US20050176680A1 - Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression - Google Patents

Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression Download PDF

Info

Publication number
US20050176680A1
US20050176680A1 US11/007,795 US779504A US2005176680A1 US 20050176680 A1 US20050176680 A1 US 20050176680A1 US 779504 A US779504 A US 779504A US 2005176680 A1 US2005176680 A1 US 2005176680A1
Authority
US
United States
Prior art keywords
pharmaceutically acceptable
polymorph
clathrate
solvate
crystal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/007,795
Other languages
English (en)
Inventor
Karim Lalji
Timothy Barberich
Judy Caron
Thomas Wessel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sunovion Pharmaceuticals Inc
Original Assignee
Sepracor Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sepracor Inc filed Critical Sepracor Inc
Priority to US11/007,795 priority Critical patent/US20050176680A1/en
Assigned to SEPRACOR INC. reassignment SEPRACOR INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CARON, JUDY, BARBERICH, TIMOTHY J., LALJI, KARIM, WESSEL, THOMAS
Publication of US20050176680A1 publication Critical patent/US20050176680A1/en
Priority to US11/761,235 priority patent/US8097625B2/en
Priority to US13/305,007 priority patent/US20120122874A1/en
Priority to US14/448,499 priority patent/US20140343069A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Sleep is controlled by two biological processes, the homeostatic drive and the circadian rythym.
  • the homestatic drive manifests itself as an increased drive for sleep. This drive for sleep accumulates across the period of wakefulness (typically daytime) and dissipates across the sleep period.
  • the circadian rhythm of sleep-wake shows a biphasic curve with the greatest drive for sleep occurring between midnight and 5 AM, and between 2 PM and 4 PM. It is believed that major circadian influences are an alerting pulse in the evening and in the morning. It is the interaction of these processes which give rise to the 24-hour sleep schedule. For individuals with a usual sleep period of 11 PM to 7 AM, sleep onset in the evening occurs primarily as a function of homeostatic drive.
  • insomnia refers to the perception of inadequate or non-restful sleep by a patient. Insomnia is a frequent complaint, reported by 32% of the adult population surveyed in the Los Angeles area (Bixler et al, Amer. Journal of Psychiatry 136:1257-1262, 1979), and 13% of the population surveyed in San Marino, Italy (Lugaresi et al., Psychiatric Annals 17:446-453, 1987). Fully 45% of the surveyed adult population of Alachua County, Florida, reported trouble getting to sleep or staying asleep (Karacan et al., Social Science and Medicine 10:239-244, 1976). The prevalence of insomnia has also been shown to be related to the age and sex of the individuals, being more prevalent in older individuals, especially adults aged 65 and over, and in females.
  • CNS central nervous system
  • insomnia shifted away from barbiturates and other CNS depressants toward the benzodiazepine class of sedative-hypnotic agents.
  • This class of compounds produces a calming effect that results in a sleep-like state in humans and animals, with a greater safety margin than prior hypnotics.
  • many benzodiazepines possess side effects that limit their usefulness in certain patient populations. These problems include synergy with other CNS depressants (especially alcohol), the development of tolerance upon repeat dosing, dependency, withdrawal, rebound insomnia following discontinuation of dosing, hangover effects the next day and impairment of psychomotor performance and memory.
  • Next day sleepiness and memory impairment which can include amnesia for events occurring prior to and after drug administration, is of particular concern in the elderly whose cognitive functions may already be impaired by the aging process.
  • insomnia More recent treatments for insomnia have used non-benzodiazepine compounds, which show an improved side effect profile over the benzodiazepine class of sedative-hypnotics.
  • zaleplon which is marketed by Jones Pharma as SONATA®, was been approved by the FDA; zaleplon is a pyrazolopyrimidine-based compound (see U.S. Pat. No. 4,626,538).
  • Other non-benzodiazepine compounds and/or methods for making or using the same have also been reported (see, e.g., U.S. Pat. Nos. 4,794,185, 4,808,594, 4,847,256, 5,714,607, 4,654,347; 5,538,977, 5,891,891).
  • Attempts have also been disclosed to provide controlled-release dosage forms, particularly in the context of zolpidem and salts thereof (see WO 00/33835 and EP 1 005 863 A1).
  • Norepinephrine and serotonin are mammalian neurotransmitters that play important roles in a wide variety of physiological processes.
  • Norepinephrine also called noradrenaline, is a neurotransmitter that doubles part-time as a hormone.
  • norepinephrine helps to regulate arousal, dreaming, and moods.
  • As a hormone it acts to increase blood pressure, constrict blood vessels and increase heart rate—responses that occur when we feel stress.
  • Serotonin (5-hydroxytryptamine, 5-HT) is widely distributed in animals and plants, occurring in vertebrates, fruits, nuts, and venoms. A number of congeners of serotonin are also found in nature and have been shown to possess a variety of peripheral and central nervous system activities. Serotonin may be obtained from a variety of dietary sources; however, endogenous 5-HT is synthesized from tryptophan through the actions of the enzymes tryptophan hydroxylase and aromatic L-amino acid decarboxylase. Both dietary and endogenous 5-HT are rapidly metabolized and inactivated by monoamine oxidase and aldehyde dehydrogenase to the major metabolite, 5-hydroxyindoleacetic acid (5-HIAA).
  • 5-HIAA 5-hydroxyindoleacetic acid
  • Serotonin is implicated in the etiology or treatment of various disorders, particularly those of the central nervous system, including anxiety, depression, obsessive-compulsive disorder, schizophrenia, stroke, obesity, pain, hypertension, vascular disorders, migraine, and nausea. Recently, understanding of the role of 5-HT in these and other disorders has advanced rapidly due to increasing understanding of the physiological role of various serotonin receptor subtypes.
  • Neurotransmitters produce their effects as a consequence of interactions with cellular receptors.
  • Neurotransmitters including serotonin, are synthesized in brain neurons and stored in vesicles. Upon a nerve impulse, they are released into the synaptic cleft, where they interact with various postsynaptic receptors.
  • the actions of 5-HT are terminated by three major mechanisms: diffusion; metabolism; and uptake back into the synaptic cleft through the actions of specific amine membrane transporter systems.
  • the major mechanism by which the action of serotonin is terminated is by uptake through presynaptic membranes.
  • 5-HT acts on its various postsynaptic receptors, it is removed from the synaptic cleft back into the nerve terminal through an uptake mechanism involving a specific membrane transporter in a manner similar to that of other biogenic amines.
  • the actions of 5-HT, or any neurotransmitter can be modulated by agents that: stimulate or inhibit its biosynthesis; agents that block its storage; agents that stimulate or inhibit its release; agents that mimic or inhibit its actions at its various postsynaptic receptors; agents that inhibit its reuptake into the nerve terminal; and agents that affect its metabolism.
  • the present invention generally relates to pharmaceutical compositions comprising a sedative agent; and an antidepressant, including without limitation serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dopamine reuptake inhibitors, CRS antagonists and 5-HT 2A receptor modulators.
  • the sedative agent is a GABA receptor modulating compound.
  • the sedative agent is eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the pharmaceutical compositions of the invention are useful in the treatment of various sleep disorders.
  • the present invention also relates to a method of treating a patient suffering from a sleep abnormality, insomnia, or depression comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention.
  • the present invention relates to a method for augmentation of antidepressant therapy in a patient comprising administering to the patient a therapeutically effective amount of a sedative agent.
  • the sedative agent is eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention also relates to a method for eliciting a dose-sparing effect in a patient undergoing treatment with an antidepressant comprising administering to the patient a therapeutically effective amount of a sedative agent.
  • the sedative agent is eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to a method for reducing depression relapse in a patient who received antidepressant treatment comprising administering to the patient a therapeutically effective amount of a sedative agent.
  • the sedative agent is administered chronically or long-term.
