HK1142005A - Methods and compositions comprising desvenlafaxine or duloxetine for treating sleep-related breathing disorders - Google Patents

Abstract

Provided herein are methods of treating a sleep-related breathing disorder, such as obstructive sleep apnea, comprising the administration of O-desmethylvenlafaxine or duloxetine.

Description

Methods and compositions comprising desmethylvenlafaxine or duloxetine for treating sleep-related breathing disorders

This application claims priority to U.S. provisional application 60/922,466, filed on 9/4/2007, which is hereby incorporated by reference in its entirety.

1. Field of the invention

The present disclosure relates to methods and compositions for treating sleep-related respiratory disorders.

2. Background of the invention

Over the past years, efforts have been devoted to studying discrete populations of sleep disorders that occur primarily during sleep and cause constant drowsiness throughout the waking hours, thereby presenting substantial economic losses (e.g., loss of thousands of individuals' time) or occupational safety factors (e.g., employee inattentiveness during the operation of heavy machinery). Sleep-related breathing disorders are characterized by a repetitive reduction in breathing (hypopnea), a periodic cessation of breathing (apnea), or a continuous or sustained reduction in ventilation.

Sleep apnea is generally defined as the intermittent cessation of nasal and mouth airflow during sleep. An apnea duration of at least 10 seconds is generally considered important, but in most individuals the apnea duration is 20-30 seconds and can be as long as 2-3 minutes. Although the minimum number of apneas considered clinically important is still uncertain, most individuals currently of interest to the medical community have at least 10 to 15 apneic events per hour of sleep.

Sleep apnea is classified into three categories: central, obstructive and mixed. In central sleep apnea, the neural drive of all respiratory muscles is temporarily stopped. In obstructive sleep apnea, despite continuous respiratory drive, airflow is stopped due to airway obstruction. Mixed apneas are variants of obstructive sleep apnea, which consists of a central apnea followed by an obstructive portion. The most common type of apnea is obstructive sleep apnea.

Obstructive Sleep Apnea Syndrome (OSAS) has been identified in 24% of working men and 9% of similar women and peaks at the age of sixty. Habitual severe snoring, an almost invariable feature of OSAS, has been described in up to 24% of middle-aged men and 14% of women of the same age, and is more common in older individuals.

A decisive event in obstructive sleep apnea syndrome is an obstruction of the upper respiratory tract (often at the oropharyngeal level). The resultant apnea often leads to progressive apnea until the individual briefly awakens from sleep, opening the airway and thus resuming airflow.

An important factor that contributes to upper airway collapse in OSAS is the creation of a critical negative pressure during inspiration that exceeds the ability of the airway dilator and abductor muscles to maintain airway stability. Sleep plays a key role in reducing the activity of upper airway muscles, including the dilator and abductor muscles.

In most individuals with OSAS, the patency of the airway is also structurally reduced and thus prone to obstruction. In a small number of individuals, this structural reduction is often due to a significant tissue abnormality, i.e., adenoid tonsillar hypertrophy, retrognathic or lingual hypertrophy. However, in most individuals predisposed to OSAS, this structural abnormality is simply due to a slight reduction in airway size, i.e., "pharyngeal crowding. Obesity also often results in a reduction in the size of the upper respiratory tract. The effects of snoring (in fact high frequency tremor of the soft tissues of the palate and pharynx, caused by the smaller size of the upper airway cavity) often exacerbate this diminution by creating edema in the soft tissues.

The repeated occurrence of nocturnal asphyxia and sleep arousal, characteristic of OSAS, leads to a series of secondary physiological events, which in turn cause clinical complications of the syndrome. The most common manifestations are neuropsychiatric and behavioral disorders, which are thought to be caused by sleep fragmentation and slow wave sleep loss due to repetitive arousal responses. Nocturnal cerebral hypoxia is also thought to play an important role. The most common manifestation is excessive daytime sleepiness. OSAS is currently considered to be the leading cause of daytime drowsiness and is considered to be an important risk factor for motor vehicle accident-like problems. Other related symptoms include impaired intelligence, memory loss, personality disorders, and impotence.

Other important manifestations are natural cardiopulmonary respiration, which is thought to be caused by the recurrent occurrence of nocturnal asphyxia. Most individuals exhibit a periodic slowing of the heart rate to 30 to 50 beats per minute during apnea and then tachycardia to 90 to 120 beats per minute during the ventilatory phase. A small number of individuals develop severe bradycardia, including 8 to 12 second-lasting cardiac arrest or dangerous tachyarrhythmias, including non-sustained ventricular tachycardia. OSAS also aggravates left ventricular failure in patients with primary heart disease. This complication is most likely due to a combination of increased left ventricular afterload secondary to intrathoracic negative pressure during each obstructive event, recurrent nocturnal hypoxemia, and chronically elevated sympathetic adrenal activity.

Currently, the most common treatment for adults with sleep apnea and other sleep-related breathing disorders is mechanical therapy delivering Positive Airway Pressure (PAP) (e.g., continuous positive airway pressure, CPAP). In PAP therapy, an individual wears a sealingly attached plastic mask over the nose while sleeping. The mask is connected to a compressor that forces gas into the nose, thereby creating a positive pressure in the patient's airway. The principle of this method is to provide a mechanical "splinting" effect to the airway pressurization which prevents airway collapse and thus prevents obstructive sleep apnea. Although a therapeutic response is observed in patients receiving PAP therapy, many patients cannot tolerate such a device or stress and reject treatment. Furthermore, recent covert monitoring studies clearly indicate that the long-term compliance of PAP therapy is extremely poor.

Various upper respiratory tract and craniofacial surgical procedures have been attempted to treat OSAS. It has been reported that adenotonsillectomy can effectively cure OSAS in many children, but upper respiratory surgery has a poor cure rate for adult patients with OSAS. Surgical success rates can be reduced by 50% in the event of apnea and there is no available method to identify individuals who can benefit from the surgery and those who cannot.

