WO2007092334A1 - Method of treating sleep disorders - Google Patents

Abstract

The invention relates to a method of treating a subject having a sleep disorder by administering emedastine or a pharmaceutically effective salt thereof. The invention further relates to a method of sleep modulation by administering to a subject emedastine, or a pharmaceutically effective salt thereof.

Description

METHOD OF TREATING SLEEP DISORDERS

BACKGROUND OF THE INVENTION

Sleep disorders arising from difficulty in falling asleep or remaining asleep are a significant medical issue, resulting in problem sleepiness that can impair health, quality of life, and safety for those affected. Such disorders can arise from endogenous conditions, e.g., sleep apnea, insomnia, and the like, or from external stresses, e.g., the disruptive effect of shift work schedules or "jet lag" on normal sleep patterns.

Existing pharmaceutical treatments for inducing sleep include sedatives or hypnotics, e.g., benzodiazepine or barbiturate derivatives, and milder compounds, e.g., antihistamines. However, these treatments are known to have numerous drawbacks, including rebound insomnia after a prolonged period of treatment, delayed onset of desired sedative effects on administration, persistence of unwanted sedative effects past the desired sleep period, side effects due to nonspecific activity, e.g., psychomotor and memory deficits, and the like.

Many compounds that are used for inducing sleep have undesirable side effects. In particular, many compounds that are Hl receptor antagonists are known to inhibit the hERG K-+- ion channel, which is associated with cardiac rhythm abnormalities. Other issues include, for example, prolongation of the QT interval in a subject's electrocardiogram or central nervous system (CNS) side effects, such decreased muscle tone, drooping eyelids, and the like. Also, many such compounds have a slow onset of sedative effect coupled with persistence of CNS side effects past the desired sleep period, e.g._f drowsiness. Furthermore, Hl receptor antagonists can bind to muscarinic receptors, leading to anti-cholinergic side effects, e.g., blurred vision, dry mouth, constipation, urinary problems, dizziness, anxiety, and the like.

Physicians often recommend or prescribe antihistamines when an alternative to hypnotics is desired. For example, hypnotics can be habit forming, lose their effectiveness after extended use and are often metabolized more slowly. Many hypnotics also produce a number of side effects when used to treat sleep disorders, including REM sleep inhibition, rebound insomnia, disproportionate myorelaxation and memory impairment.

Although known sleep-inducing compounds are effective for treating sleep-onset insomnia (e.g., a subject's difficulty in falling asleep) there are few sleep-inducing compounds that effectively treat sleep maintenance insomnia (e.g., maintaining a subject's sleep throughout a normal sleep period after falling asleep). There is a need for improved pharmaceutical treatments for inducing sleep in subjects in need of such treatment.

SUMMARY OF THE INVENTION

In general, in an aspect, the invention provides a method of treating a subject for a sleep disorder by administering to a subject in need of treatment for a sleep disorder a therapeutically effective amount of emedastine or a pharmaceutically effective salt thereof.

The method is used, for example, to treat sleep disorders including circadian rhythm abnormality, insomnia, parasomnia, sleep apnea syndrome, narcolepsy and hypersomnia. In general, in one aspect, the method is used to treat circadian rhythm abnormalities including jet lag, shift-work disorders, delayed sleep phase syndrome, advanced sleep phase syndrome and non-24 hour sleep-wake disorder. In another aspect, the method is used to treat insomnia including extrinsic insomnia, psychophysiologic insomnia, altitude insomnia, restless leg syndrome, periodic limb movement disorder, medication-dependent insomnia, drug- dependent insomnia, alcohol-dependent insomnia and insomnia associated with mental disorders.

In general, in another aspect, the method treats parasomnias including somnambulism, pavor nocturnus, REM sleep behavior disorder, sleep bruxism and sleep enuresis. In yet another aspect, the method is used to treat sleep apnea disorder including central sleep apnea, obstructive sleep apnea and mixed sleep apnea. Additionally, the method is used to treat other sleep disorders such as narcolepsy or hypersomnia.

The method includes the use of a pharmaceutically acceptable salt of emedastine, such as emedastine fumarate, emedastine diftirmarate, and emedastine nitrate in the treatment of a sleep disorder. In one embodiment, emedastine, or a pharmaceutically acceptable salt thereof, is administered as a monotherapy. In another embodiment, emedastine is co- administered with one or more additional agents as a co-therapy. Emedastine is administered orally, nasally, transdermally, pulmonarily, inhalationally, buccally, sublingually, intraperintoneally, intravenously, rectally, intrapleurally, intrathecally or parenterally. In one embodiment, emedastine or a pharmaceutically acceptable salt thereof is administered orally. Emedastine or a pharmaceutically acceptable salt thereof is included in a pharmaceutical composition and is administered to a subject, including a human subject. Other subjects include farm animals, companion animals, laboratory animals and wild animals. In another aspect, the invention involves modulating sleep by administering a therapeutically effective amount of emedastine, or a pharmaceutically effective salt thereof, to a subject. The method modulates sleep several ways, including decreasing the time to sleep onset, increasing sleep consolidation {e.g., increasing the average sleep bout length or increasing the maximum sleep bout length), or increasing total sleep time.

The above description sets forth rather broadly the more important features of the present invention in order that the detailed description thereof that follows may be understood, and in order that the present contributions to the art may be better appreciated. Other objects and features of the present invention will become apparent from the following detailed description considered in conjunction with the examples.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a graph indicating the effect of emedastine on NREM sleep. Fig. 2 is a graph indicating the effect of emedastine on REM sleep. Fig. 3 is a graph indicating the effect of emedastine on sleep bout length.

DETAILED DESCRIPTION

The details of one or more embodiments of the invention are set forth in the accompanying description below. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the case of conflict, the present specification will control.

The present invention relates to the use of the antihistamine emedastine to treat sleep disorders. Emedastine, or l-(2-ethoxyethyl)-2-(4-methyl-l,4-diazepan-l-yl)-lH- benzo[d]imidazole, has the following chemical structure:

Emedastine is described in U.S. Pat. No.4,430,343. In Japan, emedastine fumarate is marketed as a treatment for allergy-related conditions such as allergic rhinitis, urticaria, eczema, dermatitis, pruritus cutaneous and prurigo by Kanebo Pharmaceuticals under the tradename DAREN™ and by Kowa Pharmaceuticals under the tradename REMICUT™. In the United. States, emedastine is used to treat ophthalmic disorders as developed by Alcon Laboratories. See, e.g.,U.S. Pat. Nos. 5,441,958, 5,668,133 and 6,375,973. EMADINE™ is a 0.05% ophthalmic solution indicated for the temporary relief of the signs and symptoms of allergic conjunctivitis in the United States.

The invention provides a method of treating a subject for a sleep disorder by administering to a subject a therapeutically effective amount of emedastine or a pharmaceutically effective salt thereof. Effective sleep modulators have certain characteristics that correspond with increased efficacy and decreased side effects. These characteristics include a desired half-life in a subject, controlled onset of desired sedative effects, and minimal to no detectable effect on psychomotor or other central nervous system (CNS) side effects (e.g., memory deficits, decreased muscle tone, drooping eyelids or drowsiness). For example, effective sleep modulators have a half life in humans of less than 7 hours, less than 6 hours, less than 5 hours, less than 4 hours, approximately 3 hours, or in the range of 3 to 7 hours.

As described herein, the inventors have discovered that emedastine is a promising compound for treatment of sleep disorders. First, unlike many hypnotics, emedastine does not inhibit REM sleep. Consequently, emedasώie-induced sleep may more closely resemble a person's natural sleep cycles. Second, use of emedastine does not result in rebound insomnia. Finally, emedastine does not disproportionally inhibit locomotor activity or adversely effect body temperature.

"Treating", includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc. "Treating" or "treatment" of a disease state includes: (1) inhibiting the disease state, i.e._t arresting the development of the disease state or its clinical symptoms; or (2) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.

"Preventing" means preventing the disease state, i.e., causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.

"Disease state" means any disease, condition, symptom, or indication.

Emedastine or a pharmaceutically acceptable salt thereof is administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, emedastine is administered orally. One skilled in the art will recognize the advantages of certain routes of administration.

The method treats a variety of sleep disorders including circadian rhythm abnormality, insomnia, parasomnia, sleep apnea syndrome, and narcolepsy. In a one embodiment, the method treats circadian rhythm abnormalities including jet lag, shift-work disorders, delayed sleep phase syndrome, advanced sleep phase syndrome and non-24 hour sleep-wake disorder. In another embodiment, the method treats insomnia including extrinsic insomnia, psychophysiologic insomnia, altitude insomnia, restless leg syndrome, periodic limb movement disorder, medication-dependent insomnia, drug-dependent insomnia, alcohol- dependent insomnia and insomnia associated with mental disorders.

In another embodiment, the method treats parasomnias including somnambulism, pavor nocturnus, REM sleep behavior disorder, sleep bruxism and sleep enuresis. In yet another embodiment, the method treats sleep apnea disorder including central sleep apnea, obstructive sleep apnea and mixed sleep apnea. Additionally, the method treats other sleep disorders such as narcolepsy or hypersomnia.