  • the sedative agent is eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • FIG. 3 depicts a schematic diagram of a clinical-study protocol used to assess the safety and efficacy of compositions and methods of the present invention.
  • FIG. 4 depicts graphically fluoxetine titration as a function of length of treatment and co-administration with a placebo or eszopiclone.
  • FIG. 5 depicts graphically Subjective Wake Time After Sleep Onset (WASO) as a function of length of treatment with a placebo or eszopiclone.
  • WASO Subjective Wake Time After Sleep Onset
  • FIG. 6 depicts a chart of Subjective Sleep Latency (SL) as a function of length of treatment with a placebo or eszopiclone.
  • FIG. 7 depicts a chart of Subjective Total Sleep Time (TST) as a function of length of treatment with a placebo or eszopiclone.
  • TST Subjective Total Sleep Time
  • FIG. 8 depicts a chart of improvement from baseline in Ham-D-17 as a function of length of treatment with a placebo or eszopiclone.
  • FIG. 9 depicts a chart of improvement from baseline in Ham-D-17 (excluding questions related to insomnia) as a function of length of treatment with a placebo or eszopiclone.
  • FIG. 10 depicts a chart of improvement from baseline in Clinical Global Impression (severity) as a function of length of treatment with a placebo or eszopiclone.
  • FIG. 11 depicts a chart of Clinical Global Impression (Global Improvement) as a function of length of treatment with a placebo or eszopiclone.
  • FIG. 12 depicts a graph of Time to Onset of 50% Antidepressant Response on HAM-D6 (Maier) Scores as a function of treatment with a placebo or eszopiclone.
  • FIG. 13 depicts a graph of Time to Onset of 30% Antidepressant Response on HAM-D6 (Maier) Scores as a function of treatment with a placebo or eszopiclone.
  • FIG. 14 depicts an Insomnia Severity Index (ISI) questionnaire used in the clinical-study protocol to assess the safety and efficacy of compositions and methods of the present invention.
  • ISI Insomnia Severity Index
  • FIG. 15 depicts a portion of an Acute Health Survey questionnaire used in the clinical-study protocol to assess the safety and efficacy of compositions and methods of the present invention.
  • FIG. 16 depicts a portion of an Acute Health Survey questionnaire used in the clinical-study protocol to assess the safety and efficacy of compositions and methods of the present invention.
  • the present invention relates generally to pharmaceutical compositions containing two or more active agents that when taken together improve the quality of sleep for a patient.
  • the present invention relates to a pharmaceutical composition comprising an antidepressent and a sedative agent.
  • the present invention relates to a pharmaceutical composition comprising a serotonin reuptake inhibitor and a sedative agent.
  • the present invention relates to a pharmaceutical composition comprising a NRI and a sedative agent.
  • the present invention relates to a pharmaceutical composition comprising a 5-HT 2A modulator and a sedative agent.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a dopamine reuptake inhibitor and a sedative agent.
  • the sedative agent is a GABA receptor modulating compound.
  • the sedative agent is eszopiclone, or a pharmaceutically acceptable salt, solvate, clatherate, polymorph, or co-crystal thereof
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep disorder comprising the step of administering to said patient a therapeutically effective dose of a pharmaceutical composition containing two or more active agents that when taken together improve the quality of sleep or sleep disorders for said patient.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression comprising the step of administering to said patient a therapeutically effective dose of a pharmaceutical composition of the invention.
  • said pharmaceutical composition comprises a serotonin reuptake inhibitor and a sedative agent. In certain embodiments, said pharmaceutical composition comprises a norepinephrine reuptake inhibitor and a sedative agent. In certain embodiments, said pharmaceutical composition comprises a 5-HT 2A modulator and a sedative agent. In certain embodiments, said pharmaceutical composition comprises a dopamine reuptake inhibitor and a sedative agent. In a preferred embodiment, the sedative is eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof. In another embodiment, said pharmaceutical composition comprises eszopiclone and a SRI. In yet another embodiment, said pharmaceutical composition comprises eszopiclone and fluxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one or both of them.
  • the present invention relates to a method for augmentation of antidepressant therapy in a patient comprising administering to the patient a therapeutically effective amount of a sedative agent.
  • a sedative agent is eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention also relates to a method for eliciting a dose-sparing effect in a patient undergoing treatment with an antidepressant comprising administering to the patient a therapeutically effective amount of a sedative agent.
  • the sedative agent is eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to a method for reducing depression relapse in a patient who received antidepressant treatment comprising administering to the patient a therapeutically effective amount of a sedative agent.
  • the sedative agent is administered chronically or long-term.
  • the sedative agent is eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the National Sleep Foundation's 2002 Sleep in America survey assessed the occurrence of four symptoms of insomnia in adults in the United States: difficulty falling asleep; waking a lot during the night; waking up too early and not being able to get back to sleep; and waking up feeling unrefreshed. In the survey, 58% of the respondents reported experiencing at least one of these symptoms a few nights a week or more, and 35% reported difficulties every night or almost every night within the past year (National Sleep Foundation. 2002 Sleep in America Poll. Washington, DC: WB & A Market Research, 2002,1-43).
  • insomnia The major types of insomnia are often described as primary and secondary insomnia (as in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Text Revision. 4th ed. Washington, DC: American Psychiatric Publishing, Inc, 2000 [DSM]), chronic versus acute/transient insomnia, intrinsic versus extrinsic insomnia (as in the International Classification of Sleep Disorders [ICSD]), and sleep-onset versus sleep maintenance (Diagnostic Classification Steering Committee. International Classification of Sleep Disorders (ICSD): Diagnostic and Coding Manual. Rochester, Minn.: American Sleep Disorders Association, 1990). Many patients with sleep disturbance will fall into more than one of these categories or will have unspecified dissatisfaction with the quality of their sleep (Roth T. Int. J. Clin. Pract. Suppl. 2001,3-8).
  • the fourth edition of the DSM defines insomnia as difficulties in sleep onset (or initiation), difficulties in sleep maintenance, or sleep that is non restorative.
  • Chronic insomnia may result from several different sources (Rajput et al., Am. Fam. Physician, 1999, 60:1431-1438). Patients with chronic insomnia can often have several sleep complaints simultaneously and experience a range of sleep disturbances, including prolonged latency to sleep onset, increased time awake during the sleep period, and reduced total sleep time (Benca R M, J. Clin. Psychiatry, 2001, 62 Suppl 10:33-38).
  • WASO wake time after sleep onset
  • WASO sleep fragmentation
  • WASO is a particularly sensitive measure of sleep improvement.
  • WASO may include a number of microarousals, as well as all periods of fill wakefulness, and thus increases in WASO of only a few minutes may be indicative of substantially improved sleep continuity.
  • insomnia can be directly correlated to severity of next-day functional impairment.
  • patients with chronic insomnia experience a subjective deterioration in waking behaviors and psychosocial functioning, including impaired memory, concentration, ability to accomplish tasks, and enjoyment of interpersonal relationships (Roth et al., Sleep, 1999, 22 Suppl 2:S354-S358).
  • Psychiatric disorders are pathological conditions of the brain characterized by identifiable symptoms that result in abnormalities in cognition, emotion or mood, or the highest integrative aspects of behavior. These disorders may vary in severity of symptoms, duration, and functional impairment. Psychiatric disorders afflict millions of people worldwide resulting in tremendous human suffering and economic burden due to lost productivity. Mood disorders are a type of psychiatric disorder often defined as a group of heterogeneous, typically recurrent illnesses including unipolar (depressive) and bipolar (manic-depressive) disorders characterized by pervasive mood disturbances, psychomotor dysfunction, and vegetative symptoms. Suicide, the most serious complication in patients with mood disorders, is the cause of death in 15 to 25% of untreated patients with mood disorders; unrecognized or inadequately treated depression contributes to 50 to 70% of all completed suicides.