Thus, there is a need for treatment of individuals suffering from various sleep-related respiratory disorders. There is also a need for a viable treatment of sleep-related breathing disorders that can promote patient compliance.

3. Summary of the invention

The present invention provides methods of treating one or more sleep-related breathing disorders in a patient comprising administering O-desmethylvenlafaxine or a pharmaceutically acceptable salt or solvate thereof.

In certain embodiments, the O-desmethylvenlafaxine is enantiomerically enriched (+) or (-) for the treatment of cancer. In some embodiments, the O-desmethylvenlafaxine is enriched for the (-) enantiomer. In some embodiments, (-) -O-desmethylvenlafaxine is substantially free of the (+) enantiomer.

The present invention also provides a method of treating one or more sleep-related breathing disorders in a patient comprising administering duloxetine or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the sleep-related breathing disorder is obstructive sleep apnea.

4. Detailed description of the invention

4.1 methods of treatment

The present invention provides methods of treatment with O-desmethylvenlafaxine. In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of O-desmethylvenlafaxine. The enantiomerically enriched mixture may comprise, for example, at least 60 mole percent of one enantiomer, or more preferably at least 75, 90, 95 or 99 mole percent or more of one enantiomer. In certain embodiments, the O-desmethylvenlafaxine is enriched for the (-) enantiomer. In certain embodiments, (-) -O-desmethylvenlafaxine is substantially free of the (+) enantiomer. In certain embodiments, the O-desmethylvenlafaxine is enantiomerically enriched. In certain embodiments, (+) -O-desmethylvenlafaxine is substantially free of the (-) enantiomer. The term "substantially free" as used herein means, for example, that in the composition or mixture of compounds, the impurity or relatively unwanted substance is less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% relative to the target compound. For example, if a composition or mixture of compounds contains 98 grams of the (-) -enantiomer and 2 grams of the (+) -enantiomer, it can be said that 98 mole percent of the (-) -enantiomer and only 2% of the (+) -enantiomer are contained.

The present invention provides a method of treating one or more sleep-related breathing disorders in a patient comprising administering to the patient a therapeutically effective amount of O-desmethylvenlafaxine, or a pharmaceutically acceptable salt or solvate thereof.

In certain embodiments, the O-desmethylvenlafaxine is enantiomerically enriched (+) or (-) for the treatment of cancer. In some embodiments, the O-desmethylvenlafaxine is enriched for the (-) enantiomer. In some embodiments, (-) -O-desmethylvenlafaxine is substantially free of the (+) enantiomer.

In certain embodiments, O-desmethylvenlafaxine is administered in combination with a second active agent. In certain such embodiments, the second agent is a sleep-aid agent, an agent that treats excessive daytime sleepiness, an anti-obesity agent, or an agent that stabilizes respiratory drive.

In certain embodiments, O-desmethylvenlafaxine is administered in combination with positive airway pressure therapy.

In certain embodiments, O-desmethylvenlafaxine is administered orally, sublingually, or by oral inhalation.

In some embodiments, the sleep-related breathing disorder is obstructive sleep apnea.

The present invention also provides a method of treating one or more sleep-related breathing disorders in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of duloxetine or a pharmaceutically acceptable salt or solvate thereof.

In certain embodiments, duloxetine is administered in combination with a second active agent. In certain such embodiments, the second agent is a sleep-aid agent, an agent that treats excessive daytime sleepiness, an anti-obesity agent, or an agent that stabilizes respiratory drive.

In certain embodiments, duloxetine is administered in combination with positive airway pressure therapy.

In certain embodiments, duloxetine is administered by oral, sublingual administration or by oral inhalation.

In certain embodiments, the sleep-related breathing disorder is obstructive sleep apnea.

In certain embodiments, wherein O-desmethylvenlafaxine or duloxetine is administered in combination with a sleep aid, the sleep aid can be any suitable sleep aid. Such sleep aids include, but are not limited to, zopiclone, diphenhydramine, ramelteon, benzodiazepines (such as flurazepam, quazepam, triazolam, sultam, and temazepam), non-benzodiazepine receptor agonists (such as zolpidem or zaleplon), melatonin, gaboxadol, antihistamines (such as diphenhydramine), sedative antidepressants (such as trazodone, amitriptyline, and doxepin), and/or pharmaceutically acceptable salts or solvates thereof. In certain embodiments, the sleep aid is zopiclone.

In certain embodiments, wherein O-desmethylvenlafaxine or duloxetine is administered in combination with an agent for treating excessive daytime sleepiness, the agent for treating excessive daytime sleepiness may be any suitable agent for treating excessive daytime sleepiness. Such agents for treating excessive daytime sleepiness include, but are not limited to, modafinil, caffeine, amphetamines (e.g., amphetamine, methamphetamine, dextroamphetamine, and levoamphetamine), SDZ-NV1-085, mazindol, methylpiperidine acetate, and/or pharmaceutically acceptable salts or solvates thereof.

In certain embodiments, wherein O-desmethylvenlafaxine or duloxetine is administered in combination with an anti-obesity agent, the anti-obesity agent may be any suitable anti-obesity agent. Such anti-obesity agents include, but are not limited to, orlistat, sibutramine, phendimetrazine, phentermine, diethylpropion, benzphetamine, mazindol, dextroamphetamine, rimonabant, cetistat, GT 389-255, APD356, pramlintide/AC 137, PYY3-36, AC 162352/PYY3-36, oxyntomodulin, TM30338, AOD 9604, oleoyl-estrone, bromocriptine, ephedrine, leptin, pseudoephedrine, and/or pharmaceutically acceptable salts or solvates thereof.

In certain embodiments, wherein O-desmethylvenlafaxine or duloxetine is administered in combination with an agent that stabilizes the respiratory drive force, the agent that stabilizes the respiratory drive force may be selected from any suitable agent that stabilizes the respiratory drive force. Such agents that stabilize respiratory drive include, but are not limited to, topiramate, amantadine, bupropion, modafinil, r-modafinil, SDZ-NV1-085, 5-HT1A agonists (such as bupropion, gepirone, anepirone, and ORG 13011), zonisamide, and/or pharmaceutically acceptable salts or solvates thereof.