In some embodiments, emedastine is administered as a pharmaceutically acceptable salt. One skilled in the art will recognize the various methods for creating pharmaceutically acceptable salts and identifying the appropriate salt. In one embodiment, the pharmaceutically acceptable salt is emedastine fumarate or emedastine nitrate. In another embodiment, emedastine or pharmaceutically acceptable salt thereof is included in a pharmaceutical composition.

In another embodiment, the invention involves modulating sleep by administering a therapeutically effective amount of emedastine, or a pharmaceutically effective salt thereof, to a subject. The method modulates sleep several ways including decreasing the time to sleep onset, increasing total sleep time, and increasing sleep consolidation (e.g., increasing the average sleep bout length, and increasing the maximum sleep bout length).

A "subject" includes mammals, e.g., humans, companion animals {e.g., dogs, cats, birds, and the like), farm animals (e.g., cows, sheep, pigs, horses, fowl, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, birds, and the like). For example, the subject is human.

A "subject in need of treatment" has a sleep disorder that can affect the subject's ability to fall asleep and/or remain asleep, and/or results in unrefreshing sleep.

As used herein, the term "sleep disorder" includes conditions recognized by one skilled in the art as sleep disorders, for example, conditions known in the art or conditions which are proposed to be sleep disorders or discovered to be sleep disorders. See, for example, Thorpy, MJ International Classification of Sleep Disorders, Revised: Diagnostic and Coding Manual. American Sleep Disorders Association; Rochester, Minnesota 1997; and ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification, National Center for Health Statistics, Hyattsville, MD.

For example, sleep disorders can be generally classed into dyssomnias, e.g., intrinsic, extrinsic, and circadian rhythm disorders; parasomnias, e.g., arousal, sleep-wake transition, and rapid eye movement (REM) associated disorders, and other parasomnias; disorders associated with mental, neurological, and other medical disorders; and other sleep disorders.

Intrinsic sleep disorders include, for example, psychophysiological insomnia, sleep state misperception, idiopathic insomnia, narcolepsy, recurrent hypersomnia, idiopathic hypersomnia, post-traumatic hypersomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement disorder, restless legs syndrome, and the like.

Extrinsic sleep disorders include, for example, inadequate sleep hygiene, environmental sleep disorder, altitude insomnia, adjustment sleep disorder, insufficient sleep syndrome, limit-setting sleep disorder, sleep-onset association disorder, food allergy insomnia, nocturnal eating (drinking) syndrome, hypnotic-dependent sleep disorder, stimulant-dependent sleep disorder, alcohol-dependent sleep disorder, toxin-induced sleep disorder, and the like.

Circadian rhythm sleep disorders include, for example, time-zone change (jet lag) syndrome, shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome, non-24-h sleep-wake disorder, and the like. Arousal sleep disorders include, for example, confusional arousals, sleepwalking, sleep terrors, and the like.

Sleep-wake transition disorders include, for example, rhythmic movement disorder, sleep starts, sleeptalking, nocturnal leg cramps, and the like.

REM-associated sleep disorders include, for example, nightmares, sleep paralysis, impaired sleep-related penile erections, sleep-related painful erections, REM sleep-related sinus arrest, REM sleep behavior disorders, and the like.

Other parasomnias include, for example, sleep bruxism, sleep enuresis, sleep-related abnormal swallowing syndrome, nocturnal paroxysmal dystonia, sudden unexplained nocturnal death syndrome, primary snoring, infant sleep apnea, congenital central hypoventilation syndrome, sudden infant death syndrome, benign neonatal sleep myoclonus, and the like.

A "sleep disorder" also arises in a subject that has other medical disorders, diseases, or injuries, or in a subject being treated with other medications or medical treatments, where the subject as a result has difficulty falling asleep and/or remaining asleep, or experiences unrefreshing sleep, e.g., the subject experiences sleep deprivation. For example, some subjects have difficulty sleeping after undergoing medical treatment for other conditions, e.g., chemotherapy or surgery, or as a result of pain or other effects of physical injuries.

The term "treating a sleep disorder" also includes treating a sleep disorder component of other disorders, such as CNS disorders (e.g., mental or neurological disorders such as anxiety). Additionally, the term "treating a sleep disorder" includes the beneficial effect of ameliorating other symptoms associated with the disorder.

It is well known in the art that certain medical disorders, for example, central nervous system (CNS) disorders, e.g. mental or neurological disorders, e.g., anxiety, can have a sleep disorder component, e.g., sleep deprivation. Thus, "treating a sleep disorder" also includes treating a sleep disorder component of other disorders, e.g., CNS disorders. Further, treating the sleep disorder component of CNS disorders can also have the beneficial effect of ameliorating other symptoms associated with the disorder. For example, in some subjects experiencing anxiety coupled with sleep deprivation, treating the sleep deprivation component also treats the anxiety component. Thus, the present invention also includes a method of treating such medical disorders.

For example, sleep disorders associated with mental disorders include psychoses, mood disorders, anxiety disorders, panic disorder, addictions, and the like. Specific mental disorders include, for example, depression, obsessive compulsive disorder, affective neurosis/disorder, depressive neurosis/disorder, anxiety neurosis; dysthymic disorder, behavior disorder, mood disorder, schizophrenia, manic depression, delirium, alcoholism, and the like.

Sleep disorders associated with neurological disorders include, for example, cerebral degenerative disorders, dementia, parkinsonism, Huntington's disease, Alzheimer's, fatal familial insomnia, sleep related epilepsy, electrical status epilepticus of sleep, sleep-related headaches, and the like. Sleep disorders associated with other medical disorders include, for example, sleeping sickness, nocturnal cardiac ischemia, chronic obstructive pulmonary disease, sleep-related asthma, sleep-related gastroesophageal reflux, peptic ulcer disease, fibrositis syndrome, and the like.

In some circumstances, sleep disorders are also associated with pain, e.g., neuropathic pain associated with restless leg syndrome; migraine; hyperalgesia, pain; enhanced or exaggerated sensitivity to pain, such as hyperalgesia, causalgia and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; arthritic pain; sports injury pain; pain related to infection, e.g., HIV, post-polio syndrome, and post-herpetic neuralgia; phantom limb pain; labor pain; cancer pain; post- chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions associated with visceral pain including irritable bowel syndrome, migraine and angina; and the like.

Other sleep disorders include, for example, short sleeper, long sleeper, subwakefulness syndrome, fragmentary myoclonus, sleep hyperhidrosis, menstrual- associated sleep disorder, pregnancy-associated sleep disorder, terrifying hypnagogic hallucinations, sleep-related neurogenic tachypnea, sleep-related laryngospasm, sleep choking syndrome, and the like.

Insomnia is typically classed into sleep onset insomnia, where a subject takes more than 30 minutes to fall asleep; and sleep maintenance insomnia, where the subject spends more than 30 minutes awake during an expected sleep period, or, for example, waking before the desired wake-up time with difficulty or an inability to get back to sleep. In one embodiment, emedastine is effective in treating sleep onset and sleep maintenance insomnias, insomnia resulting from circadian rhythm adjustment disorders, or insomnia resulting from CNS disorders. Another embodiment is treating a subject for a circadian rhythm adjustment disorder. Another embodiment is treating a subject for insomnia resulting from a mood disorder. In other embodiments, a subject is treated for sleep apnea, somnambulism, night

S terrors, restless leg syndrome, sleep onset insomnia, and sleep maintenance insomnia; or sleep onset insomnia or sleep maintenance insomnia. Emedastine is effective for treating sleep onset insomnia. Emedastine is also effective for treating sleep maintenance insomnia.

The term "nonREM peak sleep time" is defined as an absolute peak amount of nonREM sleep per hour post treatment, with drug administration occurring at Circadian Time (CT) 18, which is 6 hours after lights off in a nocturnal laboratory rat when housed in a LD 12: 12 (12-hours light and 12 hours dark) light-dark cycle. The nominal criteria of 55% nonREM sleep per hour is equivalent to 33 minutes of nonREM sleep per hour.

As used herein, the term "cumulative nonREM sleep" is defined as the net total aggregate increase in the number of minutes of nonREM sleep, measured throughout the entire duration of a drug's soporific effect, which typically, but not always occurs in the first 6 hours post-treatment, adjusted for the net total aggregate number of minutes of nonREM sleep that occurred during the corresponding non-treatment baseline times of day recorded 24 hours earlier, relative to like vehicle control treatment.

As defined herein, the term "sleep bout" refers to a discrete episode of continuous or near continuous sleep, comprised of nonREM sleep, REM sleep, or both nonREM and REM sleep stages, delimited prior and after the episode by greater than two contiguous 10 second epochs of wakefulness. The following non-limiting description illustrates this concept: WWWWSSSSWSSSSSSSWWSSSSSSSWWWW. wherein each letter represents the predominant state of arousal (S=sleep, W=wake) observed each 10 seconds. The measured sleep "bout" is 21 ten-second epochs or 3-5 minutes in duration.