  • Depression is an affective disorder, the pathogenesis of which cannot be explained by any single cause or theory.
  • the most widely accepted hypothesis involves abnormal function of the catecholamine (primarily norepinephrine) and/or serotonin transmitter systems.
  • norepinephrine primarily norepinephrine
  • serotonin transmitter systems primarily norepinephrine
  • most forms of depression are associated with a deficiency of norepinephrine and/or serotonin at functionally important adrenergic or serotonergic receptors.
  • drugs that enhance the concentrations of norepinephrine (NE) and/or serotonin at these receptors should alleviate to an extent the symptoms of depression.
  • TCAs tricyclic antidepressants
  • SSRIs selective 5-HT reuptake inhibitors
  • Fluoxetine PROZAC®
  • sertraline ZOLOFT®
  • paroxetine PAXIL®
  • Fluoxetine was approved also for the treatment of obsessive-compulsive disorder. These agents do not appear to possess greater efficacy than the TCAs, nor do they generally possess a faster onset of action; however, they do have the advantage of a lower side-effect profile.
  • paroxetine is the most potent inhibitor of 5-HT uptake, fluoxetine the least.
  • Sertaline is the most selective for 5-HT versus NE uptake, fluoxetine the least selective. Fluoxetine and sertraline produce active metabolites, while paroxetine is metabolized to inactive metabolites.
  • the SSRIs in general, affect only the uptake of serotonin and display little or no affinity for various receptor systems including muscarinic, adrenergic, dopamine, histamine, or 5-HT receptors.
  • Venlafaxine (EFFEXOR®) is a recently introduced antidepressant, differing from the classical TCAs and the SSRIs chemically and pharmacologically in that it acts as a potent inhibitor of both 5-HT and norepinephrine uptake, as well as weakly inhibiting dopamine uptake. Its major metabolite, O-desmethylvenlafaxine, shares a similar profile. Neither venlafaxine nor its major metabolite have significant affinity for muscarinic, histaminergic, benzodiazephine, mu opioid, or adrenergic alpha-1 receptors. It is administered as a racemic mixture.
  • the clinician's initial approach is to increase the dose of the antidepressant. If the patient's response remains unsatisfactory after increasing the dose, the most common approaches that many clinicians will pursue are: a) switching to another antidepressant; or b) adding a second antidepressant; or c) attempting an augmentation therapy by administering agents such as lithium carbonate, thyroid hormone (triiodothyronine), psychostimulants, modafinil, atypical antipsychotics, buspirone, or pindolol.
  • agents such as lithium carbonate, thyroid hormone (triiodothyronine), psychostimulants, modafinil, atypical antipsychotics, buspirone, or pindolol.
  • the first involves switching the patient to another antidepressant agent that may have different pharmacodynamic and pharmacokinetic characteristics from the first agent.
  • the second attempts to utilize an antidepressant agent that will produce synergistic effects with the first agent.
  • the third approach relies on potential augmentation of the concurrently administered original antidepressant by agents that in and of themselves may have limited or no direct antidepressant effect.
  • central nervous system stimulants may also produce an augmentation effect in antidepressant therapy, but there is concern that these agents can produce tolerance and put the patient at risk for physical and psychological dependence and possible drug abuse.
  • Some clinicians utilize atypical antipsychotics at low doses and buspirone which are generally well tolerated and may have additional utility in treating concomitant anxiety in depressed patients that are refractory to their antidepressants. Pindolol has also been shown to accelerate clinical responses in some but not all clinical studies reported.
  • SRI Serotonin Reuptake Inhibitors
  • a dose of an SRI or a pharmaceutically acceptable salt thereof suitable for administration to a human will be in the range of 0.01 to 50 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 3 mg per kilogram body weight per day. Unless otherwise stated all weights of active ingredients are calculated in terms of drug per se.
  • the desired dose is presented as two, three, four, five or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing about 5 to 50 mg.
  • Citalopram is a selective, centrally acting serotonin reuptake inhibitor having antidepressant activities.
  • the antidepressant activity of the compound has been reported in several publications, e.g., J. Hyttel Prog. Neuro - Psychopharniacol. & Biol. Psychiat. 1982, 6, 277-295; and A. Gravem Acta Psychiatr. Scand. 1987, 75, 478-486.
  • the compound has further been disclosed to show effects in the treatment of dementia and cerebrovascular disorders. See EP-A 474580. Christensen et al. reported on the pharmacology of citalopram in Eur. J. Pharmacol. 1977, 41, 153.
  • citalopram is administered in the form of its hydrobromide salt marketed under the name Cipralmil.
  • Citalopram has the chemical name 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile. Citalopram was first disclosed in DE 2,657,271 and U.S. Pat. No. 4,136,193. The structure of citalopram is presented below.
  • the size of a prophylactic or therapeutic dose of citalopram in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 1 mg to about 80 mg.
  • a daily dose range should be between about 5 mg to about 50 mg.
  • a daily dose range should be between about 10 mg to about 30 mg.
  • a daily dosage of 15, 20, or 25 mg may be preferred depending upon patient response.
  • the therapy may be initiated at a lower dose, perhaps about 4 mg to about 6 mg and increased up to about 10 mg or higher depending-on the patient's global response. It may be necessary to use dosages outside these ranges in some cases.
  • Duloxetine is an antidepressant that functions by inhibiting the reuptake of serotonin and norepinephrine.
  • Duloxetine has the chemical name N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine and is usually administered as the hydrochloride salt. In certain instances, duloxetine is administered as the (+) enantiomer.
  • the word “duloxetine” will be used here to refer to any acid addition salt or the free base of the molecule.
  • Duloxetine was first taught by U.S. Pat. No. 4,956,388, which discloses its high potency.
  • Duloxetine is generally administered orally in the form of a tablet or a capsule full of enteric coated granules. The chemical structure of duloxetine is given below.
  • the size of a prophylactic or therapeutic dose of duloxetine in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 1 mg to about 150 mg.
  • a daily dose range should be between about 5 mg to about 80 mg.
  • a daily dose range should be between about 5 mg to about 50 mg.
  • a daily dosage of 10, 20, or 30 mg may be preferred depending upon patient response.
  • the therapy may be initiated at a lower dose, perhaps about 4 mg to about 6 mg and increased up to about 10 mg or higher depending-on the patient's global response. It may be necessary to use dosages outside these ranges in some cases.
  • Escitalopram is the S-enantiomer of citalopram. Escitalopram is greater than 100 times more potent in inhibiting serotonin reuptake compared to the R-enantiomer. Escitalopram does significantly affect reuptake of norepinephrine or dopamine. In addition, escitalopram has negligible affinity for the adrenergic, dopamine (D 1-5 ), histamine (H 1-3 ), muscarinic (M 1-5 ), and benzodiazepine receptors. Generally, escitalopram is administered as its oxalate salt under the name LEXAPROTM.
  • Escitalopram has the chemical name (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile oxalate. Citalopram was first disclosed in DE 2,657,271, corresponding to U.S. Pat No. 4,136,193. The structure of citalopram is presented below.
  • the size of a prophylactic or therapeutic dose of escitalopram in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 1 mg to about 80 mg.
  • a daily dose range should be between about 5 mg to about 50 mg.
  • a daily dose range should be between about 10 mg to about 30 mg.
  • a daily dosage of 15, 20, or 25 mg may be preferred depending upon patient response.
  • the therapy may be initiated at a lower dose, perhaps about 4 mg to about 6 mg and increased up to about 10 mg or higher depending on the patient's global response. In elderly patients, a 10 mg dosage may be optimal. It may be necessary to use dosages outside these ranges in some cases.
  • Fluoxetine is a potent, highly selective reuptake inhibitor of serotonin and is indicated for the treatment of depression and obsessions and compulsions related to obsessive-compulsive disorder (OCD).