The administration of the active agent provided by the present invention, or a pharmaceutically acceptable salt or solvate thereof, and a second active agent to a patient may be carried out simultaneously or sequentially, by the same or different routes of administration. The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without breaking down before entering the bloodstream) and the disease being treated. One mode of administration of the compounds provided herein is oral. The route of administration of the second active agent or ingredient is well known to those skilled in the art. See, for example, Physicians' Desk Reference (60 th edition, 2006).

Both (-) -O-desmethylvenlafaxine and duloxetine showed inhibition of 5-hydroxytryptamine (5-HT) and Norepinephrine (NE) reuptake. Without wishing to be bound by a particular theory, this dual inhibition results in an increase in 5-HT and NE levels in the central nervous system. Without wishing to be bound by a particular theory, this dual inhibitory activity may mediate the utility of these compounds for the treatment of sleep-related breathing disorders, such as obstructive sleep apnea. Still not wishing to be bound by a particular theory, an increase in 5-HT and NE levels in the brain produces stimulation of nerves that regulate upper airway muscle status, such as cranial nerve XII (hypoglossal nerve), which in turn controls the genioglossus muscle. Without wishing to be bound by a particular theory, modulation of these muscle conditions will keep the upper airway open during sleep, thereby preventing apneic events.

The invention also provides uses of metabolites of the disclosed compounds (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (+) -O-desmethylvenlafaxine or (-) -O-desmethylvenlafaxine). The term "metabolite" is intended to include compounds produced by metabolism of a parent compound under normal physiological conditions. For example, an N-methyl group can be cleaved to produce the corresponding N-demethylated metabolite. Specific metabolites include those that exhibit similar activity as the parent compound (e.g., metabolites suitable for treating one or more sleep-related respiratory disorders in a patient).

The dosage of a compound provided by the present invention, or a pharmaceutically acceptable salt or solvate thereof, can vary depending on various factors, such as the particular indication to be treated, the age and condition of the patient, the amount of the second active agent used (if any), the route of administration, and the outcome sought for the treatment. In general, the compounds provided herein, or pharmaceutically acceptable salts or solvates thereof, can be used in amounts of from about 0.001mg to about 100mg per day, and can be adjusted in a conventional manner (e.g., the same amount is administered daily during a treatment, prevention or control period), periodically (e.g., for one week, for a rest of one week), or in increasing or decreasing amounts during the course of treatment.

Any suitable route of administration may be used in the methods of treatment provided herein. Such routes include, but are not limited to, oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topical (e.g., eye drops or other ophthalmic agents), transdermal, or transdermal administration.

The disclosed compounds (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (+) -O-desmethylvenlafaxine or (-) -O-desmethylvenlafaxine) are administered to a patient. In certain embodiments, the patient is a mammal, e.g., a human or non-human mammal.

4.2 pharmaceutical compositions and dosage forms

When administered to a patient, a compound disclosed herein (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (+) -O-desmethylvenlafaxine or (-) -O-desmethylvenlafaxine) and/or another active agent may be administered as a pharmaceutical composition. The pharmaceutical compositions may be presented in a single, single unit dosage form. Pharmaceutical compositions and dosage forms provided by the invention comprise a compound provided by the invention, or a pharmaceutically acceptable salt or solvate thereof. The pharmaceutical compositions and dosage forms may also comprise one or more excipients.

Examples of dosage forms include, but are not limited to: a tablet; a caplet; capsules (e.g., soft gel capsules); a cachet; a lozenge; a lozenge; a dispersant; suppositories; powder; aerosols (e.g., nasal sprays or inhalers); gelling; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil emulsions), solutions and elixirs; a liquid dosage form suitable for parenteral administration to a patient; eye drops or other ophthalmic formulations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted into liquid dosage forms that can be administered to a patient parenterally.

The composition, shape and type of dosage form generally depends on its use. For example, a dosage form for acute treatment of a disease may contain a greater amount of one or more active ingredients than a dosage form for chronic treatment of the same disease. Similarly, parenteral dosage forms may contain smaller amounts of one or more of the active ingredients they contain than oral dosage forms used to treat the same disease. Various modes of use of a particular dosage form may vary, as will be apparent to those skilled in the art. See, for example, Remington's pharmaceutical Sciences, 18 th edition, Mack Publishing, Easton PA (1990).

Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions, such as water or physiological buffered saline; or other solvents or vehicles such as glycols, glycerol, oils such as olive oil or injectable organic esters. In a preferred embodiment, the aqueous solution is pyrogen-free or substantially pyrogen-free when the pharmaceutical composition is for human administration. Excipients may be selected, for example, to achieve sustained release of the agent or to selectively target one or more cells, tissues or organs. The pharmaceutical compositions may take such dosage unit forms as tablets, capsules, dispersion capsules, granules, powders, syrups, suppositories, injections and the like. The composition may also be present in a transdermal delivery system, for example, in a skin patch.

The pharmaceutically acceptable carrier may comprise a physiologically acceptable agent useful, for example, to stabilize or enhance absorption of the compound (duloxetine or O-desmethylvenlafaxine). Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose or dextran; antioxidants, such as ascorbic acid or glutathione; a chelating agent; low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The pharmaceutical composition (formulation) may also be a liposome or other polymer matrix into which, for example, an active agent may be incorporated. Liposomes, for example, liposomes composed of phospholipids or other lipids, are non-toxic, physiologically acceptable, and metabolically acceptable carriers that are relatively easy to prepare and administer.

The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, according to 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.

The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the human body. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) vitamins and their derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate, ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline water; (18) a ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible materials employed in pharmaceutical formulations.