Sleep Consolidation: An emedastine composition (e.g., salt or emedastine in combination with another pharmaceutical agent) is considered effective if, in adult male Wistar rats, (i) the absolute duration of longest continuous sleep episodes (Le., "sleep bout") post-treatment is greater than 13 minutes in duration; (ii) the net longest sleep bout post treatment is greater than or equal to 3 minutes when adjusted for baseline 24 hours earlier and calculated relative to vehicle treatment; and (iii) the mean absolute duration of every sleep bout when averaged per hour, on an hour by hour basis, is greater than or equal to 5 minutes. The aforementioned selection criteria assume that stages of sleep and wakefulness are determined continuously every 10 seconds (e.g., 10 second sleep scoring "epochs"), that sleep and wakefulness are measured polygraphically using EEG and EMG criteria, and sleep episodes (comprised of nonREM and/or REM sleep) are defined as continuous "bouts" until the episode is interrupted by greater than two contiguous 10 second epochs of wakefulness. As used herein, the term "longest sleep bout length" is defined as the total number of minutes an animal remains asleep (nonREM and/or REM sleep stages) during the single longest sleep episode or "bout" that occurred beginning in a given hour, post-treatment. The "sleep bout length" measurement criteria assumes sleep is measured continuously in 10 second epochs, and is scored based upon the predominant state, computed or otherwise determined as a discrete sleep stage (where sleep stages are defined as nonREM sleep, REM sleep, or wakefulness) during the 10 second interval that defines the epoch.

The term "average sleep bout length" is defined as the average duration (in minutes) of every sleep bout that began in a given hour, independent of the individual duration of each episode or bout.

Concurrently Measured Side Effects: Emedastine is considered effective if, in adult, male Wistar rats, the compound (i) does not produce appreciable amounts of rebound insomnia; (ii) does not appreciably inhibit REM sleep; and (iii) does not disproportionately inhibit locomotor motor activity and/or motor tone relative to the normal effects of sleep itself. The threshold definitions for these three side-effect variables are as follows:

"Rebound insomnia" is defined as period of rebound, paradoxical, or compensatory wakefulness that occurs after the sleep promoting effects of a hypnotic or soporific agent.

Rebound insomnia is typically observed during the usual circadian rest phase 6-18 hours post-treatment at CT-18 (6 hours after lights-off, given LD 12:12), but can occur at any time during the initial 30 hours post-treatment. Rebound is considered unacceptable when, in the adult, male Wistar rat, excess cumulative wakefulness associated with rebound insomnia is greater than 10 % reduction in average of hourly NonREM sleep times during post- treatment circadian rest phase (lights-on).

In adult, male Wistar rats, rebound insomnia manifests as an increase in wakefulness relative to corresponding times at baseline (24 hours earlier) subsequent to a drug-induced sleep effect, and rebound insomnia is measured cumulatively.

. "REM sleep inhibition" is defined as the reduction of REM sleep time post-treatment at CT-18 (6 hours after lights-off; LD 12: 12) or at CT-5 (5 hours after lights-on; LD 12:12). Compounds that reduce REM sleep time by greater than 15 minutes (relative to baseline and adjusted for vehicle treatment) when administered at either CT-18 or CT-5 are considered unacceptable. Compared with NREM sleep or wakefulness, REM sleep causes ventilatory depression and episodic cardiovascular changes. During rebound insomnia, the physiological effects of REM sleep are magnified and interrupt the normal sleep cycles.

As defined herein, "disproportionate locomotor activity inhibition" is a reduction of locomotor activity that exceeds the normal and expected reduction in behavioral activity attributable to sleep. Logic dictates that if an animal is asleep, there will normally be a corresponding reduction in locomotor activity. If a hypnotic or soporific compound reduces locomotor activity levels in excess of 20% greater than that explained by sleep alone, the compound is deemed unacceptable. Locomotor activity (LMA) or motor tone may be quantified objectively using any form of behavioral locomotor activity monitor (non-specific movements, telemetry-based activity monitoring, 3 -dimensional movement detection devices, wheel running activity, exploratory measures, electromyographic recording, etc.) so long as it is measured concurrently with objective sleep-wakefulπess measures in the same animal.

In one embodiment, locomotor activity within the animal's cage is measured using a biotelemetry device surgically implanted in the animal's peritoneal cavity; the implantable device and associated telemetry receiver detects if and how much animal moves within the cage. Sleep and wakefulness are measured in 10 second epochs simultaneously. Counts of locomotor activity per unit time are divided by the concurrent amount of wakefulness per the same unit, yielding a "locomotor activity intensity" (LMAI) measure for that unit time. Hypnotic or soporific compounds administered at CT-18 (6 hours after Hghts-off; LD 12:12) that decrease locomotor activity per unit time awake by greater than 20% relative to vehicle would be judged unacceptable.

An "effective amount" refers to an amount of a compound, or a combination of compounds, of the disclosed invention effective when administered alone or in combination to a subject in need of treatment, ameliorates symptoms arising from a sleep disorder, e.g., results in the subject falling asleep more rapidly, results in more refreshing sleep, reduces duration or frequency of waking during a sleep period, or reduces the duration, frequency, or intensity of other dyssomnias, parasomnias. For example, an effective amount refers to an amount of emedastine present in a formulation or on a medical device given to a recipient patient or subject sufficient to elicit biological activity, for example, sleep promoting activity.

A combination of compounds optionally is a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. vol.22, pp. 27-55 (19S4), occurs when the effect of the compound when administered in combination is greater than the additive effect of the compound when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, or increased sleep-promoting effect, lower hangover, or some other beneficial effect of the combination compared with the individual components.

The amount of the disclosed compound to be administered to a subject will depend on the particular disorder, the mode of administration, co-administered compounds, if any, and the characteristics of the subject, such as general health, other diseases, age, sex, genotype, body weight, tolerance to drugs and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. Effective amounts of the disclosed compound typically range between about intravenous, 0.01 mg/kg per day to about 200 mg/kg per day; intramuscular, 1 to about 500 mg/kg; orally 0.01 to about 1000 mg/kg; intranasal instillation, 5 to about 1000 mg/kg; and aerosol, 5 to about 1000 mg/kg of host body weight. In one embodiment, emedastine or a pharmaceutically acceptable salt is administered at a dosage of between 0.1 mg and 100 mg per day. In another embodiment, emedastine or a pharmaceutically acceptable salt is administered at a dosage of between 0.1 mg per day and about 20 mg/day. In another embodiment, emedastine or a pharmaceutically acceptable salt is administered at a dosage of between 2 and 20 mg/day. In another embodiment, emedastine or a pharmaceutically acceptable salt is administered at a dosage of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15 mg/day. In another embodiment, emedastine or a pharmaceutically acceptable salt is administered at a dosage of 1, 2, 3, 4, and 5 mg/day. Emedastine is administered in a single or divided dose. Techniques for administration of the disclosed compound of the invention can be found in Remington: the Science and Practice of Pharmacy, 19^th edition, Mack Publishing Co., Easton, PA (1995).

"A therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

"Pharmacological effect" as used herein encompasses effects produced in the subject that achieve the intended purpose of a therapy. As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

"Pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient.

The compound of the invention is capable of further forming salts. AU of these forms are also contemplated within the scope of the claimed invention.

A "pharmaceutically acceptable salt" or "salt" of the emedastine is a product of emedastine that contains one or more ionic bonds and is typically produced by reacting the disclosed compound with either an acid or a base, suitable for administering to a subject.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compound wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include, the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc. Other examples include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo-[2.2.2]-oct-2-ene-l-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The invention also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from emedastine by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of the compound with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, for example. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990). For example, salts can include, but are not limited to, the hydrochloride and acetate salts of the aliphatic amine-containing compound of the present invention.

In some embodiments, emedastine and its salts also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.

The disclosed compound, and salts or solvates thereof may exist in more than one crystal form, e.g., as "crystal polymorphs" or "polymorphs". The terms "crystal polymorphs" or. "polymorphs", or "crystal forms" means crystal structures in which a compound (or salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have die same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of emedastine can be prepared by crystallization under different conditions. For example, using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallization, and the like. Polymorphs are also obtained by heating or melting the disclosed compound followed by gradual or fast cooling. The presence of polymorphs is determined by solid probe nuclear magnetic resonance spectroscopy, infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction, and other techniques known to one skilled in the art.

In addition, a crystal polymorphism may be present but is not limiting, but any crystal form may be single or a crystal form mixture, or an anhydride or hydrate. Further, so-called metabolite which is produced by degradation of the present compound in vivo is included in the scope of the present invention.

The term "antihistamine" refers to a compound that binds to an Hl receptor and blocks the activity of histamine, and/or reduces the constitutive activity of the receptor.

The compound of the present invention can also be prepared as a prodrug, for example a pharmaceutically acceptable prodrug. The terms "pro-drug" and "prodrug" are used interchangeably herein and refer to any compound which releases an active parent drug in vivo. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compound of the present invention can be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compound, methods of delivering the same and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, sulfhydryl, carboxy, or carbonyl group is bonded to any group that may be cleaved in vivo to form a free hydroxy!, free amino, free sulfhydryl, free carboxy or free carbonyl group, respectively.