  • OCD obsessive-compulsive disorder
  • the use of fluoxetine for indications other than treating depression is also disclosed in the following: U.S. Pat. Nos. 4,594,358, 4,647,591, 4,683,235, 4,940,585, 4,999,382, 5,151,448, 5,356,934, 5,446,070, 5,589,511, and PCT Application WO 92/18005.
  • the anti-depressant action of fluoxetine appears to be based on its capacity to selectively inhibit the uptake of serotonin by the neurons of the central nervous system.
  • Fluoxetine is described in U.S. Pat. No. 4,314,081 and has the chemical name N-methyl-3-(p-trifluormethylphenoxy)3-phenylpropylamine. Fluoxetine is generally marketed as the racemic mixture of its two enantiomers in the form of a hydrochloride salt under the name Prozac. Fluoxetine hydrochloride is a white crystalline solid (molecular weight 345.79 g/mol) that has a solubility of 14 mg/mL in water. Other methods for the production of fluoxetine and new intermediates are disclosed in U.S. Pat. No. 5,225,585. The chemical structure of fluoxetine hydrochloride is shown below:
  • fluoxetine hydrochloride PROZAC®
  • fluoxetine hydrochloride has an elimination half-life of from 1-9 days, averaging about 2-3 days. Additional product information, including dosage and administration, can be found in the Physicians' Desk Reference, 48th Edition, 1994, pp. 877-880.
  • the size of a prophylactic or therapeutic dose of fluoxetine in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 1 mg to about 150 mg.
  • a daily dose range should be between about 5 mg to about 80 mg.
  • a daily dose range should be between about 10 mg to about 20 mg.
  • a daily dosage of 30, 40, or 60 mg may be preferred depending upon patient response.
  • the therapy may be initiated at a lower dose, perhaps about 4 mg to about 8 mg and increased up to about 10 mg or higher depending-on the patient's global response. It may be necessary to use dosages outside these ranges in some cases.
  • Fluvoxamine is an inhibitor of serotonin reuptake that is used to treat depression and obsessive-compulsive disorder. Fluvoxamine is described in U.S. Pat. No. 4,085,225 and Neth. U.S. Pat. No. 7,503,310. The therapeutic activity of fluvoxamine has been described by Claassen et al. in Brit. J. Pharmacol. 1977, 60, 505; De Wilde et al. in J. Affective Disord. 1982, 4, 249; and Benfield et al. in Drugs 1986, 32, 313. The efficacy of fluvoxamine has been established for obsessive-compulsive outpatients in double-blind, placebo-controlled clinical trials.
  • fluvoxamine is administered in form of its maleate salt under the name Luvox.
  • Luvox is a crystalline solid that melts at 120-121.5° C.
  • the chemical name of fluvoxamine is 5-methoxy-1-[4-(trifluoromethyl)-phenyl]-1-pentanone O-(2-aminoethyl)oxime and the structure is presented below.
  • a prophylactic or therapeutic dose of fluvoxamine in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 1 mg to about 600 mg.
  • a daily dose range should be between about 10 mg to about 300 mg.
  • a daily dose range should be between about 50 mg to about 200 mg.
  • a daily dosage of 75, 100, 125, or 150 mg may be preferred depending upon patient response.
  • the therapy may be initiated at a lower dose, perhaps about 20 mg to about 25 mg and increased up to about 50 mg or higher depending-on the patient's global response. It may be necessary to use dosages outside these ranges in some cases. In instances where the dosage is greater than 100 mg per day, the total dosage may need to be administered in two separate doses. A reduced dosage may be required for In elderly patients or patients suffering from liver conditions. Children of 8-17 years of age should be given a starting dose of 25 mg. In certain instances, young girls may need to be given a lower dosage than boys of similar age.
  • Milnacipran is a inhibitor of serotonin and norepinephrine reuptake which is used to treat depression. Milnacipran is also known in the art as F2207, TN-912, dalcipran, midalcipran, and midalipran. The NE:5-HT selectivity of milnacipran is 2:1. See Moret et al. Neuropharmacology 1985, 24, 1211-1219 and Palmier et al. Eur. J. Clin. Pharmacol. 1989, 3, 235-238. Quite significantly, milnacipran has been used as an antidepressant in approximately 400,000 patients, and is known to be non-toxic in humans. Milnacipran was well tolerated and usually produced no more adverse effects than placebo in clinical trials at dosages of 100 mg/day or 200 mg/day (Spencer and Wilde Drugs 1998, 56, 405-427).
  • Milnacipran has the chemical name (N,N-diethyl-2-aminomethyl-1-phenylcyclo-propanecarboxamide). Procedures for the preparation of Milnacipran are given U.S. Pat. No. 4,478,836. The pharmacological activity of Milnacipran is described by Moret and coworkers in Neuropharmacology 1985, 24, 1211-19. Additional information regarding milnacipran may be found in the Merck Index, 12 th Edition, at entry 6281. The structure of Milnacipran is presented below.
  • milnacipran may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or optical isomerism. It should be understood that the invention encompasses any tautomeric, conformational isomeric, optical isomeric and/or geometric isomeric forms of the NE 5-HT SNRI compounds having one or more of the utilities described herein, as well as mixtures of these various different forms. For example, as is clear from the above structural diagram, milnacipran is optically active.
  • milnacipran may be administered in entantiomerically pure form (e.g., the pure dextrogyral enantiomer) or as a mixture of dextogyral and levrogyral enantiomers, such as a racemic mixture.
  • entantiomerically pure form e.g., the pure dextrogyral enantiomer
  • mixture of dextogyral and levrogyral enantiomers such as a racemic mixture.
  • similarcipran refers to both enantiomerically pure forms of milnacipran as well as to mixtures of milnacipran enantiomers.
  • Methods for separating and isolating the dextro- and levrogyral enantiomers of milnacipran and other NE 5-HT SNRI compounds are well-known (see Grard et al. Electrophoresis 2000, 21, 3028-3034).
  • a prophylactic or therapeutic dose of milancipran in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 1 mg to about 400 mg.
  • a daily dose range should be between about 50 mg to about 250 mg.
  • a daily dose range should be between about 100 mg to about 200 mg.
  • a daily dosage of 110, 130, 150, or 170 mg may be preferred depending upon patient response.
  • the therapy may be initiated at a lower dose, perhaps about 20 mg to about 30 mg and increased up to about 50 mg or higher depending-on the patient's global response. It may be necessary to use dosages outside these ranges in some cases.
  • Paroxetine is phenylpiperidine compound used to treat major depressive disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, generalized anxiety disorder, and posttraumatic stress disorder.
  • the therapeutic properties of paroxetine are attributed to inhibition of neuronal reuptake of serotonin.
  • Paroxetine is generally marketed as the hydrochloride salt under the name PAXIL®.
  • Paroxetine is reported in U.S. Pat. Nos. 3,912,743 and 4,007,196 while the activity profile of the drug is given in Lassen et al. Eur. J. Pharmacol. 1978, 47, 351; Hassan et al. Brit. J. Clin. Pharmacol. 1985, 19, 705; Laursen et al.
  • Dosage forms include immediate release tablets, extended release tablets, capsules and suspensions.
  • the active substance in the commercial forms has been paroxetine hydrochloride and specifically with regard to tablets and other solid forms the active ingredient has been paroxetine hydrochloride hemihydrate as described in U.S. Pat. No. 4,721,723 and EP 223403.
  • Paroxetine hydrochloride is an off-white powder that has the chemical name ( ⁇ )-trans 4R-(4′-fluorophenyl)-3S-[(3′4′-methylenedioxy-phenoxy)methyl]-piperidine hydrochloride.
  • Paroxetine hydrochloride melts at 120-138° C., has a molecular weight of 374.8 g/mol, and has a solubility of 5.4 mg/mL in water.
  • the structure of paroxetine hydrochloride is presented below.