Pharmaceutical compositions (formulations) comprising a compound disclosed herein (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (+) -O-desmethylvenlafaxine or (-) -O-desmethylvenlafaxine) may be administered to a subject by any of a variety of routes of administration, including, for example, orally (e.g., contained in an aqueous or non-aqueous solution or suspension, tablet, pellet, powder, granule, paste, for application to the tongue); sublingual administration; anal, rectal, or vaginal administration (e.g., as a pessary, cream, or foam); parenteral administration (including intramuscular, intravenous, subcutaneous, or intrathecal administration as, e.g., sterile solutions or suspensions); nasal administration; intraperitoneal administration; subcutaneous administration; transdermal administration (e.g., as a patch applied to the skin); and topical administration (e.g., as an emulsion, cream, or spray applied to the skin). The compounds may also be formulated for oral inhalation. In certain embodiments, the compounds disclosed herein (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (+) -O-desmethylvenlafaxine, or (-) -O-desmethylvenlafaxine) may be simply dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable for use in such routes of administration can be found, for example, in U.S. Pat. nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as the patents cited herein. The most preferred route of administration is the oral route.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that can be combined with the carrier materials to form a single dosage form will vary depending upon the host treated, the particular mode of administration. The amount of active ingredient that can be combined with the carrier materials to form a single dosage form is generally that amount of compound which produces a therapeutic effect. Generally, the amount is in the range of about 1% to about 99% of the active ingredient, preferably in the range of about 5% to about 70%, and most preferably in the range of about 10% to about 30% of 100 parts percent.

Methods of preparing these formulations or compositions comprise combining a compound provided herein with the carrier and optionally one or more accessory ingredients. In general, the formulations can be prepared by uniformly and intimately admixing the compounds provided herein with liquid carriers or finely divided solid carriers or both, and then shaping the product as desired.

Formulations suitable for oral administration may be presented as capsules, cachets, pills, tablets, lozenges (using a flavored basis, typically sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base such as gelatin and glycerin or sucrose and acacia) and/or as a mouthwash, each containing a predetermined amount of a compound provided herein as the active ingredient. The disclosed compounds may also be administered as a pill, electuary or paste.

In solid dosage forms (capsules, tablets, pills, lozenges, powders, granules, etc.) for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or calcium phosphate, and/or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binding agents, for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents such as cetyl alcohol and glyceryl monostearate; (8) absorbents such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) a colorant. For capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk lactose, as well as high molecular weight polyethylene glycols and the like as excipients.

Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binding agents (e.g., gelatin or hydroxypropylmethyl cellulose), lubricating agents, inert diluents, preservatives, disintegrating agents (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface active agents or dispersing agents. The moulding tablets may be prepared by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules, pills and granules, may optionally be formulated or prepared with coatings or shells, such as enteric coatings or other coatings well known in the pharmaceutical formulating art. They may also be formulated to provide sustained or controlled release of the active ingredient therein, using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may also be sterilized prior to use, for example, by filtration through a bacterial filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or other sterile injectable medium. These compositions may also optionally contain opacifying agents and may be of a composition that releases the active ingredient only, or preferably, in a specific part of the gastrointestinal tract, optionally in a sustained release manner. Examples of embedding compositions that may be used include, but are not limited to, polymeric substances and waxes. The active ingredient may also be in the form of microcapsules, where appropriate with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration of the active agent include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

In addition to inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, odorant, and preservative agents.

In addition to the active compounds, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylhydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof, may be included in the suspension.

Formulations for rectal, vaginal or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active agents with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

Alternatively or additionally, the composition may be formulated for delivery through a catheter, stent, wire, or other intraluminal device. Delivery through such devices may be particularly useful for delivery to the bladder, urethra, ureter, rectum or intestine.

Formulations suitable for vaginal administration may also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

Dosage forms for topical or transdermal administration of the disclosed compounds include powders, sprays, ointments, pastes, ointments, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

In addition to the active compounds, the ointments, pastes, creams and gels may contain excipients, for example animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

In addition to the compounds provided by the invention, the powders and sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder or mixtures of these substances. The spray may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Transdermal patches have the additional advantage of providing controlled delivery of compounds to the body. Such dosage forms may be prepared by dissolving or dispersing the plasticized compound in a suitable medium. Absorption enhancers may also be used to increase the flow of the compound across the skin. The rate of such flow can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

Ophthalmic preparations, eye ointments, powders, solutions, and the like are also within this range.

The phrases "parenteral administration" and "administered parenterally" as used herein refer to modes of administration other than enteral and non-topical administration, which are generally administered by injection and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subconjunctival, subarachnoid, intraspinal and intrasternal injection and infusion.

Pharmaceutical compositions suitable for parenteral administration may comprise one or more active agents and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that can be used in the pharmaceutical compositions include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained in a variety of ways, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size of the dispersion, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, ascorbic acid, and the like). It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like in the compositions. In addition, sustained absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption (e.g., aluminum monostearate and gelatin).

In some cases, to prolong the effect of a drug, it is desirable to slow the absorption of the drug injected subcutaneously or intramuscularly. This can be achieved by using liquid suspensions of crystalline or amorphous materials that have poor water solubility. The rate of absorption of the drug then depends on its off-rate, which in turn depends on crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered drug form may be achieved by dissolving or suspending the drug in an oil carrier.

Injectable depot (depot) forms can be prepared by forming a microcapsule matrix of the compound of interest in a biodegradable polymer, such as polylactic acid compound-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

When the compounds disclosed herein are administered as pharmaceuticals to humans and animals, they may be administered directly, or as a pharmaceutical composition comprising, for example, 0.1% to 99.5% (more preferably 0.5 to 90%) of the active ingredient and a pharmaceutically acceptable carrier.

Methods of introduction may also be provided by a device that may be filled or biodegradable. Various sustained release polymer devices have been developed in recent years and tested for controlled delivery of drugs, including proteinaceous biopharmaceuticals, in vivo. Various biocompatible polymers (including hydrogels), including biodegradable and non-biodegradable polymers, can be used to form implants that provide sustained release of a compound at a specific target site.

The actual dosage level of the active ingredient in the pharmaceutical composition can be varied so as to obtain an effective amount of the active ingredient that will produce the desired therapeutic response for a particular patient, composition, and mode of administration, without producing toxicity to the patient.

