OR AHI <5 + RDI >10, as determined by 3 nights of home ARES device utilization.

5. Age >21.

6. BMI <35.

7. Epworth Sleepiness Scale >10, to confirm a current diagnosis of UARS or mild OSAS.

8. Not currently using CPAP (patients with <3 days of CPAP use in the last 3 months will be allowed).

9. Non-smokers, with no history of smoking for >2 years.

10. Females must be either postmenopausal (no menses for at least 1 year) or status-post hysterectomy or oophorectomy (bilateral) or, if of childbearing potential, must have a negative urine pregnancy test prior to randomization, and be using a medically acceptable form of contraception for the duration of the study, (e.g., hormonal birth control, IUD, double barrier [male condom, female condom, diaphragm] or a barrier method plus a spermicidal agent [contraceptive foam, jelly or cream]).

11. Patients must be willing and able to properly use the ARES home sleep study device.

12. Average snoring >30dB for >20% of total sleep time (TST), as determined by 3 nights of home ARES device utilization. [00144] Primary criteria for exclusion:

1. Clinically significant comorbidity, including any unstable cardiovascular, gastrointestinal, metabolic, pulmonary (e.g., asthma, COPD), renal, neurological, hepatic, hematologic, immunologic, endocrine, and/or neoplastic disease based on Principal Investigator judgment.

2. Hypertension (However, those patients with controlled hypertension: i.e., systolic <140mmHg and diastolic <90mmHg, for at least 3 months prior to TxO/Baseline will be allowed to enroll).

3. Patients with evidence of active liver disease (levels of AST, ALT and/or alkaline phosphatase >2x ULN for the laboratory performing the test.

4. Patients with a white blood cell count below normal range, or a count >1.5x the ULN.

5. Patients with anemia, as defined by hemoglobin <80% lower limit of normal.

6. Patients with impaired renal function, as evidenced by a creatinine value >1.2x ULN.

7. Severe craniofacial abnormalities.

8. Previous or current history of a generalized or partial seizure disorder, or current treatment for any form of seizure disorder (excluding seizure during childhood).

9. Concomitant use of any stimulant medications, including modafinil.

10. Concomitant use of opioids.

1 1. Concomitant use of sedative hypnotics, tranquilizers, sedating antihistamines (non-sedating antihistamines will be allowed), or benzodiazepines.

12. Concomitant use of domperidone or other gastric prokinetic agents/GERD agents, including PPIs and H2 -blockers.

13. Concomitant use of pseudoephedrine or other nasal decongestants.

14. Concomitant use of anticonvulsant medication(s).

15. Current diagnosis of any psychiatric illness, including any psychotic, schizoaffective, and/or major affective disorder(s) based on DSM-IV criteria.

16. Patients who are receiving concomitant therapy with MAO-A or -B inhibitors, tricyclics, tetracyclics, SSRI agents, NARI agents, SNRI agents, alpha-agonists (such as clonidine or tizanidine), anti-obesity medications (i.e., sibutramine, phentermine, orlistat) or St. John's Wort.

17. Current diagnosis of any substance abuse disorder, based on investigator opinion.

18. Pregnant or lactating females.

19. Concomitant use of drugs having known cytochrome P450 3A4 or 2D6 induction or inhibition properties. Enrollment of patients using any drugs listed in the appendix will require advance approval from the sponsor.

[00145] Test drug, dosage, mode of administration: One week following completion of the baseline period, patients will be randomized into one of two groups. Each group will receive either placebo or 60 mg of pseudoephedrine and 15 mg of metopimazine (MET+PE treatment) orally, approximately 30-60 minutes before bedtime, for 14 days (Period 1). This will be followed by a two week washout period. In Period 2, patients who received the placebo during Period 1 will receive MET+PE for 14 days and vice versa.

[00146] Data collection: During the study periods, home sleep testing will be performed on Nights 1 , 4, 7, 10, 13 and 14 using ARES: a diagnostic device that measures AHI, ODI, RDI, and snoring intensity, frequency and duration. This will necessitate only one visit to the study site during each study period for the purpose of having the data downloaded. The planned schedule will provide sufficient data points to observe whether or not there is a trend in the study parameters over the two-week period, as well as to give 2 nights of data at the end of the period, which will be averaged in order to compensate for internight variability.

Example 2: Pharmaceutical Compositions:

Example 2a: Oral Composition

[00147] To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound (e.g., a D2 antagonist) is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration. A sympathomimetic agent is formulated using a similar procedure. Optionally, a sympathomimetic agent is co-formulated with the D2 antagonist in the oral composition.