"Prodrug" includes a precursor form of the drug which is metabolically converted in vivo to produce the active drug. The invention further contemplates the use of prodrugs which are converted in vivo to the sleep modulating compounds used in the methods of the invention (see, e.g., R. B. Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chp. 8). Such prodrugs can be used to alter the biodistribution {e.g., to allow compounds which would not typically cross the blood-brain barrier to cross the blood-brain barrier) or the pharmacokinetics of the sleep modulating compound. For example, an anionic group, e.g., a carboxylate, sulfate or sulfonate, can be esterifϊed, e.g., with an alkyl group (e.g., a methyl group) or a phenyl group, to yield an ester. When the ester is administered to a subject, the ester is cleaved, enzymatically or non- enzymatically, reductively or hydrolytically, to reveal the anionic group. Such an ester can be cyclic, e.g., a cyclic sulfate or sulfone, or two or more anionic moieties may be esterified through a linking group. An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate sleep modulating compound which subsequently decomposes to yield the active sleep modulating compound. In one embodiment, the prodrug is a reduced form of a carboxylate, sulfate or sulfonate, e.g., an alcohol or thiol, which is oxidized in vivo to the sleep modulating compound. Furthermore, an anionic moiety can be esterified to a group which is actively transported in vivo, or which is selectively taken up by target organs.

Examples of prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetates, formates, phosphates, sulfates, and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups, esters groups (e.g., ethyl esters, morpholinoethanol esters) of carboxyl functional groups, N-acyl derivatives (e.g., N-acetyl) N-Mannich bases, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups and the like, see Bundegaard, H. "Design of Prodrugs" pi -92, Elesevier, New York- Oxford (1985).

As used herein, a "pharmaceutical composition" is a formulation containing emedastine or a pharmaceutically acceptable salt thereof in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salts thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that is required.

In an embodiment, the compound described herein, and the pharmaceutically acceptable salts thereof are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. Techniques for formulation and administration of the disclosed compound of the invention can be found in Remington: the Science and Practice of Pharmacy, above.

Typically, the compound is prepared for oral administration, wherein the disclosed compound or salts thereof are combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, pills, powders, syrups, solutions, suspensions and the like.

The tablets, pills, capsules, and the like contain from about 1 to about 99 weight percent of the active ingredient and a binder such as gum tragacanth, acacias, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch or alginic acid; a lubricant such as magnesium stearate; and/or a sweetening agent such as sucrose, lactose, saccharin, xylitol, and the like. When a dosage unit form is a capsule, it often contains, in addition to materials of the above type, a liquid carrier such as a fatty oil.

In some embodiments, various other materials are present as coatings or to modify the physical form of the dosage unit. For instance, in some embodiments, tablets are coated with shellac, sugar or both. In some embodiments, a syrup or elixir contains, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor, and the like.

For some embodiments relating to parental administration, the disclosed compound, or salts, solvates, or polymorphs thereof, can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. Injectable compositions can be aqueous isotonic solutions or suspensions. The compositions can be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, for example, about 1 to 50%, of the active ingredient.

For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like are used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable salts of the compound. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The terms "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

For rectal administration, suitable pharmaceutical compositions are, for example, topical preparations, suppositories or enemas. Suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, the compositions may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, such as about 1 to 50%, of the active ingredient.

In some embodiments, the compound is formulated to deliver the active agent by pulmonary administration, e.g., administration of an aerosol formulation containing the active agent from, for example, a manual pump spray, nebulizer or pressurized metered-dose inhaler. In some embodiments, suitable formulations of this type also include other agents, such as antistatic agents, to maintain the disclosed compound as an effective aerosol.

The term "pulmonary" as used herein refers to any part, tissue or organ whose primary function is gas exchange with the external environment, e.g., O₂/CO₂ exchange, within a patient. "Pulmonary" typically refers to the tissues of the respiratory tract. Thus, the phrase "pulmonary administration" refers to administering the formulations described herein to any part, tissue or organ whose primary function is gas exchange with the external environment (e.g., mouth, nose, pharynx, oropharynx, laryngopharyπx, larynx, trachea, carina, bronchi, bronchioles, alveoli). For purposes of the present invention, "pulmonary" also includes a tissue or cavity that is contingent to the respiratory tract, in particular, the sinuses.

A drug delivery device for delivering aerosols comprises a suitable aerosol canister with a metering valve containing a pharmaceutical aerosol formulation as described and an actuator housing adapted to hold the canister and allow for drug delivery. The canister in the drug delivery device has a head space representing greater than about 15% of the total volume of the canister. Often, the polymer intended for pulmonary administration is dissolved, suspended or emulsified in a mixture of a solvent, surfactant and propellant. The mixture is maintained under pressure in a canister that has been sealed with a metering valve.

For nasal administration, either a solid or a liquid carrier can be used. The solid carrier includes a coarse powder having particle size in the range of, for example, from about 20 to about 500 microns and such formulation is administered by rapid inhalation through the nasal passages. In some embodiments where the liquid carrier is used, the formulation is administered as a nasal spray or drops and includes oil or aqueous solutions of the active ingredients.

Also contemplated are formulations that are rapidly dispersing dosage forms, also known as "flash dose" forms. In particular, some embodiments of the present invention are formulated as compositions that release their active ingredients within a short period of time, e.g., typically less than about five minutes, in one embodiment, less than about ninety seconds, in another embodiment, less than about thirty seconds and in another embodiment, less than about ten or fifteen seconds. Such formulations are suitable for administration to a subject via a variety of routes, for example by insertion into a body cavity or application to a moist body surface or open wound.

Typically, a "flash dosage" is a solid dosage form that is administered orally, which rapidly disperses in the mouth, and hence does not require great effort in swallowing and allows the compound to be rapidly ingested or absorbed through the oral mucosal membranes. In some embodiments, suitable rapidly dispersing dosage forms are also used in other applications, including the treatment of wounds and other bodily insults and diseased states in which release of the medicament by externally supplied moisture is not possible.

"Flash dose" forms are known in the art; see for example, effervescent dosage forms and quick release coatings of insoluble microparticles in U.S. Pat. Nos. 5,578,322 and 5,607,697; freeze dried foams and liquids in U.S. Pat. Nos. 4,642,903 and 5,631,023; melt spinning of dosage forms in U.S. Pat. Nos. 4,855,326, 5,380,473 and 5,518,730; solid, free- form fabrication in U.S. Pat. No. 6,471,992; saccharide-based carrier matrix and a liquid binder in U.S. Pat. Nos. 5,587,172, 5,616,344, 6,277,406, and 5,622,719; and other forms known to the art.

The term "immediate release" is defined as a release of compound from a dosage form in a relatively brief period of time, generally up to about 60 minutes. The term "modified release" is defined to include delayed release, extended release, and pulsed release. The term "pulsed release" is defined as a series of releases of drug from a dosage form. The term "sustained release" or "extended release" is defined as continuous release of a compound from a dosage form over a prolonged period.

Also contemplated are formulations, e.g., liquid formulations, including cyclic or acyclic encapsulating or solvating agents, e.g., cyclodextrins, polyethers, or polysaccharides {e.g., methylcellulose), or polyanionic β-cyclodextrin derivatives with a sodium sulfonate salt group separate from the lipophilic cavity by an alkyl ether spacer group or polysaccharides. In one embodiment, the agent is methylcellulose. In another embodiment, the agent is a polyanionic β-cyclodextrin derivative with a sodium sulfonate salt separated from the lipophilic cavity by a butyl ether spacer group, e.g., CAPTISOL® (CyDex, Overland, KS). One skilled in the art can evaluate suitable agent/disclosed compound formulation ratios by preparing a solution of the agent in water, e.g., a 40% by weight solution; preparing serial dilutions, e.g. to make solutions of 20%, 10, 5%, 2.5%, 0% (control), and the like; adding an excess (compared to the amount that can be solubilized by the agent) of the disclosed compound; mixing under appropriate conditions, e.g., heating, agitation, sonication, and the like; centriruging or filtering the resulting mixtures to obtain clear solutions; and analyzing the solutions for concentration of the disclosed compound.

In addition to the therapeutic formulations described above, a therapy including emedastine optionally includes co-administeration with one or more additional therapies, e.g., drugs or physical or behavioral treatments (e.g., light therapy, electrical stimulation, behavior modification, cognitive therapy, circadian rhythm modification, and the like). Such a practice is referred to as "combination therapy." The other therapy or therapies in the combination therapy include therapies recognized by one skilled in the art as desirable in combination with the compound of the invention, for example, therapies known to the art or therapies which are proposed or discovered in the art for treating sleep disorders or treating diseases associated with sleep disorders, for example, therapies for any of the sleep disorders or other conditions disclosed herein. In some embodiments, the compound is administered as a combination therapy, whereas it is administered as a monotherapy in other embodiments. In one embodiment, emedastine is administered as a monotherapy.

"Combination therapy" (or "co-therapy") includes the administration of a compound of the invention and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). "Combination therapy" may, but generally is not, intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention. "Combination therapy" is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.

Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical. "Combination therapy" also embraces the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment). Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

For example, in some embodiments where the other therapy is a drug, it is administered as a separate formulation or in the same formulation as the compound of the invention. Emedastine is administered in combination therapy with any one or more of commercially-available, over-the-counter or prescription medications, including, but not limited to antimicrobial agents, fungistatic agents, germicidal agents, hormones, antipyretic agents, antidiabetic agents, bronchodilators, antidiarrheal agents, antiarrhythmic agents, coronary dilation agents, glycosides, spasmolytics, antihypertensive agents, antidepressants, antianxiety agents.anxyolytics, other psychotherapeutic agents, corticosteroids, analgesics, contraceptives, nonsteroidal anti-inflammatory drugs, blood glucose lowering agents, cholesterol lowering agents, anticonvulsant agents, other antiepileptic agents, immunomodulators, anticholinergics, antipsychotics, sympatholytics, sympathomimetics, vasodilatory agents, anticoagulants, antiarrhythmics, prostaglandins having various pharmacologic activities, diuretics, sleep aids, antihistaminic agents, antineoplastic agents, oncolytic agents, antiandrogens, antimalarial agents, antileprosy agents, dopaminergic agents, and various other types of drugs. See Goodman and Gilman's The Basis of Therapeutics (Eighth Edition, Pergamon Press, Inc., USA, 1990) and The Merck Index (Eleventh Edition, Merck & Co., Inc., USA, 1989). In one embodiment, emedastine is administered in combination therapy with anxyolytics, antipsychotics, benzodiazepine compounds and compounds with benzodiazepine subunits, and dopaminergic agents. In another embodiment, emedastine is administered in combination therapy with calcium channel alpha(2) delta subunit modulators (e.g., gabapentin and pregabalin), GABA agonists (e.g., SONATA®), 5HT-2A antagonists (e.g, eplivanserin and pruvanserin, AVE 8488), 5HT-2A inverse agonists (e.g., APD125), orexin antagonists (e.g., GW649868), hypocretin antagonists, and melatonin antagonists.