The dosage form selected will depend upon a variety of factors including the activity of the particular active agent or ester, salt or amide thereof employed, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of the treatment, other drugs, compounds and/or substances used in combination with the particular compound employed, the age, sex, weight, condition, health and prior medical history of the patient being treated and like factors well known in the medical arts.

A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, to achieve a desired therapeutic effect, the physician or veterinarian can start administering the amount of agent used in the pharmaceutical composition at a level below that which is desired and gradually increase the dose until the desired effect is achieved.

In general, a suitable daily dose of the active agent is the lowest dose of the compound that produces a therapeutic effect. Such effective dosages will generally depend upon the factors described above.

If desired, an effective daily dose of the active compound is administered alone as one, two, three, four, five, six or more sub-doses, optionally in unit dosage form, at appropriate intervals throughout the day. In certain embodiments, the active compound may be administered twice or three times daily. In a preferred embodiment, the active compound will be administered once daily.

The patient receiving such treatment is any animal in need thereof, including primates, particularly humans, and other mammals such as horses, cattle, pigs, sheep; and poultry and pets in general.

In certain embodiments, the disclosed compounds (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (+) -O-desmethylvenlafaxine, or (-) -O-desmethylvenlafaxine) may be administered alone or in combination with another therapeutic or therapeutic agent type. The phrase "co-administration" as used herein refers to the administration of two or more different therapeutic compounds in any form such that the second compound is administered while the previously administered therapeutic compound is still acting in vivo (e.g., the two compounds may act simultaneously in the patient, which may include a synergistic effect of the two compounds). For example, the different therapeutic compounds may be administered in the same formulation, or in separate formulations, simultaneously or sequentially. Thus, an individual receiving such treatment may benefit from the combined action of different therapeutic compounds. Furthermore, "co-administration" refers to administration of a compound provided herein (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (+) -O-desmethylvenlafaxine, or (-) -O-desmethylvenlafaxine) in any form in combination with a second, non-drug treatment (e.g., positive airway pressure treatment) that occurs when a compound provided herein acts in vivo (e.g., both treatment mechanisms act simultaneously on the patient, which may include a synergistic effect of both mechanisms). Thus, individuals receiving such treatment may benefit from the combined effects of the different therapies.

It is contemplated that the disclosed compounds (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (+) -O-desmethylvenlafaxine or (-) -O-desmethylvenlafaxine) are administered to a subject (e.g., a mammal, preferably a human) in a therapeutically effective amount (dose). By "therapeutically effective amount" is meant a concentration of the compound sufficient to elicit the desired therapeutic effect, such as the treatment or prevention of sleep-related breathing disorders, e.g., obstructive sleep apnea. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age and medical history of the individual. Other factors that affect the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder to be treated, the stability of the compound, and, if desired, another type of therapeutic agent administered with the active agent. A larger total dose may be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al, (1996) Harrison's Principles of Internal Medicine, 13 th edition, 1814-.

The invention also provides pharmaceutically acceptable salts or solvates of the disclosed compounds (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (+) -O-desmethylvenlafaxine or (-) -O-desmethylvenlafaxine). Without wishing to be bound by a particular theory, duloxetine and venlafaxine are basic and therefore can react with any number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts, since they are amines. Acids commonly used to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic and phosphoric acid, and organic acids such as p-toluenesulfonic, methanesulfonic, oxalic, p-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acids, and related inorganic and organic acids. Thus, such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, hex, Citrate, lactate, beta-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylethanolate, hippurate, gluconate, lactobionate and the like.

The pharmaceutically acceptable acid addition salts of the compounds provided by the present invention (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (+) -O-desmethylvenlafaxine or (-) -O-desmethylvenlafaxine) may also exist as various solvates, for example, with water, methanol, ethanol, dimethylformamide and the like. Mixtures of such solvates may also be prepared. Such solvates may be derived from the solvent of crystallization, either inherent to the preparation or crystallization solvent, or incidental to such solvents.

Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium hydrogensulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants such as ascorbyl palmitate, t-Butylparacresol (BHA), di-t-Butylparacresol (BHT), lecithin, propylgallate, alpha-tocopherol, etc.; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

The present invention also provides a kit comprising:

a) one or more single dosage forms comprising a compound provided herein (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (-) -O-desmethylvenlafaxine, or (+) -O-desmethylvenlafaxine) and a pharmaceutically acceptable excipient; and

b) instructions for administering the single dose form to treat sleep-related breathing disorders such as obstructive sleep apnea.

The present invention also provides a kit comprising:

a) a first pharmaceutical formulation comprising a compound provided herein (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (-) -O-desmethylvenlafaxine, or (+) -O-desmethylvenlafaxine);

b) a second pharmaceutical formulation comprising at least one of the following: sleep-aiding agents, agents for treating excessive daytime sleepiness, anti-obesity agents, or agents that stabilize respiratory drive; and

c) instructions for administering the first and second pharmaceutical preparations.

In certain embodiments, the invention provides methods for a healthcare provider to conduct a pharmaceutical business by producing a formulation of a compound provided herein (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (-) -O-desmethylvenlafaxine, or (+) -O-desmethylvenlafaxine) or a kit provided herein and promoting the benefits of using the formulation or kit in the treatment or prevention of sleep-related breathing disorders such as obstructive sleep apnea.

In certain embodiments, the invention provides methods of promoting a health care provider's pharmaceutical business by producing a formulation of a compound provided herein (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (-) -O-desmethylvenlafaxine or (+) -O-desmethylvenlafaxine) or a kit provided herein for administration in combination with a sleep-aid agent, an agent for treating excessive daytime sleepiness, an anti-obesity agent or an agent that stabilizes respiratory drive, and promoting the benefits of using the formulation or kit in the treatment or prevention of sleep-related breathing disorders such as obstructive sleep apnea.