  • U.S. Pat. No. 5,874,447 describes paroxetine sulfonate salts, including paroxetine methane sulfonate also known as paroxetine mesylate. These sulfonate salts have advantageous properties in comparison to the known salts, including the hydrochloride salts. For example, the sulfonate salts have high water solubility and good thermal stability, making them useful in forming a commercial paroxetine dosage form.
  • the U.S. Pat. No.5,874,447 patent discloses that tablets can be made by any known method including a dry technique (direct compression, dry granulation) or a wet technique (wet granulation).
  • the size of a prophylactic or therapeutic dose of paroxetine in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 1 mg to about 90 mg.
  • a daily dose range should be between about 5 mg to about 50 mg.
  • a daily dose range should be between about 10 mg to about 40 mg.
  • a daily dosage of 15, 20, or 30 mg may be preferred depending upon patient response.
  • the therapy may be initiated at a lower dose, perhaps about 4 mg to about 8 mg and increased up to about 10 mg or higher depending-on the patient's global response. It may be necessary to use dosages outside these-ranges in some cases.
  • Sertraline is a serotonin reuptake inhibitor which is marketed as an antidepressant. It is disclosed by U.S. Pat. No.4,536,518. The therapeutic effect of sertraline is attributed to inhibition of CNS neuronal uptake of serotonin. Clinical studies in man indicate that sertraline blocks the uptake of serotonin in human platelets. In addition, in vitro studies indicate that it is a very poor inhibitor of norepinephrine and dopamine neuronal uptake. Sertraline is a naphthaleneamine that is generally marketed as the hydrochloride salt under the brand name ZOLOFT®.
  • Sertraline hydrochloride has the molecular formula C 17 H 17 NCl 2 .HCl and has the chemical name (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride.
  • the preparation of sertraline may be carried using preparatory methods such as those described in Welch, et al. European Patent Application 30,081 and U.S. Pat. No. 4,536,518.
  • the chemical structure of Sertraline hydrochloride is presented below.
  • a prophylactic or therapeutic dose of sertraline in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 1 mg to about 500 mg.
  • a daily dose range should be between about 10 mg to about 200 mg.
  • a daily dose range should be between about 20 mg to about 100 mg.
  • a daily dosage of 30, 50, 70, or 80 mg may be preferred depending upon patient response.
  • the therapy may be initiated at a lower dose, perhaps about 10 mg to about 15 mg and increased up to about 20 mg or higher depending-on the patient's global response. It may be necessary to use dosages outside these ranges in some cases. Additional information for sertraline hydrochloride including product information, dosage amounts, and administration is given in Physicians' Desk Reference, 48th Edition, 1994, pp. 2000-2003.
  • Clomipramine is an antidepressent described in U.S. Pat. No. 3,467,650. In certain instances, clomipramine may be administered in the form of a hydrochloride salt named Anafranil. Clomipramine has the chemical name 3-Chloro-10,11-dihydro-N,N-dimethyl-5H-dibenz[b,f]azepine-5-propanamine. The structure of clominpramine is presented below.
  • the size of a prophylactic or therapeutic dose of clominpramine in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 1 mg to about 300 mg.
  • a daily dose range should be between about 10 mg to about 200 mg.
  • a daily dose range should be between about 25 mg to about 100 mg.
  • a daily dosage of 40, 60, or 80 mg may be preferred depending upon patient response.
  • the therapy may be initiated at a lower dose, perhaps about 5 mg to about 10 mg and increased up to about 20 mg or higher depending-on the patient's global response. It may be necessary to use dosages outside these ranges in some cases.
  • Femoxetine is an antidepressant reported in U.S. Pat. No. 3,912,743.
  • the chemical name for femoxetine is (3R-trans)-3-[4-Methoxyphenoxy)-methyl]-1-methyl-4-phenylpiperidine.
  • femoxetine may be administered in the form of a hydrochloride salt.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. In general, the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 900 mg. Preferably, a daily dose range should be between about 10 mg to about 200 mg.
  • Indalpine is serotonin reuptake inhibitor that may be used to treat depression. Indalpine was disclosed in U.S. Pat. No. 4,064,255. The pharmacological activity is discussed in G. LeFur et al. Life Sci. 1978, 23, 1959 and R. Ashkenazi et al. Brit. J. Pharmacol. 1983, 79, 765 and 915. In certain instances, indalpine can be administered as the monohydrochloride salt. Indalpine has the chemical name 3-[2-(4-Piperidinyl)ethyl]-1H-indole and has the structure presented below.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 900 mg.
  • a daily dose range should be between about 10 mg to about 200 mg.
  • Alaproclate is a serotonin reuptake inhibitor that has the chemical name 2-(4-chlorophenyl)-1,1-dimethyl 2-aminopropanoate. In certain instances, Alaproclate is administered as a hydrochloride salt.
  • the size of a prophylactic or therapeutic dose in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. In general, the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 900 mg. Preferably, a daily dose range should be between about 10 mg to about 200 mg.
  • Cericlamine has the chemical name ( ⁇ )3-(3,4-dichlorophenyl)-2-dimethylamino-2-methylpropan-1-ol.
  • the preparation of cericlamine is described in EP 237 366, J. Chem. Soc. Perkin Trans. I 1996, 1495-1498, and U.S. Pat. No. 6,121,491.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 900 mg.
  • a daily dose range should be between about 10 mg to about 200 mg.
  • Ifoxetine has the chemical name ( ⁇ )-bis-[cis-3-hydroxy-4-(2,3-dimethyl-phenoxy)]-piperidine sulfate.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 900 mg.
  • a daily dose range should be between about 10 mg to about 200 mg.
  • Additional serotonin reuptake inhibitors contemplated for the instant invention include buspirone, clovoxamine, cyanodothiepin, dapoxetine, imipramine, litoxetine, lofepramine, nefazodone, norzimeldine, trazodone, venlafaxine, viqualine, and zimeldine.
  • 5-HT 1 five main subgroups of 5-HT receptors, named 5-HT 1 , 5-HT 2 , 5-HT 3 and 5-HT 4 , were recognized based on receptor binding profiles, the biological activity of the ligands for the receptors, and secondary messenger coupling. Additional research has lead to the identification-of 5-HT 1F , 5-HT 5 , 5-HT 6 and 5-HT 7 receptors.
  • the recognition that different subtypes of 5-HT exist is important for drug design because compounds which selectivity inhibit only one of the 5-HT subtypes may offer reduced side effects compared to a therapeutic agent that broadly inhibits many of the 5-HT subtypes.
  • the 5-HT 2 receptor family is comprised of the 5-HT 2A , 5-HT 2B and 5-HT 2C receptor subtypes.
  • the 5-HT 2C receptor had been termed 5-HT 1C before researchers determined that it is structurally very similar to the 5-HT 2 receptors.
  • the 5-HT 2A , 5-HT 2B and 5-HT 2C receptors are single protein molecules of 458-471 amino acids. Each of the receptors are thought to be linked to the phosphoinositol hydrolysis signal transduction system via the a subunit of the Gq GTP binding protein.
  • the 5-HT 2A receptor is located in the cortex, claustrum and basal ganglia. Biological testing in rodents revealed that stimulation or agonism of 5-HT 2A receptors causes head shaking and may mediate the effects of hallucinogens.
  • 5-HT 2A modulators include compounds that are 5-HT 2A receptor antagonists, which block the activity of agonists and have little to no intrinsic activity on the receptor, and 5-HT 2A inverse agonists, which are compounds that have negative intrinsic activity on the receptor.
  • 5-HT 2A receptor antagonists e.g., ritanserin, have been reported to improve sleep quality.
  • 5-HT 2A receptor antagonists are also useful in treating migraine, depression, and schizophrenia.
  • MDL 100,907 is a potent 5-HT 2A receptor antagonist and thus is useful for treating a variety of conditions.