In addition, emedastine also may be administered in conjunction with any one or combination of the commercially-available, over-the-counter or prescription medications, including, but not limited to Avobenzene/padimate-O. ACCUPRIL® tablets (quinapril hydrochloride), Accutane capsules (isotretinoin), Achromycin V capsules (the monohydrochloride of (4S-(4.alpha., 4a.alpha.,5a.alpha.,6.beta., 12a.alpha.,))-4- (dimethylamino)-l,4,4a,5,5a,6,l l,12a-octBPydro-3,6,10,12,1 2a-pentBPydroxy-6-methyl- 1,1 l-dioxo^-naphthacenecarboxamide), Actifed cough syrup (codeine phosphate, triprolidine hydrochloride and pseudoephedrine hydrochloride), Aldactazide tablets (spironolactone and hydrochlorothiazide), ALDOCLOR® tablets (methyldopa and chlorothiazide), Aldoril tablets (methyldopa-hydrochlorothiazide), Alferon® N injection (interferon .alpha.-n3 (human leukocyte derived)), ALT ACE™ capsules (ramipril), AMBIEN® tablets (Zolpidem tartrate), Anafranil capsules (clomipramine hydrochloride), ANAPROX® tablets (naproxen sodium), Ancobon capsules (flucytosine), Ansaid tablets (flurbiprofen), Apresazide capsules (hydralazine hydrochloride and hydrochlorothiazide), Asendin tablets (2-chloro-ll-(l-piperazinyl)dibenz(b,f)(l,4)-oxazepine), Atretol™ tablets (carbamazepine), Aureomycin ophthalmic ointment (chlortetracycline hydrochloride), Azo Gantanol® tablets (sulfamethoxazole and phenazopyridine hydrochloride), Azo Gantrisiπ tablets (sulfisoxazole and phenazopyridine hydrochloride), Azulfidine® tablets and EN-tabs (5-((p-(2-pyridylsulfamoyl)phenyl)-azo)salicylic acid), Bactrim tablets (trimethoprim and sulfamethoxazole), Bactrim I. V. infusion (trimethoprim and sulfamethoxazole), Bactrim pediatric suspension (trimethoprim and sulfamethoxazole), Bactrim suspension (trimethoprim and sulfamethoxazole), Bactrim tablets (trimethoprim and sulfamethoxazole), Benadryl® capsules (diphenhydramine hydrochloride USP), Benadryl® kapseals (diphenhydramine hydrochloride USP), Benadryl® tablets (diphenhydramine hydrochloride USP), Benadryl® parenteral (diphenhydramine hydrochloride USP)₅ Benadryl® steri-vials, ampoules, and steri- dose syringe (diphenhydramine hydrochloride USP), Capoten tablets (captopril), Capozide tablets (captopril-hydrochlorothiazide), Cardizem® CD capsules (diltiazem hydrochloride), Cardizem® SR capsules (diltiazem hydrochloride), Cardizem® tablets (diltiazem hydrochloride), Chibroxin sterile ophthalmic solution (with oral form) (norfloxacin), Children's Advil® suspension (ibuprofen), Cipro® LV. (ciprofloxacin), Cipro® tablets (ciprofloxacin), Claritin tablets (loratadine), Clinoril tablets (sulindac), Combipres® tablets (clonidine hydrochloride and chlorthalidone), Compazine® injection (prochlorperazine maleate), Compazine® multi-dose vials (prochlorperazine maleate), Compazine® syringes (prochlorperazine maleate), Compazine® spansule capsules (prochlorperazine maleate), Compazine® suppositories (prochlorperazine maleate), Compazine® syrup (prochlorperazine maleate), Compazine® tablets (prochlorperazine maleate), Cordarone tablets (amiodarone hydrochloride), Corzide tablets (nadolol andbendroflumethiazide), Dantrium capsules (dantrolene sodium), Dapsone tablets (4-4¹ diaminodiphenylsulfone), DAYPRO® caplets (oxaproxin), Declomycin tablets (demeclacycline or (4S- (4.alpha.,4a.alpha.,5a.alpha.,6.beta.,12a.alpha.))-7-Chloτo-4-dimethyl amino)- l,4,4a,5,5a,6,l l,12a-octBPydro-3,6,10,12,12a-pentBPydroxy-l,l 1-dioxo -2- naphthacenecarboxamide monohydrochloride), DECONAMINE®. capsules (chloφheniramine maleate and d-psuedoephedrine hydrochloride), DECONAMINE® syrup (chlorpheniramine maleate and d-psudoephedrine hydrochloride), DECONAMINE® tablets (chlorpheniramine maleate and d-psudoephedrine hydrochloride), Depakene capsules (valproic acid), Depakene syrup (valproic acid), Depakote sprinkle capsules (divalproex sodium), Depakote tablets (divalproex sodium), DiaBeta® tablets (glyburide), Diabinese tablets (chlorpropamide), Diamox parenteral (acetazolamide), Diamox sequels (acetazolamide), Diamox tablets (acetazolamide), Dimetane-DC cough syrup (brompheniramine maleate, phenylpropanolamine hydrochloride and codeine phosphate), Dimetane-DX cough syrup (brompheniramine maleate, phenylpropanolamine hydrochloride and codeine phosphate), Dipentum® capsules (olsalazine sodium), Diucardin tablets (hydroflumethiazide), Diupres tablets (reserpine and chlorothiazide), Diuril oral suspension (chlorothiazide), Diuril sodium intravenous (chlorothiazide), Diuril tablets (chlorothiazide), Dolobid tablets (diflunisal), DORYX® capsules (doxycycline hyclate), Dyazide capsules (hydrochlorothiazide and triamterene), Dyrenium capsules (triamterene), Efudex cream (5- fluorouracil), Efudex solutions (5-fluorouracil), Elavil injection (amitriptyline HCl), Elavil tablets (amitriptyline HCl), Eldepryl tablets (selegiline hydrochloride), Endep tablets (amitriptyline HCl), Enduron tablets (methyclothiazide), Enduronyl Forte tablets (methyclothiazide and deserpidine), Enduronyl tablets (methyclothiazide and deserpidine), Ergamisol tablets (levamisole hydrochloride), Esidrix tablets (hydrochlorothiazide USP), Esimil tablets (guanethidine monosulfate TJSP and hydrochlorothiazide USP), Etrafon Forte tablets (perphenazine, USP and amitriptyline hydrochloride, USP), Etrafon 2-10 tablets (perphenazine, USP and amitriptyline hydrochloride, USP), Etrafon tablets (perphenazine, USP and amitriptyline hydrochloride, USP), Etrafon-A tablets (perphenazine, USP and amitriptyline hydrochloride, USP), Eulexin capsules (flutamide), Exna tablets (benzthiazide), FUDR injection (floxuridine), Fansidar tablets (Nl-(5,6-dimethoxy-4-pyrimidinyl) sulfanilamide (sulfadoxine) and 2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine (pyrimethamine), Feldene capsules (piroxicam), Flexeril tablets (cyclobenzaprine hydrochloride), FLOXIN® LV. (ofloxacin injection), FLOXINS® tablets (ofloxacin), Fluorouracil injection (5-fluoro-2,4 (lH,3H)-pyrimidinedione), Fulvicin tablets (griseofulvin), Gaboxadol (THIP hydrochloride), Gantanol® suspension (sulfamethoxazole), Gantanol® tablets (sulfamethoxazole), Gantrisin ophthalmic ointment/solution (sulfisoxazole), Gantrisin pediatric suspension (sulfisoxazole), Gantrisin syrup (sulfisoxazole), Gantrisin tablets (sulfisoxazole), Glucotrol tablets (glipizide), Glynase PresTab tablets (glyburide), Grifulvin V tablets (griseofulvin), Grifulvin oral suspension (griseofulvin), Gristactin capsules (griseofulvin), Grisactin tablets (griseofulvin), Gris-PEG tablets (griseofulvin), Grivate tablets (griseofulvin), Grivate suspension (griseofulvin), Haldol Decanoate 50 injection (haloperidol decanoate), Haldol Decanoate 100 injection (haloperidol decanoate), Haldol tablets (haloperidol decanoate), Hibistat germicidal hand rinse (chlorhexidine gluconate), HISMANAL® tablets (astemizole), HydroDIURIL tablets (hydrochlorothiazide), Hydromox tablets (quinethazone), Hydropres tablets (reserpine and hydrochlorothiazide), Inderide® tablets (propranolol hydrochloride and hydrochlorothiazide), Inderides capsule® (propranolol hydrochloride and hydrochlorothiazide), Indiplon (neurocrine), Intal inhaler (cromolyn sodium), Intron A injection (recombinant interferon .alpha.-2b), Lamprene capsules (clofazimine), Lasix oral solution (furosemide), Lasix tablets (furosemide), Lasix injection (furosemide), Limbitrol tablets (chlordiazepoxide and amitriptyline hydrochloride), Lodine capsules (etodolac), Lopressor HCT tablets (metoprolol tartrate USP and hydrochlorothiazide USP), Lotensin tablets (benazepril hydrochloride), LOZOL® tablets (indapamide), Ludiomil tablets (maprotiline hydrochloride USP), LUNESTA™ (eszpiclone), Marplan tablets (isocarboxazid), MAXAQUIN® tablets (lomefloxacin HCl), Maxzide tablets (triamterene USP and hydrochlorothiazide USP), Mellaril® concentrate (thioridazine), Mellaril® tablets (thioridazine), Mellaril-S suspension (thioridazine), Mepergan injection (meperidine hydrochloride and promethazine hydrochloride), Methotrexate tablets (methotrexate), Mevacor tablets (lovastatin), Micronase tablets (glyburide), Minizide capsules (prazosin hydrochloride and polythiazide), Minocin intravenous ((4S-(4.alpha.,4a.alpha.,5a.alpha.,12a.alpha.))-4,7-bis(dimethylamino)-l,4 ,4a,5,5a,6, 11 , 12a-octBPydro-3 , 10, 12, 12a-tetrBPydroxy- 1 , 11 -dioxo-2-naphthace necarboxamide monohydrochloride), Minocin oral suspension ((4S-(4.alpha., 4a.alpha.,5a.alpha.,12a.alpha.))-4,7-bis(dimethylamino)-l,4,4a,5,5a,6,ll,l 2a-octBPydro- 3 , 10, 12, 12a-tetrBPydroxy-l , 11 -dioxo-^-naphthacenecarboxamide monohydrochloride), Minocin capsules ((4S-(4.alpha.,4a.alpha.,5a.alpha.,12a.alpha.))-4,7-bis(dimethylamino)-l,4 ,4a,5,5a,6,l l,12a-octBPydro-3,10,12,12a-tetrBPydroxy-l,l l-dioxo-2-naρhthace necarboxamide monohydrochloride), Moduretic tablets (amiloride HCl-hydrochlorothiazide), Monodox® capsules (doxycycline monohydrate), Monopril tablets (fosinopril sodium), Children's Motrin liquid suspension (ibuprofen), Motrin tablets (ibuprofen), Mykrox tablets (metolazone), NAPROSYN® suspension (naproxen), NAPROSYN® tablets (naproxen), Navane capsules (thiothixene), Navane intramuscular (thiothixene), NegGram caplets (nalidixic acid), NegGram suspension (nalidixic acid), Neptazane tablets (methazolamide), Nipent injection (pentostatin), Normodyne tablets (labetalol HCl), NOROXIN tablets (norfloxacin), Norpramin tablets (desipramine hydrochloride USP), oretic tablets (hydrochlorothiazide), Oreticyl Forte tablets (hydrochlorothiazide and deserpidine), Orinase tablets (tolbutamide), Ornade capsules (phenylpropanolamine hydrochloride and chlorpheniramine maleate), Orudis capsules (ketoprofen), Oxsoralen lotion (methoxypsoralen), PBZ tablets (tripelennamine hydrochloride USP), PBZ-SR tablets (tripelennamine hydrochloride USP), pHisoHex topical emulsion (hexachlorophene), P & S PLUS® topical tar gel (crude coal tar), Pamelor® capsules (nortriptyline HCl), Pamelor® solution (nortriptyline HCl), Paxil tablets (paroxetine hydrochloride), Pediazole oral suspension (erythromycin ethylsuccinate, USP and sulfisoxazole acetyl, USP), Penetrex.TM. tablets (enoxacin), Pentasa capsules (mesalamine), Periactin syrup (cyproheptadine HCl), Periactm tablets (cyproheptadine HCl), Phenergan tablets (promethazine hydrochloride), Phenergan injection (promethazine hydrochloride), Phenergan suppositories (promethazine hydrochloride), Phenergan syrup (promethazine hydrochloride), Polytrim® ophthalmic solution (trimethoprim sulfate and polymyxin B sulfate), Pravachol (pravastatin sodium), Prinivil®. tablets (lisinopril, MSD), Prinzide tablets (lisinopril-hydrochlorothiazide), Prolixin elixir (fluphenazine hydrochloride), Prolixin enanthate (fluphenazine hydrochloride), Prolixin injection (fluphenazine hydrochloride), Prolixin oral concentrate (fluphenazine hydrochloride), Prolixin tablets (fluphenazine hydrochloride), ProSom tablets (estazolam), Prozac® oral solution (fluoxetine hydrochloride), Prozac® oral Pulvules® (fluoxetine hydrochloride), Pyrazinamide tablets (pyrazinamide), QUINAGLUTE® tablets (quinidine gluconate), Quinidex tablets (quinidine sulfate), Relafen tablets (nabumetone), ROZEREM™ (Ramelteon), Ru-Tuss II capsules (chlorpheniramine maleate and phenylpropanolamine hydrochloride), Seldane tablets (terfenadine), Septra tablets (trimethoprim and sulfamethoxazole), Septra suspension (trimethoprim and sulfamethoxazole), Septra LV. infusion (trimethoprim and sulfamethoxazole), Septra tablets (trimethoprim and sulfamethoxazole), Ser- Ap-Es tablets (reserpine USP, hydralazine hydrochloride USP and hydrochlorothiazide USP), Smequan capsules (doxepin HCl), Solganal injection (aurothioglucose, USP), SONATA® (zaleplon), Stelazine concentrate (trifluoperazine hydrochloride), Stelaziπe injection (trifluoperazine hydrochloride), Stelazine tablets (trifluoperazine hydrochloride), Surmontil capsules (trimipramine maleate), SYMMETREL capsules and syrup (amantadine hydrochloride), Taractan concentrate (chlorprothixene), Taractan injectable (chlorprothixene), Taractan tablets (chlorprothixene), TAVIST® syrup (clemastine fumarate, USP), TAVIST® tablets (clemastine fumarate, USP), TAVIST®-! 12 hour, relief medicine (clemastine fumarate, USP), TAVIST®-D 12 hour relief medicine (clemastine fumarate, USP), Tegretol Tablets (carbamazepine USP), Tegretol suspension (carbamazepine USP), Temaril tablets (trimeprazine tartrate), Temaril syrup (trimeprazine tartrate), Temaril capsules (trimeprazine tartrate), TENORETIC® tablets (atenolol and chlorthalidone), Terramycin intramuscular solution (oxytetracycline), Thiosulfϊl Forte tablets (sulfamethizole), Thorazine ampuls (chlorpromazine hydrochloride), Thorazine concentrate (chlorpromazine hydrochloride), Thorazine multi-dose vials (chlorpromazine hydrochloride), Thorazine capsules (chlorpromazine hydrochloride), Thorazine suppositories (chlorpromazine hydrochloride), Thorazine syrup (chlorpromazine hydrochloride), Thorazine tablets (chlorpromazine hydrochloride), Timolide tablets (timolol maleate- hydrochlorothiazide), Tofranil ampuls (imipramine hydrochloride USP), Tofranil tablets (imipramine hydrochloride USP), Tofranil capsules (imipramine hydrochloride USP), Tolinase tablets (tolazamide), Triaminic Expectorant DH (phenylpropanolamine hydrochloride and guaifenesin), Triaminic oral infant drops (phenylpropanolamine hydrochloride, pheniramine maleate and pyrilamine maleate), Triavil tablets (perphenazine- amitriptyline HCl), Trilafon concentrate (perphenazine USP), Trilafon injection (perphenazine USP), Trilafon tablets (perphenazine, USP), Trinalin tablets (azatadine maleate, USP, and pseudoephedrine sulfate, USP), Vaseretic tablets (enalapril maleate- hydrochlorothiazide), Vasosulf opthalmic solution (sulfacetamide sodium-phenylephrine hydrochloride), Vasotec I. V. (enalapril maleate), Vasotec tablets (enalapril maleate), Velban® vials (vinblastine sulfate, USP), Vibramycin capsules (doxycycline monohydrate), Vibramycin intravenous (doxycycline monohydrate), Vibramycin oral suspension (doxycycline monohydrate), Vibra-Tabs tablets (oxytetracycline), Vivactil tablets (protriptyline HCl), Voltaren tablets (diclofenac sodium), X-SEB T® shampoo (crude coal tar), Zaroxolyn tablets (metolazone), ZESTORETIC® oral (lisinopril and hydrochlorothiazide), ZESTRIL® tablets (lisinopril), ZITHROMAX™ capsules (azithromycin), Zocor tablets (simvastatin), ZOLOFT® tablets (sertraline hydrochloride) and others. In one embodiment, emedastine is useful in combination with a mechanical therapy, such as CPAP. "CPAP" or "continuous βositive airway pressure" Js a mechanical treatment for sleep apnea and other sleep-related breathing disorders (including snoring) which is typically administered via the nose or mouth of the patient.