Example 2b: Sublingual (Hard Lozenge) Composition

[00148] To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, mix 100 mg of a compound (e.g., a D2 antagonist) with 420 mg of powdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 niL distilled water, and 0.42 mL mint extract. The mixture is gently blended and poured into a mold to form a lozenge suitable for buccal administration. A sympathomimetic agent is formulated using a similar procedure. Optionally a sympathomimetic agent is co-formulated with the D2 antagonist in the lozenge composition. Example 2c: Inhalation Composition

[00149] To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound (e.g., a D2 antagonist) is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration. A sympathomimetic agent is formulated using a similar procedure. Optionally a

sympathomimetic agent is co-formulated with the D2 antagonist in the nasal composition.

Example 2d: Rectal Gel Composition

[00150] To prepare a pharmaceutical composition for rectal delivery, 100 mg of a compound (e.g., a D2 antagonist) is mixed with 2.5 g of methylcelluose (1500 mPa), 100 mg of methylparapen, 5 g of glycerin and 100 mL of purified water. The resulting gel mixture is then incorporated into rectal delivery units, such as syringes, which are suitable for rectal administration. A sympathomimetic agent is formulated using a similar procedure. Optionally a sympathomimetic agent is co-formulated with the D2 antagonist in the rectal formulation.

Example 2e: Nasal spray solution [00151] To prepare a pharmaceutical nasal spray solution, 10 g of a compound (e.g., a D2 antagonist) is mixed with 30 niL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 μΐ of spray for each application. A sympathomimetic agent is formulated using a similar procedure. Optionally a sympathomimetic agent is co-formulated with the D2 antagonist in the nasal composition.

[00152] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method for treatment of sleep-related breathing disorders (SRBDs) in an individual in need thereof comprising administration of a composition comprising a dopamine-2 receptor (D2) antagonist, or a pharmaceutically acceptable salt thereof, and a sympathomimetic agent, or a pharmaceutically acceptable salt thereof, to the individual in need thereof; provided that the composition does not comprise a free base of domperidone.

2. The method of claim 1 , wherein the sleep-related breathing disorder is severe snoring.

3. The method of claim 2, wherein the severe snoring is associated with obstructive sleep apnea (OSA), central sleep apnea (CSA), obstructive sleep apnea syndrome (OSAS), upper airway resistance syndrome (UARS), obesity hypoventilation syndrome, or Cheyne-Stokes breathing.

4. The method of claim 1 , wherein the D2 antagonist is selected from acepromazine, amisulpride, amoxapine, azaperone, benperidol, bromopride, butaclamol, clomipramine, chlorpromazine, chlorprothixene, clopenthixol, droperidol, eticlopride, flupenthixol, fluphenazine, fluspirilene, haloperidol, iodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, metopimazine, nafadotride, nemonapride, penfluridol, perazine, perphenazine, pimozide, prochlorperazine, promazine, raclopride, remoxipride, risperidone, spiperone, spiroxatrine, stepholidine, sulpiride, sultopride, tetrahydropahnatine, thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, and ziprasidone, or a pharmaceutically acceptable salt thereof.

5. The method of any one of claims 1 -4, wherein the D2 antagonist does not cause central nervous system effects.

6. The method of any one of claims 1 -5, wherein the D2 antagonist is metopimazine, or a pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1 -6, wherein the sympathomimetic agent is selected from cyclopentamine, phenylephrine, phenylpropanolamine, mephentermine, midodrine, methoxamine, metaraminol, oxymetazoline, tetryzoline, xylometazoline, naphazoline, tramazoline, metizoline, tuaminoheptane, fenoxazoline, tymazoline, epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine,

propylhexedrine, or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1 -6, wherein the sympathomimetic agent is ephedrine or pseudoephedrine, or a pharmaceutically acceptable salt thereof.

9. The method of any one of claims 1 -8, wherein the D2 antagonist is administered in a dose of between about 1 mg/day to about 300 mg/day.

10. The method of any one of claims 1 -8, wherein the D2 antagonist is administered in a dose of between about 1 mg/day to about 60 mg/day.

11. The method of any one of claims 1 -10, wherein the sympathomimetic agent is administered in a dose of between about 15 mg/day to about 240 mg/day.

12. The method of any one of claims 1 -10, wherein the sympathomimetic agent is administered in a dose of between about 60 mg/day to about 120 mg/day.

13. The method of any one of claims 1 -12, wherein the D2 antagonist is orally administered in an immediate release form.

14. The method of any one of claims 1 -12, wherein the D2 antagonist is orally administered in an extended release form.

15. The method of any one of claims 1 -14, wherein the sympathomimetic agent is orally administered in an immediate release form.