In certain embodiments, the invention provides methods of administering a pharmaceutical product by providing a distribution network that sells formulations of compounds provided herein (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (-) -O-desmethylvenlafaxine, or (+) -O-desmethylvenlafaxine) or kits provided herein, and providing instructional material to a patient or physician for using the formulations to treat or prevent sleep-related breathing disorders, such as obstructive sleep apnea.

In certain embodiments, the present invention provides a distribution network for providing a formulation of a compound provided herein (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (-) -O-desmethylvenlafaxine or (+) -O-desmethylvenlafaxine) or a kit provided herein for marketing and co-administration with sleep-aids, agents for treating excessive daytime sleepiness, anti-obesity agents or agents that stabilize respiratory drive, and providing instructional material for the use of the formulation to a patient or physician for the treatment or prevention of sleep-related breathing disorders such as obstructive sleep apnea.

In certain embodiments, the invention provides methods of determining a therapeutic profile of efficacy and toxicity of a given formulation in an animal by determining an appropriate formulation or dose of a compound provided herein (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (-) -O-desmethylvenlafaxine or (+) -O-desmethylvenlafaxine) to administer for the treatment or prevention of sleep-related breathing disorders such as obstructive sleep apnea, and providing a distribution network that sells the given formulation with acceptable therapeutic profiles for pharmaceutical business. In certain embodiments, the method further comprises providing a sales team that promotes the formulation to a healthcare provider.

In certain embodiments, the present invention provides methods for determining the therapeutic profile of efficacy and toxicity of a given formulation in an animal by determining the appropriate formulation or dosage of a compound provided herein (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (-) -O-desmethylvenlafaxine or (+) -O-desmethylvenlafaxine) for treatment or prevention of sleep-related breathing disorders such as obstructive sleep apnea to be administered in combination with a sleep-aid, an agent for treating excessive daytime sleepiness, an anti-obesity agent or an agent for stabilizing respiratory drive, and for marketing a distribution network of the given formulation with acceptable therapeutic profiles for pharmaceutical business. In certain embodiments, the method further comprises providing a sales team that promotes the formulation to a healthcare provider.

In certain embodiments, the present invention provides methods of providing pharmaceutical practice by determining an appropriate formulation or dose of a compound provided herein (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (-) -O-desmethylvenlafaxine, or (+) -O-desmethylvenlafaxine) for administration to treat or prevent sleep-related breathing disorders such as obstructive sleep apnea, and granting a third party the right to further develop and market the formulation.

In certain embodiments, the present invention provides methods of determining an appropriate formulation or dosage of a compound provided herein (e.g., duloxetine, (±) -O-desmethylvenlafaxine, (-) -O-desmethylvenlafaxine or (+) -O-desmethylvenlafaxine) for treating or preventing sleep-related breathing disorders such as obstructive sleep apnea by administering in combination with a sleep-aid agent, an agent for treating excessive daytime sleepiness, an anti-obesity agent, or an agent that stabilizes respiratory drive, and authorizing to a third party a right to further develop and sell said formulation for pharmaceutical practice.

The term "healthcare provider" refers to an individual or organization that provides healthcare for a person, community, or the like. Examples of "healthcare providers" include doctors, hospitals, retirement communities of uninterrupted care, technical care facilities, subacute care facilities, clinics, multi-purpose clinics, independent outpatient centers, home healthcare facilities, and HMOs.

As used herein, to "prevent" treatment of a disease or disorder means that the compound in the statistical sample reduces the occurrence of the disease or disorder in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disease or disorder relative to an untreated sample.

The term "treatment" includes prophylactic and/or therapeutic treatment. The term "prophylactic or therapeutic" treatment is art-recognized and includes the administration of one or more of the subject compositions to the host. If administered before the clinical symptoms of the adverse condition (e.g., disease or other adverse condition of the host animal) occur, the treatment is prophylactic (i.e., it protects the host from developing the adverse condition), whereas if administered after the adverse condition appears, the treatment is therapeutic (i.e., it aims to reduce, ameliorate or stabilize the existing adverse condition or its side effects).

5. Examples of the embodiments

The inhibition of functional uptake of 5-HT, NE or DA by the compounds provided herein was tested in synaptosomes prepared from rat whole brain, hypothalamus or striatum, respectively, or in whole cells of cloned human transporters expressing 5-HT, NE or DA cultured in vitro. The concentration of radioligand used in the assay is equal to or lower than the K of the monoamine substrate and its cognate transporter_M. Compounds were tested in duplicate at 5 to 10 different concentrations to obtain a full inhibition curve. IC was then determined by nonlinear regression analysis of the inhibition curves₅₀Values (concentration of control activity inhibiting 50%).

5.1 functional reuptake assay of 5-hydroxytryptamine against rat reuptake transporter

5-HT uptake was quantified using synaptosomes isolated from the cortex of male Wistar rats in 0.32M sucrose buffer. By using a test compound and³H]5-Hydroxytryptamine (0.1)μ Ci/spot) were incubated for 15 minutes at 37 ℃ in microwells to allow the synaptosomes to take up radiolabeled 5-HT.

Synaptic corpuscle and [ 2 ]³H]5-Hydroxytryptamine in the presence of 25mM NaHCO₃11mM glucose and 50. mu.M ascorbic acid in Krebs buffer pH 7.4. The incubation buffer was oxidized 5 minutes before incubation. The basal control was incubated at 4 ℃ for 15 minutes to avoid any uptake. After incubation, the cells were incubated with a medium containing 25mM NaHCO₃The unidilter 96-well GFB Packard plate washed with Krebs buffer of (1) is filtered to remove free [ 2 ], [ 2 ]³H]5-hydroxytryptamine to stop uptake. The scintillation fluid is then used to measure the radioactivity associated with the synaptosomes retained on the unifilter corresponding to uptake using a microplate scintillation counter (Topcount, Packard). Nonspecific binding was measured in the presence of excess cold, unlabeled ligand. Specific binding was obtained by subtracting non-specific binding from total binding.