Under CPAP treatment, an individual wears a tight-fitting plastic mask over the nose when sleeping. The mask is attached to a compressor, which forces air into the nose creating a positive pressure within the patient's airways. The principle of the method is that pressurizing the airways provides a mechanical "splinting" action, which prevents or lessens airway collapse and therefore, obstructive sleep apnea. Although an effective therapeutic response is observed in most patients who undergo CPAP treatment, many patients cannot tolerate the apparatus or pressure and refuse treatment. Moreover, recent covert monitoring studies demonstrated that long-term compliance with CPAP treatment is very poor. It is known that patients remove their mask while sleeping.

In one aspect, the compound of the invention is administered in conjunction with a CPAP device to promote sleep. In another aspect, the compound of the invention is administered in conjunction with a CPAP device to improve sleep. In another aspect, the compound of the invention is administered in conjunction with a CPAP device to improve compliance regarding with CPAP treatment. Without wishing to be bound by theory, it is thought that by administering an effective amount of a sleep promoting compound of the invention to a patient in conjunction with CPAP treatment, the patient will sleep better and more soundly and therefore, not be as likely to remove the mask.

In one embodiment, the compound of the present invention is administered prior to the CPAP treatment. In another embodiment, the compound of the present invention is administered at substantially the same time as the CPAP treatment. In one embodiment, parallel administration of an effective amount of the compound is accomplished by adding an additional aerosol channel to the air pressure treatment portion of the CPAP device, thus administering the compound of the present invention in a nebulized form via the nasal or oral mask of the CPAP device. Alternatively, an effective amount of the compound can be added to the water or into the liquid reservoir that is typically part of the CPAP treatment device.

Using the CPAP mask treatment, the compound of the invention is administered in a low concentration throughout the night, or at higher concentrations, as a bolus, at different time points in the beginning and during the course of the night. In another aspect, emedastiπe is evaluated using the in vivo sleep-wake and physiological assessment criteria shown in Table 1:

Table 1

Methods for evaluating these sleep-wake and physiological assessment criteria are described above. The "absolute value" shown in second column of Table 1 refers to the value as determined, while the "change" value shown in the third column of Table 1 reflects an adjusted value in which the absolute value is the difference from vehicle, when the vehicle values are adjusted for baseline.

In one embodiment, the longest sleep bout is greater than 13 minutes in duration. In another, it is greater than 17 minutes in duration. In another embodiment, the net longest sleep bout post treatment is greater than or equal to 3 minutes in duration. In another, it is greater than or equal to 6 minutes in duration.

Other in vivo sleep-wake and physiological assessment criteria used include measurement of acute body temperature and latent body temperature as a change in baseline relative to vehicle. The acute body temperature change should not exceed — 0.50⁰C, and the latent body temperature change should not exceed + 0.50 ⁰C at Time 1-6 hours. The acute body temperature (Ti^) is adjusted for the corresponding baseline measured 24 hours earlier, relative to vehicle (the decrease from vehicle). The latent body temperature, measured 7-18 hours post drug treatment (T_7-Is), is adjusted for the corresponding baseline measured 24 hours earlier, relative to vehicle (the decrease from vehicle).

All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

EXAMPLES

EXAMPLE 1: Emedastine is a Sleep-Inducing Agent

Sleep-wakefulness, locomotor activity and body temperature were monitored in male Wistar rats treated with emedastine 10 mg/kg. Treatments were administered at CT-18, the peak of the activity dominated period (6 hours after lights-off), and produced soporific (sleep- inducing) effects characterized by increased non-REM sleep time, increased sleep continuity, but without evidence of REM sleep inhibition or rebound insomnia.

Adult, male Wistar rats (250 g at time of surgery, Charles River Laboratories, Raleigh, NC) were anesthetized by administration of 2% Isofluraπe and surgically prepared with a cranial implant to permit chronic electro-encephalogram (EEG) and electromyogram (EMG) recording. Body temperature and locomotor activity were monitored via a miniature transmitter (Minimitter®, Sunriver, Oregon) surgically placed in the abdomen. The cranial implant consisted of stainless steel screws (two frontal [+3.2 AP from bregma, ±2.0 ML] and two occipital [-6.9 AP, ±5.5 ML]) for EEG recording. As used above, ML means medial- lateral. Two Teflon-coated stainless steel wires were positioned under the nuchal trapezoid muscles for EMG recording. All leads were soldered to a miniature connector prior to surgery, and gas sterilized in ethylene oxide. The implant assembly was affixed to the skull with dental acrylic. A minimum of three weeks was allowed for surgical recovery before emedastine experimentation.

Each rat was permanently housed in its own individual recording cage located within separate, ventilated compartments of custom-designed stainless steel cabinets. Each Nalgene microisolator cage was enhanced with a filter-top riser and low-torque swivel- commutator. Food and water were available ad libitum. A 24-hr light-dark cycle (12 hours on, 12 hours oft) was maintained throughout the study. Animals were undisturbed for at least 48 hours before and after emedastine treatments.

Sleep and wakefulness were determined using "SCORE-2000™" - a comprehensive preclinical sleep-wake and physiological monitoring system. The system monitored amplified EEG (bandpass 1-30 Hz; digitization rate 400 Hz), digitally integrated EMG (bandpass 10-100 Hz), body temperature and non-specific locomotor activity (LMA) via telemetry, and drinking and feeding activity, continuously and simultaneously. Arousal states were classified on-line as NREM sleep, REM sleep, wake, or theta-dominated wake every 10 seconds using EEG feature extraction and pattern-matching algorithms. The classification algorithm used individually-taught EEG-arousal-state templates, plus EMG criteria to differentiate REM sleep from theta-dominated wakefulness, plus behavior- dependent contextual rules. Drinking and locomotor activity (LMA) were recorded as discrete events every 10 seconds, body temperature each minute. Locomotor activity was detected by a custom modified telemetry receiver (Minimitter®, Bend, Oregon) beneath the cage. Telemetry measures (LMA and body temperature) were not part of the scoring algorithm; thus, sleep-scoring and telemetry data were independent measures.

Compounds were administered at CT- 18, the peak of the activity-dominated period, in order to ensure (i) prior wakefulness was sufficient to interact positively with hypnotic- drug effects, and (H) sufficient time was allowed to view the time course of the treatment effect before lights-on (6 hours post-treatment). Compounds were suspended in sterile 0.25% methylcellulose (lml/kg).

The effect of emedastine (10 mg/kg) on sleep was tested using a parallel groups study design. Vehicle controls were drawn from a large pool (N > 200): a subset of the pooled vehicle controls was selected, based on computerized matching with the 24-hour pre-treatment baseline of the active treatment group.

As shown in Figure 1, treatment of rats with emedastine significantly increased NREM sleep for 2 hours post-treatment. In this figure, emedastine, 10 mg/kg PO (HYl 0198), treatment is indicated by the thin line; mean ± SEM, and the methylcellulose vehicle control (1 mg/kg PO) treatment is indicated by the wide grey line; ± SEM. The time of treatment is indicated by a triangle. The arrow highlights drug effect. Twelve rats were treated with emedastine, and twelve rats were treated with vehicle.

Emedastine treatment did not, however, produce REM sleep inhibition, as shown in Figure 2, or rebound insomnia at 10 mg/kg in male Wistar rats. REM sleep inhibition and rebound insomnia are undesirable side effects commonly observed in currently marketed prescription sedative hypnotics. In this figure, emedastine, 10 mg/kg PO (HY10198), treatment is indicated by the thin line with error bars; mean ± SEM, and the methylcellulose vehicle control (1 mg/kg PO) treatment is indicated by the wide grey line; ± SEM. The time of treatment is indicated by a triangle. Twelve rats were treated with emedastine, and twelve rats were treated with vehicle.