  • MDL 100,907 has been evaluated for the treatment of various neurological disorders, including schizophrenia. WO 99/56750 and J. Pharm. Exp. Ther. 1996, 277, 968-9881.
  • MDL 100,907 has been shown to exert a tonic inhibitory influence on dopamine efflux in the medial prefrontal cortex. See European Journal of Pharmacology 1995, 273, 273-279.
  • MDL 100,907 is highly selective in its activity at the 5-HT 2A receptor compared to other receptors, and, as such, has reportedly fewer side effects.
  • MDL 100,907 is useful in the treatment of sleep disorders, such as insomnia and obstructive sleep apnea. See U.S. Pat. Nos. 6,277,864 and 6,613,779.
  • MDL 100,907 has the chemical name (+)- ⁇ -(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol and can be prepared as described in U.S. Pat. No. 5,134,149 and WO 91/18602. Compounds that are structurally similar to MDL 100,907 are described in EP 0208235. In addition, the present invention encompasses a composition comprising mixture of MDL 100,907 and its enantiomer. The structure of MDL 100,907 is presented below:
  • the dosage range at which MDL 100,907 exhibits its ability to block the effects of serotonin at the 5-HT 2A receptor can vary depending upon the particular disease or condition being treated and its severity, the patient, the formulation, other underlying disease states that the patient is suffering from, and other medications that may be concurrently administered to the patient.
  • MDL 100,907 will exhibit its serotonin 5-HT 2A antagonist properties at dosages of between about 0.001 mg/kg of patient body weight/day to about 100 mg/kg of patient body weight/day.
  • Sustained release formulations may contain multiples of the foregoing dosages depending upon over what period the active ingredient is released.
  • the dosage of the compounds of the present invention may be determined by administering the compound to an animal and determining the plasma level of the active ingredient.
  • MDL 100,907 it is advantageous to administer MDL 100,907 in the form of a prodrug.
  • a prodrug is a compound that gets converted to the active drug after the compound is administered.
  • Carr and coworkers have described ester derivatives of MDL 100,907 that function as prodrugs for MDL 100,907. See U.S. Pat. Nos. 6,028,083 and 6,063,793.
  • the structure of the ester derivatives of MDL 100,907, as will be referred to as “Pro MDL 100,907” hereafter, is presented below: wherein, R is C 1 -C 20 alkyl.
  • Pro MDL 100,907 also refers to a stereoisomer or pharmaceutically acceptable salt thereof.
  • Pro MDL 100,907 Procedures for the preparation of Pro MDL 100,907 can be found in U.S. Pat. Nos. 6,028,083 and 6,063,793.
  • the dosage range at which Pro MDL 100,907 exhibits its ability to block the effects of serotonin at the 5-HT 2A receptor can vary depending upon the particular disease or condition being treated and its severity, the patient, the formulation, other underlying disease states that the patient is suffering from, and other medications that may be concurrently administered to the patient.
  • Pro MDL 100,907 will exhibit its serotonin 5-HT 2A modulator properties at dosages of between about 0.001 mg/kg of patient body weight/day to about 100 mg/kg of patient body weight/day.
  • Sustained release formulations may contain multiples of the foregoing dosages depending upon over what period the active ingredient is released.
  • the dosage of the compounds of the present invention may be determined by administering the compound to an animal and determining the plasma level of the active ingredient.
  • SR 46349B is a highly selective antagonist of the 5-HT 2A receptor. SR 46349B has virtually no affinity for the 5-HT 1A , 5-HT 1B , and 5-HT 1D receptors, and has a moderate affinity for the 5-HT 2C receptor. In studies on isolated tissues, the absence of activity of SR 46349B on rat stomach fundus indicates a 5-HT 2A specificity versus 5-HT 2B (M. Rinaldi-Carmona et al. J. Pharmacol. Exp. Ther. 1992, 759-768). In rodents, it has been shown that this compound predominantly binds to the regions of the brain containing the 5-HT 2 receptor (M. Rinaldi-Carmona et al.
  • SR 46349B has the chemical name (1Z,2E)-1-(2-fluorophenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one-O-(2-dimethyl-aminoethyl)oxime hemifumarate.
  • SR 46349B can be prepared as described in EP 0373998 B1.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. In general, the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 900 mg. Preferably, a daily dose range should be between about 10 mg to about 200 mg.
  • the structure of SR 46349B is presented below: YM 992
  • YM 992 is an morpholine derivative described in by Takeuchi and coworkers in Eur. J. Pharmacol. 1997, 329, 27-35.
  • the chemical name of YM 992 is (S)-2-[[(7-Fluoro-2,3-dihydro-1H-inden-4-yl)-oxy]methyl]morpholine hydrochloride.
  • the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 900 mg.
  • a daily dose range should be between about 10 mg to about 200 mg.
  • the structure of YM 992 is presented below: Fananserin
  • Fananserin is a 5-HT 2A receptor antagonist described by Doble A. and coworkers in Br. J. Pharmacol. 1992, 105, 27-36.
  • the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 900 mg.
  • a daily dose range should be between about 10 mg to about 200 mg.
  • the structure of fananserin is presented below: Oxazolidine Compounds A
  • WO 98/38189 A series of oxazolidine derivatives that have 5-HT 2A receptor-antagonizing properties are described in WO 98/38189. Methods for preparing the oxazolidine compounds are given in WO 98/38189.
  • the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 900 mg.
  • a daily dose range should be between about 10 mg to about 200 mg.
  • the generic structure of the Oxazolidine Compounds A, as disclosed in WO 98/38189, is presented below. The definitions of the substituents of the generic structure can be found in WO 98/38189 which is hereby incorporated by reference. Phenylindole Compounds A
  • the piperidinyl compound A is N- ⁇ 1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl ⁇ -N-(4-fluorobenzyl)-N′-(4-isobutoxybenzyl)carbamide, hydrochloride; N- ⁇ 1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl ⁇ -N-(4-fluorobenzyl)-2-[4-(2-hydroxy-2-methylpropoxy)phenyl]acetamide, tartrate; N-(4-Fluorobenzyl)-N-(piperidin-4-yl)-2-(4-isobutoxyphenyl)acetamide; N- ⁇ 1-[3-(3,5-Dimethylpiperidin-1-yl)propyl]piperidin-4-yl ⁇ -N-(4-fluorobenzyl)-2-(4-is
  • spiroazacyclic compounds that modulate the 5-HT 2A receptor have been described in U.S. patent application 2003/0166928. Methods for preparing the spiroazacyclic compounds are presented in U.S. patent application 2003/0166928.
  • the total daily dose ranges for the conditions described herein, is from about 1 mg to about 900 mg.
  • a daily dose range should be between about 10 mg to about 200 mg.
  • the generic structure of the spiroazacyclic compounds A as disclosed in U.S. patent application 2003/0166928, is presented below. The definitions of the substituents of the generic structure can be found in U.S. patent application 2003/0166928 which is hereby incorporated by reference.
  • said spiroazacyclic compound of formula C is 1-oxa-4,9-diaza-spiro[5.5]undecan-3-one; 1-oxa-3,8-diaza-spiro[4.5]decan-2-one; 1,3,8-triaza-spiro[4.5]decan-2-one; 1,2,9-triaza-spiro[5.5]undecan-3-one; 1,2,8-triaza-spiro[4.5]decan-3-one; 1,2,8-triaza-spiro[4.5]decan-3-one; 1,2,4,8-tetraaza-spiro[4.5]decan-3-one; 2,4,9-triaza-spiro[-5.5]undecan-3-one; 2,8-diaza-spiro[4.5]decan-3-one; 2-oxa-4,9-diaza-spiro[5.5]undecan-3-one; 1-thia-3,8-diaza-spiro[4.5]-decan-2-one; 1-oxa
  • said azacyclic compound of formula D is N-(1-(1-methylethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide, N-(1-(2,2-dimethylethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide, N-(1-pentylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide, N-(1-hexylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide, N-(1-cyclohexylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide, N-(1-cyclopentylpiperidin-4-yl)-N
  • norepinephrine reuptake inhibitors are norepinephrine reuptake inhibitors, and no doubt many more will be identified in the future. In the practice of the present invention, it is intended to include reuptake inhibitors which can be identified using the protocol described by Wong et al., Drug Development Research, 6, 397 (1985). In certain embodiments, the norepinephrine reuptake inhibitors used in the present invention are characterized in being selective for the inhibition of neurotransmitter reuptake relative to their ability to act as direct agonists or antagonists at other receptors.