The reference compound is propiimidazole, which is at 10^-11M to 10^-5Test 10 concentrations in M range to obtain IC₅₀The value is obtained. See, e.g., Perovics and″Pharmacological profile ofhypericum extract：effect on serotonin uptake by postsynaptic receptors，″Arzeim.Forsch./Drug Res.，45：1145-1148(1995)。

venlafaxine, racemic O-desmethylvenlafaxine, (+) -O-desmethylvenlafaxine and (-) -O-desmethylvenlafaxine were evaluated in this assay. The results are shown in table 1.

5.2 5-Hydroxytryptamine functional reuptake assay for human reuptake transporter

Testing of inhibition of human 5-hydroxytryptamine reuptake transporter Using a published method Using recombinant human 5-hydroxytryptamine transporter expressed in HEK-293 cells (Gu H, Wall S, Rudnick G.Stable expression)of biological amine transporters variables differences in inhibitorsities, kinetics, and ion dependency. J Biol chem.269 (10): 7124-7130, 1994)). Human 5-hydroxytryptamine transporter expressed in HEK-293 cells was plated prior to assay. The test compound and/or vehicle is administered to the cells (5X 10)⁵Perml) in a modified Tris-HEPES buffer solution (pH 7.1) at 25 ℃ for 20 minutes, followed by addition of 65nM [ mu ] m³H]5-hydroxytryptamine and incubation continued for 10 min. Filtering the bound cells and counting tritium entering the cells using a liquid scintillation counter to determine [ 2 ]³H]5-hydroxytryptamine uptake. [³H]The 5-hydroxytryptamine uptake showed significant inhibitory activity relative to a 50% or more (. gtoreq.50%) reduction in 10. mu.M fluoxetine. Compounds were screened at 10, 1, 0.1, 0.01 and 0.001 μ M. The reference compound tested was fluoxetine, which resulted in an IC₅₀The value was 7.1 nM.

Venlafaxine, racemic O-desmethylvenlafaxine, (+) -O-desmethylvenlafaxine, (-) -O-desmethylvenlafaxine, and duloxetine were evaluated in this assay. The results are shown in table 1.

5.3 dopamine functional reuptake assay for rat reuptake transporter

Dopamine uptake was quantified using synaptosomes isolated from male Wistar rat striatum in 0.32M sucrose buffer. By using a test compound and³H]-the synaptosomes (20. mu.g protein/dot) were incubated for 15 min at 37 ℃ in the presence of dopamine (0.1. mu. Ci/dot) to allow the synaptosomes to take up the radiolabeled dopamine. The experiment was performed in deep microwells.

Synaptic corpuscle and [ 2 ]³H]Dopamine in solution containing 25mM NaHCO₃11mM glucose and 50. mu.M ascorbic acid in Krebs buffer pH 7.4. The incubation buffer was oxidized 5 minutes before incubation. The basal control was incubated at 4 ℃ for 15 minutes to avoid any uptake. After incubation, the cells were incubated with a medium containing 25mM NaHCO₃The unidilter 96-well GFBPackard plate washed with Krebs buffer of (1) was filtered to remove free [ 2 ]³H]Dopamine to stop uptake. The scintillation fluid is then used to measure the radioactivity associated with the synaptosomes retained on the unifilter corresponding to uptake using a microplate scintillation counter (Topcount, Packard).

Reference compound is GRB 12909 at 10^-11M to 10^-68 concentrations were tested in the M range to obtain IC₅₀The value is obtained. See, Jankowsky et al, "Characterisation of sodium-dependent³H]GBR-12935binding in brain：a radioligand for selective labeling of thedopamine transport complex，″J.Neurochem，46：1272-1276(1986)。

Venlafaxine, racemic O-desmethylvenlafaxine, (+) -O-desmethylvenlafaxine and (-) -O-desmethylvenlafaxine were evaluated in this assay. The results are shown in table 1.

5.4 dopamine functional reuptake assay for human reuptake transporter

Inhibition of human dopamine reuptake transporter protein was tested using the recombinant human dopamine transporter expressed in CHO-K1 cells using published methods (Prist upa, Z.B., Wilson, J.M., Hoffman, B.J., Kish, SJ.and Niznik, H.B.pharmacological specificity of the bound and native human dopamin transporter: separation of³H]GBRl2，935binding.MoI.Pharmacol.45: 125-135, 1994). Human recombinant dopamine transporter expressed in CHO-K1 cells was plated prior to assay. The test compound and/or vehicle is administered to the cells (4X 10)⁵Perml) in a modified Tris-HEPES buffer solution (pH 7.1) at 25 ℃ for 20 minutes, followed by addition of 50nM [ mu ] m³H]Dopamine and incubation was continued for 10 min. Obtaining a lysate from the lysed cells and measuring the amount of tritium in the lysate using a liquid scintillation counter to determine [ 2 ]³H]Dopamine uptake. [³H]Dopamine uptake showed significant inhibitory activity relative to a 50% or more (. gtoreq.50%) reduction in 10. mu.M nomifensine. Compounds were screened at 10, 1, 0.1, 0.01 and 0.001 μ M. Referencing of the testThe compound is nomifensine, and the IC obtained therefrom₅₀The value was 11 nM.

Venlafaxine, racemic O-desmethylvenlafaxine, (+) -O-desmethylvenlafaxine, (-) -O-desmethylvenlafaxine, and duloxetine were evaluated in this assay. The results are shown in table 1.

5.5 Noradrenaline functional reuptake assay for rat reuptake transporter

Norepinephrine uptake was quantified using synaptosomes isolated from the hypothalamus of male Wistar rats in 0.32M sucrose buffer. By using a test compound and³H]-the synaptosomes (100. mu.g protein/dot) were incubated for 20 minutes at 37 ℃ in the presence of norepinephrine (0.1. mu. Ci/dot) to allow the synaptosomes to take up the radiolabeled norepinephrine. The experiment was performed in deep microwells.