Emedastine 10 mg/kg also did not show a disproportionate inhibition of locomotor activity (locomotor activity per unit time awake), nor adverse effects on body temperature. As shown in Figure 3, emedastine increased sleep continuity, as assessed by sleep bout length at 10 mg/kg in male Wistar rats. In this figure, emedastine, 10 mg/kg PO (HTY 10198), treatment is indicated by the thin line; mean ± SEM, and the methylcellulose vehicle control treatment is indicated by the wide grey line; ± SEM. The time of treatment is indicated by a triangle. The arrow highlights drug effect. Twelve rats were treated with emedastine, and twelve rats were treated with vehicle.

Emedastine has sedative hypnotic qualities that include increased sleep time, increased sleep consolidation (sleep continuity), but treatment with emedastine does not inhibit REM sleep. Emedastine also does not produce rebound insomnia, and showed no evidence of causing disproportional locomotor inhibition or body temperature adverse effects in rats.

EXAMPLE 2: Specificity for Hl Histamine Receptors

Binding assays are performed using emedastine in competitive binding assays with known standards for the Hl histamine receptor, and the Ml, M2, and M3 muscarinic receptors.

The histamine Hl assays are described in Chang, et al., Journal of Neurochemistry 32: 1653-1663 (1979); Martinez-Mir, et al., Brain Res. 526:322-327 (1990); Haaksma, et al, Pharmac. Ther. 47:73-104 (1990). The muscarinic assays are described in Buckley, et al., MoI. Pharmacol. 35:469-476 (1989). The assays are performed according to the preceding articles, with the following modifications.

For the histamine Hl assays, the receptors are obtained from bovine cerebellar membrane tissue, with a B_max (receptor number) of 6.2 femtomol/mg tissue (wet weight) and a KD (binding affinity) of 1.3 nM. A radioactive ligand ([³H]pyrilamine (15-25)Ci/rnmol), Ki 1.9 nM, final concentration 2.0. nM) is employed, and 10 μM triprolidine (Ki 3.3 nM) is employed as a non-specific determinant, reference compound, and positive control. The receptor and the radioactive ligand are combined with the test compound at a range of test compound concentrations from about 10^'10 to about 10^"6 M, and the mixture is incubated out in 50 mM Na-KPO₄ (pH 7.5) at 25 ⁰C for.60 minutes. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity from the displaced radioactive ligand trapped onto the filters is determined and compared to control values in order to measure any interactions of the test compound with the histamine Hl binding site. For the muscarinic assays, the receptors are obtained from human recombinant receptors expressed in CHO cells (PerkinElmer, Inc., Wellesley, MA). The radioactive ligand employed is [³H]-scopolamine, N-methyl chloride (80-100 Ci/mmol). (-)- Methylscopolamine bromide, 1.0 μM, is employed as the non-specific determinant, reference compound, and positive control. After incubation, reactions are terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity from the displaced radioactive ligand trapped onto the filters is determined and compared to control values in order to measure any interactions of the test compound with the respective receptor.

For the Ml receptor assay, the B_max (receptor number) is 4.2 picomol/mg protein, and the K_D (binding affinity) of the receptor is 0.05 nM. The radioactive ligand is employed at a final concentration 0.5 nM, while the (-)-methylscopolamine bromide had a Ki of 0.09 nM. The receptor and the radioactive ligand are combined with the test compound at a range of test compound concentrations from about 10^"12 to about 10^"5 M, incubated in Dulbecco's Phosphate Buffered Saline (PBS) for 60 minutes at 25 ⁰C, and worked up as described above.

For the M2 receptor assay, the B_max (receptor number) is 2.1 picomol/mg protein, and the K_D (binding affinity) of the receptor is 0.29 nM. The radioactive ligand is employed at a final concentration 0.5 nM, while the (-)-methylscopolamine bromide has a Ki of 0.3 nM. The receptor and the radioactive ligand are combined with the test compound at a range of test compound concentrations from about 10^"12 to about 10^'5 M, incubated in Dulbecco's Phosphate Buffered Saline (PBS) for 60 minutes at 25 ⁰C, and worked up as described above.

For the M3 receptor assay, the B_max (receptor number) is 4.0 picomol/mg protein, and the K_D (binding affinity) of the receptor is 0.14 nM. The radioactive ligand is employed at a final concentration 0.2 nM, while the (-)-methylscopolamine bromide has a Ki of 0.3 nM. The receptor and the radioactive ligand are combined with the test compound at a range of test compound concentrations from about lO^'12 to about 10^"s M, incubated in 50 mM TRIS- HCl (pH 7.4) containing 10 mM MgCl₂, 1 mM EDTA for.60 minutes at 25 ⁰C, and worked up as described above.

Binding to Hl can be an indication of the desired sleep-inducing activity of the compound. Binding to muscarinic receptors shows non-specific binding, and can indicate anti-cholinergic activity which can result in undesired side effects, e.g., the side effects of many known antihistamines, e.g., blurred vision, dry mouth, constipation, urinary problems, dizziness, anxiety, and the like. A decrease in the binding of the compound to the M1-M3 receptors, relative the binding of the compound to the Hl receptor, is an indication of the greater specificity of the compound for the histamine receptor over the muscarinic receptor. Moreover, a drug with increased specificity for the histamine receptor would possess less anti-cholinergic side effects.

Emedastiπe HYl 0198

] Binding Safety % inhibition (S). 1 uM

Hl 93.39

Central Muscarinic (ns) 44.98

Peripheral Muscarinic (ns) 30.38

Sigma (ns) 24.21

Na⁺ site 2 25.77

Ml Human 25.98

M2 Human 14.0

Dopamine Transporter 13.25

Receptor Species KLaM ct](ns) >10k α₂(ns) >lθk

D₁ Human >10k

D₂₅ Human >10k

Hl Bovine 0.9

Mi Human 341

M₂ Human 1390

M₃ Human >10k

(ns) Non-Specific

OTHER EMBODIMENTS

While the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

CLAIMSWe claim:

1. Use of emedastine or a pharmaceutically effective salt thereof in the manufacture of a medicament for treatment of a sleep disorder.

2. Use of claim 1, wherein the sleep disorder is selected from the group consisting of circadian rhythm abnormality, insomnia, parasomnia, sleep apnea syndrome, and narcolepsy.

3. Use of claim 2, wherein the sleep disorder is circadian rhythm abnormality.

4. Use of claim 3, wherein the circadian rhythm abnormality is selected from the group consisting of jet lag, shift-work disorders, delayed sleep phase syndrome, advanced sleep phase syndrome and non-24 hour sleep-wake disorder.

5. Use of claim 2, wherein the sleep disorder is insomnia.

6. Use of claim 5, wherein the insomnia is selected from the group consisting of extrinsic insomnia, psychophysiologic insomnia, altitude insomnia, restless leg syndrome, periodic limb movement disorder, medication-dependent insomnia, drug- dependent insomnia, alcohol-dependent insomnia and insomnia associated with mental disorders.

7. Use of claim 2, wherein the parasomnia is selected from the group consisting of somnambulism, pavor noctumus, REM sleep behavior disorder, sleep bruxism and sleep enuresis.

S. Use of claim 2, wherein the sleep apnea syndrome selected from the group consisting of central sleep apnea, obstructive sleep apnea and mixed sleep apnea.

9. Use of claim 2, wherein the sleep disorder is narcolepsy.

10. Use of claim 1, wherein the medicament further comprises a pharmaceutically acceptable excipient.

11. Use of claim 1, wherein the emedastine or pharmaceutically acceptable salt thereof is suitable for administration at a dosage of between 2 mg and 20 mg per day.

12. Use of claim 1, wherein the emedastine or pharmaceutically acceptable salt thereof is suitable for administration at a dosage of between 1 and 5 mg per day.

13. Use of claim 1, wherein the emedastine or pharmaceutically acceptable salt thereof is suitable for co-administration with one or more additional therapies.

14. Use of claim 13, wherein the additional therapy is selected from GABA agonist, 5HT- 2 antagonist, orexin antagonist, hypocretin antagonist, and melatonin agonist.

15. Use of claim 13, wherein the additional therapy is selected from indiplon, LUNESTA™, AMBIEN®, ROZEREM™, and gaboxadol.

16. Use of claim 1, wherein the pharmaceutically acceptable salt is emedastine difumarate.

17. Use of claim 1, wherein the pharmaceutically acceptable salt is emedastine nitrate.

18. Use of claim 1, wherein emedastine, or a pharmaceutically acceptable salt thereof, is suitable for administration by a mode selected from the group consisting of oral, nasal, transdermal, pulmonary, inhalational, buccal, sublingual, intraperintoneal, intravenous, rectal, intrapleural, intrathecal and parenteral administration,,

19. Use of claim 1, wherein the suitable mode of administration is oral.

20. Use of claim 1, wherein the medicament is suitable for administration to a subject selected from the group consisting of humans, companion animals, farm animals, laboratory animals and wild animals.

21. Use of claim 20, wherein the medicament is suitable for administration to a human.

22. Use of claim 1, wherein emedastine or a therapeutically effective salt modulates sleep.

23. Use of claim 22, wherein the sleep modulation is selected from the group consisting of decreasing the time to sleep onset, increasing total sleep time, and increasing sleep consolidation.

This page deleted