16. The method of any one of claims 1 -14, wherein the sympathomimetic agent is orally administered in an extended release form.

17. The method of any one of claims 1 -16, wherein the individual is orally administered a unit dosage form that contains both the D2 antagonist and the sympathomimetic agent.

18. The method of any one of claims 1 -17, wherein the D2 antagonist is metopimazine, or a pharmaceutically acceptable salt thereof, and the sympathomimetic agent is pseudoephedrine, or a

pharmaceutically acceptable salt thereof.

19. The method of any one of claims 1 -18, wherein the D2 antagonist dosage reduces the Cmax of the D2 antagonist to minimize peak concentration side effects of the D2 antagonist.

20. The method of any one of claims 1 -19, wherein the individual has an apnea hypopnea index (AHI) of> 5 and < 15.

21. The method of any one of claims 1 -19, wherein the individual has a respiratory disturbance index (RDI) of > 5 and < 15.

22. The method of any one of claims 1 -19, wherein the individual has an oxygen desaturation index (ODI) of> 5 and < 15.

23. The method of any one of claims 1 -19, wherein the individual has a body mass index (BMI) of

< 35.

24. A method for treatment of snoring in an individual in need thereof comprising administration of a composition comprising

mephentermine, midodrine, methoxamine, metaraminol, oxymetazoline, tetryzoline, xylometazoline, naphazoline, tramazoline, metizoline, tuaminoheptane, fenoxazoline, tymazoline, epinephrine, ephedrine, pseudoephedrine, dopamine, amphetamine, methamphetamine, methylphenidate, lisdexamfetamine, cocaine, cathinone, cathine, methcathinone, benzylpiperazine,

methylenedioxypyrovalerone, 4-methylaminorex, pemoline, phenmetrazine, and propylhexedrine, or a pharmaceutically acceptable salt thereof.

25. The method of claim 24, wherein the snoring is severe snoring.

26. The method of claim 25, wherein the severe snoring is associated with obstructive sleep apnea (OSA), central sleep apnea (CSA), obstructive sleep apnea syndrome (OSAS), upper airway resistance syndrome (UARS), obesity hypoventilation syndrome, or Cheyne-Stokes breathing.

27. The method of claim 24, wherein the first agent is metopimazine, or a pharmaceutically acceptable salt thereof.

28. The method of claim 27, wherein the second agent is pseudoephedrine, or a pharmaceutically acceptable salt thereof.

29. The method of claim 27, wherein the second agent is ephedrine, or a pharmaceutically acceptable salt thereof.

30. The method of claim 27, wherein the second agent is phenylephrine, or a pharmaceutically acceptable salt thereof.

31. A method for treatment of obstructive sleep apnea syndrome (OSAS) in an individual in need thereof comprising administration of a composition comprising

(i) a first agent selected from acepromazine, amisulpride, amoxapine, azaperone, benperidol, bromopride, butaclamol, clomipramine, chlorpromazine, chlorprothixene, clopenthixol, droperidol, eticlopride, flupenthixol, fluphenazine, fluspirilene, haloperidol, iodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, metopimazine, nafadotride, nemonapride, penfluridol, perazine, perphenazine, pimozide, prochlorperazine, promazine, raclopride, remoxipride, risperidone, spiperone, spiroxatrine, stepholidine, sulpiride, sultopride, tetrahydropalmatine, thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, and ziprasidone, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof; and

32. The method of claim 31 , wherein the first agent is metopimazine, or a pharmaceutically acceptable salt thereof.

33. The method of claim 32, wherein the second agent is pseudoephedrine, or a pharmaceutically acceptable salt thereof.

34. The method of claim 32, wherein the second agent is ephedrine, or a pharmaceutically acceptable salt thereof.

35. The method of claim 32, wherein the second agent is phenylephrine, or a pharmaceutically acceptable salt thereof.

36. A pharmaceutical composition comprising metopimazine, or a pharmaceutically acceptable salt thereof, and pseudoephedrine, or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition comprising metopimazine, or a pharmaceutically acceptable salt thereof, and ephedrine, or a pharmaceutically acceptable salt thereof.

38. A pharmaceutical composition comprising metopimazine, or a pharmaceutically acceptable salt thereof, and phenylephrine, or a pharmaceutically acceptable salt thereof.

39. A kit for sleep-related breathing disorder therapy in an individual in need thereof, wherein the kit comprises:

a plurality of a first unit dosage form comprising a dopamine D2 receptor antagonist; and

a plurality of a second unit dosage form comprising a sympathomimetic agent;

wherein the dopamine D2 receptor antagonist dosage is in a form that minimizes peak concentration side effects of the dopamine D2 receptor antagonist.