Synaptic corpuscle and [ 2 ]³H]Norepinephrine in solution with 25nM NaHCO₃11mM glucose and 50. mu.M ascorbic acid in Krebs buffer pH 7.4. The incubation buffer was oxidized 5 minutes before incubation. The basal control was incubated at 4 ℃ for 20 minutes to avoid any uptake. After incubation, the cells were incubated with a medium containing 25mM NaHCO₃The unidilter 96-well GFB Packard plate washed with Krebs buffer of (1) is filtered to remove free [ 2 ], [ 2 ]³H]Norepinephrine, termination of uptake. The scintillation fluid is then used to measure the radioactivity associated with the synaptosomes retained on the unifilter corresponding to uptake using a microplate scintillation counter (Topcount, Packard).

The reference compound is protriptyline, which is at 10^-11M to 10^-513 concentrations were tested in the M range to obtain IC₅₀The value is obtained. See, e.g., Perovics and″Pharmacological profile ofhypericum extract：effect on serotonin uptake by postsynaptic receptors，″Arzeim.Forsch./Drug Res.，45：1145-1148(1995)。

venlafaxine, racemic O-desmethylvenlafaxine, (+) -O-desmethylvenlafaxine and (-) -O-desmethylvenlafaxine were evaluated in this assay. The results are shown in table 1.

5.6 norepinephrine functional reuptake assay for the human reuptake transporter

The inhibition of the human norepinephrine reuptake transporter is tested using a recombinant human norepinephrine transporter expressed in MDCK cells using a published method (Galli A, DeFelice LJ, Duke BJ, Moore KR, Blakely RD. Sodium dependent nonpipernepinephrine-induced currencies in nonpipernepine-transporter-transformed HEK-293 cells blocked byvacine and antidepresants. J. Exp biol.198: 2197 2212, 1995). The cells were plated the day before the assay. The test compound and/or vehicle is administered to the cells (2X 10)⁵Perml) in a modified Tri-HEPES buffer solution (pH 7.1) at 25 ℃ for 20 minutes, followed by addition of 25nM [ mu ] m³H]Norepinephrine and incubation continues for 10 minutes. Obtaining a lysate from the lysed cells and measuring the amount of tritium in the lysate using a liquid scintillation counter to determine [ 2 ]³H]Norepinephrine uptake. [³H]Noradrenaline uptake showed significant inhibitory activity relative to a 50% or more (. gtoreq.50%) reduction in 10. mu.M desipramine. Compounds were screened at 10, 1, 0.1, 0.01 and 0.001 μ M. The reference compound tested was desipramine, the IC obtained₅₀The value was 1.9 nM.

Venlafaxine, racemic O-desmethylvenlafaxine, (+) -O-desmethylvenlafaxine, (-) -O-desmethylvenlafaxine, and duloxetine were evaluated in this assay. The results are shown in table 1.

Table 1: inhibition of monoamine uptake as measured in rat and human monoamine transporters [ IC₅₀(nM)]

-represents a functional reuptake inhibition of less than 50% at a concentration of 10 μ M.

Table 2: IC for specific binding inhibition in radioligand binding assays₅₀And (K)_i) Value (nM)

The data shown in table 2 can be obtained according to published methods. [³H]IC for inhibition of binding of paroxetine to cloned human 5-hydroxytryptamine receptor expressed in HEK293 cells₅₀Value (and calculated K)_iValues) can be determined according to Galli A, DeFelice LJ, Duke BJ, Moore KR, Blakely RD, "Sodium-dependent nonpipenprine-induced currents in nonpipenprine-transporter-transformed HEK-293 ls blocked by cocaine and antidepresants," Journal of Experimental Biology 198: 2197 and 2212 (1995). [¹²⁵I]IC of inhibition of binding of RTI-55 to cloned human norepinephrine receptor expressed in MDCK cells₅₀Value (and calculated K)_iValue) can be determined according to Shearman LP, McReynolds AM, ZhouFC, Meyer JS, "Relationship between [125I]RTI-55-labeled coccine binding sites and the serotonin transporter in rat planta, "American Journal of physiology 275: c1621-9 (1998).

All publications and patents mentioned herein are incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions therein, will control.

While specific embodiments have been discussed, the foregoing description is for illustrative purposes only and is not intended to be limiting. Many variations of the invention will become apparent to those skilled in the art upon review of the specification and claims. The full scope of the invention should be determined from the following claims and all equivalents thereto, as well as from the specification and variations.

Claims (12)

1. A method of treating sleep-related breathing disorder in a patient, comprising administering to the patient a therapeutically effective amount of O-desmethylvenlafaxine or a pharmaceutically acceptable salt or solvate thereof.

2. The method of claim 1, wherein the O-desmethylvenlafaxine is enantiomerically enriched (+).

3. The method of claim 2, wherein the O-desmethylvenlafaxine is enriched for the (-) enantiomer.

4. The method of claim 3, wherein the O-desmethylvenlafaxine is substantially free of (+) -O-desmethylvenlafaxine.

5. The method of claim 1, wherein the O-desmethylvenlafaxine is administered in combination with a second active agent, wherein the second active agent is a sleep-aid agent, an agent to treat excessive daytime sleepiness, an anti-obesity agent, or an agent to stabilize respiratory drive.

6. The method of claim 1, wherein the O-desmethylvenlafaxine is administered in combination with positive airway pressure therapy.

7. The method of claim 1, wherein the O-desmethylvenlafaxine is administered orally, sublingually, or by buccal inhalation.

8. A method of treating sleep-related breathing disorder in a patient, comprising administering to the patient a therapeutically effective amount of duloxetine or a pharmaceutically acceptable salt or solvate thereof.

9. The method of claim 8, wherein the duloxetine is administered in combination with a second active agent, wherein the second active agent is a sleep-aid agent, an agent to treat excessive daytime sleepiness, an anti-obesity agent, or an agent to stabilize respiratory drive.

10. The method of claim 8, wherein the duloxetine is administered in combination with positive airway pressure therapy.

11. The method of claim 8, wherein the duloxetine is administered orally, sublingually, or by buccal inhalation.

12. The method of claim 8, wherein the sleep-related breathing disorder is obstructive sleep apnea.