  • the ability of compounds to inhibit the reuptake of norepinephrine may be measured by the general procedure of Wong, et al., Drug Development Research, 6, 397 (1985). Male Sprague-Dawley rats weighing 150-250 gm are decapitated and brains are immediately removed. Cerebral cortices are homogenized in 9 volumes of a medium containing 0.32 M sucrose and 10 mM glucose. Crude synaptosomal preparations are isolated after differential centrifugation at 1000 ⁇ g for 10 minutes and 17,000 ⁇ g for 28 minutes. The final pellets are suspended in the same medium and kept in ice until use within the same day.
  • Synaptosomal uptake of 3 H-norepinephrine is determined as follows. Cortical synaptosomes (equivalent to 1 mg of protein) are incubated at 37° C. for 5 minutes in 1 mL Krebs-bicarbonate medium containing also 10 mM glucose, 0.1 mM iproniazide, 1 mM ascorbic acid, 0.17 mM EDTA and 50 mM 3 H-norepinephrine. The reaction mixture is immediately diluted with 2 mL of ice-chilled Krebs-bicarbonate buffer and filtered under vacuum with a cell harvester (Brandel, Gaithersburg, Md.).
  • a suitable dose of a norepinephrine reuptake inhibitor or a pharmaceutically acceptable salt thereof for administration to a human will be in the range of 0.01 to 50 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 3 mg per kilogram body weight per day. Unless otherwise stated all weights of active ingredients are calculated in terms of drug per se.
  • the desired dose is preferably presented as two, three, four, five or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing 5 to 50 mg.
  • Desipramine has the chemical name 10,11-Dihydro-N-methyl-5H-dibenz[b,f]azepine-5-propanamine and is described in U.S. Pat. No. 3,454,554. The pharmacology is described by P. D. Hrdina et al. in Prog. Neuropsychopharmacol. 1980, 4, 591. Desipramine is generally administered as a hydrochloride salt marketed under the name Norpramin. Desipramine hydrochloride occurs as crystals which are soluble in water. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. In general, the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 900 mg. Preferably, a daily dose range should be between about 10 mg to about 200 mg. The structure of desipramine is presented below. Maprotiline
  • Maprotiline has the chemical name N-Methyl-9,10-ethanoanthracene-9(10H)-propanamine and is described in U.S. Pat. No. 3,399,201. The pharmacology is described by R. M. Pinder et al. in Drugs 1977, 13, 321. Maprotiline is generally administered as a hydrochloride salt marketed under the name Ludiomil. Maprotiline hydrochloride occurs as crystals which are slightly soluble in water. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. In general, the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 900 mg. Preferably, a daily dose range should be between about 10 mg to about 200 mg. The structure of maprotiline is presented below. Lofepramine
  • Lofepramine has been found clinically effective against disorders related to the central nervous system, especially mental depressions (B. Siwers et al., Europ. J. Clin. Pharmacol. 1970, 3, 12-17).
  • the synthesis and biological activity of lofepramine was described in British Pat. No. 1,177,525.
  • a preferred method for preparing lofepramine has been reported by E. Eriksoo and O. Rohte in Arzneiffenbachforschung 1970, 20, 1561-1569.
  • this known method presents difficulties of a pronounced nature, especially when used in full-scale production. Thus, slight unintentional variations in the process conditions often result in discoloured products, which are very difficult to purify.
  • An improved procedure for the preparation of lofepramine is described in U.S.
  • Lofepramine has the chemical name 4′-chloro-2- ⁇ [3-(10,11-dihydro-5H-dibenz(b,f)-azepinyl-(5)-propyl]-methylamino ⁇ -acetophenone and the structure is presented below.
  • the size of a prophylactic or therapeutic dose of lofepramine in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 1 mg to about 300 mg.
  • a daily dose range should be between about 10 mg to about 200 mg.
  • a daily dose range should be between about 30 mg to about 120 mg.
  • a daily dosage of 50, 75, or 100 mg may be preferred depending upon patient response.
  • the therapy may be initiated at a lower dose, perhaps about 5 mg to about 10 mg and increased up to about 20 mg or higher depending-on the patient's global response. It may be necessary to use dosages outside these ranges in some cases.
  • Reboxetine is active on the central nervous system and has been used to treat depression, oppositional defiant disorder, attention-deficit/hyperactivity disorder, and conduct disorder. See WO 99/15163, WO 95/15176, and WO 99/15177. Reboxetine does not act like most antidepressants. Reboxetine is ineffective in the 8-OH-DPAT hypothermia test, indicating that reboxetine is not a SSRI. Brian E. Leonard, “Noradrenaline in basic models of depression.” European - Neuropsychopharmacol., 7 Suppl. 1 pp. S 11-6 and S71-3 (April 1997).
  • Reboxetine is a norepinephrine reuptake inhibitor, with only marginal serotonin and no dopamine reuptake inhibitory activity. Reboxetine displays no anticholinergic binding activity in different animal models, and is substantially devoid of monoamine oxidase (MAO) inhibitory activity. Racemic reboxetine exhibits a pharmacological selectivity of serotonin (K i )/norepinephrine (K i ) of about 80.
  • Reboxetine is a safe drug, and its use in ADHD, in both adults and children, is a superior treatment for that disorder because of its improved safety.
  • the compound is particularly selective, having few if any physiological effects besides those on norepinephrine processing, and therefore is free of side effects and unwanted activities. Further, it is effective at relatively low doses, as discussed below, and may safely and effectively be administered once per day. Thus, difficulties created by the multiple dosing of patients, who are children and disorganized adults, are completely avoided.
  • the racemate form of reboxetine is well tolerated and has a wide safety range.
  • the effective dose of reboxetine for ADHD is in the range from about 1 mg/day to about 100 mg/day.
  • the preferred adult dose is in the range from about 5 to about 80 mg/day, and a more highly preferred adult dose is from about 10 to about 60 mg/day.
  • the children's dose of course is smaller, in the range from about 1 to about 70 mg/day, more preferably from about 5 to about 60 mg/day and still more preferably from about 4 to about 10 mg/day.
  • the optimum dose for each patient must be set by the physician in charge of the case, taking into account the patient's size, other medications which the patient requires, severity of the disorder and all of the other circumstances of the patient.
  • Reboxetine was first taught by U.S. Pat. No. 4,229,449 and has the chemical name 2-[ ⁇ -(2-ethoxy)phenoxy-benzyl]morpholine. Reboxetine is also described in U.S. Pat. Nos. 5,068,433; 5,391,735; 6,642,235; and in GB 2,167,407. Individual stereoisomers of reboxetine can be obtained by resolution of the racemic mixture of enantiomers using conventional methods generally known by those skilled in the art. Such methods include, but are not limited to, resolution by simple crystallization and chromatographic techniques, for example, as set forth in GB 2,167,407. The structure of reboxetine is presented below.
  • reboxetine is administered as the racemate.
  • compositions containing an optically pure (S,S) reboxetine are about 5 to about 8.5 times more effective at inhibiting the reuptake of norepinephrine than compositions containing the racemic mixture of the (R,R) and (S,S) stereoisomers.
  • the typical daily dosage of the racemic mixture i.e., commercially available reboxetine
  • the reduction in dosage does not lead to a reduction in efficacy, but the reduction or elimination of various adverse side effects was observed.
  • an optically pure (S,S) reboxetine selectively inhibits norepinephrine reuptake compared to serotonin reuptake
  • adverse side effects associated with serotonin reuptake are reduced or eliminated.
  • adverse side effects include, but are not limited to, gastrointestinal disturbances, anxiety, sexual dysfunction, and undesirable side effects associated with drug-drug interactions.
  • Oxaprotiline has the chemical name ( ⁇ )- ⁇ -[(Methylamino)-methyl]-9,10-ethanoanthracene-9(10H)-ethanol. (CAS registry number: 56433-44-4). Oxaprotiline is a promosing therapeutic agent for the treatment of depression. In an experiment where 24 patients (37 trials) with major depression where treated with oxaprotiline over 3 weeks, the-patients had a significant reduction in their Hamilton Scores. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. In general, the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 900 mg. Preferably, a daily dose range should be between about 10 mg to about 200 mg.
  • Fezolamine has the chemical name N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine-(E)-2-butenedioate (CAS registry number: 80410-36-2) and shows antidepressant activity.
  • the therapeutic affect of fezolamine is attributed to its ability to inhibit norepinephrine reuptake.
  • fezolamine was 3 to 4 fold more selective in blocking synaptosomal uptake of norepinephrine compared to serotonin or dopamine in in vitro assays. See E. R. Baizman et al. J. Pharmacol. Exp. Ther. 1987 243, 40-54.
  • the total daily dose ranges for the conditions described herein, is from about 1 mg to about 900 mg.
  • a daily dose range should be between about 10 mg to about 200 mg.
  • Tomoxetine is a notably safe drug for use in adults and children for treatment of attention deficit hyperactivity disorder. It is a superior treatment for that disorder because of its improved safety. Tomoxetine is effective at relatively low doses and may safely and effectively be administered once per day. In addition, the results from animal studies indicate that tomoxetine selectively inhibits norepinephrine uptake indicating that tomoxetine would be useful in treating depression. Tomoxetine has been administered in single oral doses up to 90 mg to humans. In addition, no serious drug-related adverse effects were observed when tomoxetine was administered to humans at a dosage of 20 or 40 mg b.i.d. for 7 days.
  • Tomoxetine has the chemical name (R)-( ⁇ )-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine.
  • the mechanism of tomoxetine's activity is attributed to its ability to inhibit norepinephrine reuptake. See Gehlert, et al. Neuroscience Letters 1993, 157, 203-06.
  • Tomoxetine is quite active in that function, and moreover is substantially free of other central nervous system activities at the concentrations or doses at which it effectively inhibits norepinephrine reuptake. Thus, it is quite free of side effects and is properly considered to be a selective drug.
  • Tomoxetine is usually administered as the hydrochloride salt.
  • the effective dose of tomoxetine for ADHD is in the range from about 5 mg/day to about 100 mg/day.
  • the preferred adult dose is in the range from about 10 to about 80 mg/day, and a more highly preferred adult dose is from about 20 to about 60 mg/day.
  • the children's dose of course is smaller, in the range from about 5 to about 70 mg/day, more preferably from about 10 to about 60 mg/day and still more preferably from about 10 to about 50 mg/day.
  • the optimum dose for each patient must be set by the physician in charge of the case, taking into account the patient's size, other medications which the patient requires, severity of the disorder and all of the other circumstances of the patient.
  • tomoxetine Since tomoxetine is readily orally absorbed and requires only once/day administration, there is little or no reason to administer it in any other way than orally. It may be produced in the form of a clean, stable crystal, and thus is easily formulated in the usual oral pharmaceutical forms, such as tablets, capsules, suspensions, and the like. The usual methods of pharmaceutical scientists are applicable. It may usefully be administered, if there is any reason to do so in a particular circumstance, in other pharmaceutical forms, such as injectable solutions, depot injections, suppositories and the like, which are well known to and understood by pharmaceutical scientists. It will substantially always be preferred, however, to administer tomoxetine as a tablet or capsule and such pharmaceutical forms are recommended.
  • (S,S)-hydroxybupropion is a metabolite of bupropion that selectively inhibits norepinephrine reuptake and does not significantly inhibit dopamine reuptake. Methods for the preparation of (S,S)-hydroxybupropion are described in U.S. Pat. No. 6,342,496.
  • (S,S)-hydroxybupropion has the chemical name (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-moipholinol and the structure is given below.
  • the present invention contemplates the use of norepinephrine reuptake inhibitors in general, including nortriptyline, maprotiline, protriptyline, trimipramine, venlafaxine, amitriptyline, amoxapine, doxepin, nefazodone, and lamotrigine.
  • Dopamine reuptake inhibitors can be identified using the rat corpus striatum assay described in U.S. patent application 20040180857, which is hereby incorporated by reference.
  • a dose of a dopamine reuptake inhibitor or a pharmaceutically acceptable salt thereof suitable for administration to a human will be in the range of 0.01 to 50 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 3 mg per kilogram body weight per day. Unless otherwise stated all weights of active ingredients are calculated in terms of drug per se.
  • the desired dose is presented as two, three, four, five or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing about 5 to 50 mg.
  • Amineptine is a synthetic, atypical tricyclic antidepressant with central nervous system stimulating effects. It has the chemical name of 7-[(10,11-dihydro-5H-dibenzo[a,d]-cycloheptene-5-yl)amino]heptanoic acid and is available as either the free base (CAS registry number 575746-09-1; shown below) or the hydrochloride salt (CAS registry number 302724-08-3). It is also known as S-1694, Maneon and Survector. Preparation of amineptine is described in U.S. Pat. No. 3,758,528 and No. 3,821,249.
  • Amineptine is an indirect dopamine agonist, selectively inhibiting dopamine uptake and inducing dopamine release, with additional stimulation of the adrenergic system. Its antidepressant effects are similar to other tricyclic antidepressant drugs but it has a more rapid action, is better tolerated and has little cardiovascular, analgesic or anorectic effects. It produces a similar spectrum of pharmacological effects to psychomotor stimulants in Schedule II of the 1971 Convention on Psychotropic Substances. Recently, the use of amineptine in the treatment of depression has been described by S. M. Channabasavanna et al. in Indian Journal of Psychiatry 1997, 39, 147-53.
  • Bupropion is marketed under the tradename WELLBUTRIN® by GlaxoSmithKline for the treatment of depression. In certain instances, bupropion is administered as its hydrochloride salt.
  • WELLBUTRIN® (bupropion hydrochloride), is an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines.
  • Bupropion is a novel, non-tricyclic antidepressant with a primary pharmacological action of monoamine uptake inhibition.
  • the drug resembles a psychostimulant in terms of its neurochemical and behavioural profiles in vivo, but it does not reliably produce stimulant-like effects in humans at clinically prescribed doses.
  • Bupropion binds with modest selectivity to the dopamine transporter, but its behavioural effects have often been attributed to its inhibition of norepinephrine uptake.
  • Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine, serotonin, and dopamine, and does not inhibit monoamine oxidase. Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behavior tasks, and, at high doses, induction of mild stereotyped behavior.
  • CNS central nervous system
  • peak plasma bupropion concentrations are usually achieved 5 within 2 hours, followed by a biphasic decline.
  • the terminal phase has a mean half-life of 14 hours, with a range of 8 to 24 hours.
  • the distribution phase has a mean half-life of 3 to 4 hours.
  • the mean elimination half-life ( ⁇ SD) of bupropion after chronic dosing is 21 ( ⁇ 9) hours, and steady-state plasma concentrations of bupropion are reached within 8 days.
  • GBR-12935 is a dopamine reuptake inhibitor described by A. R. Burkeyl and coworkers in J. of Neuroscience 1999, 19, 4169-4179. Its chemical name is 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride.
  • Venlafaxine is dopamine reuptake inhibitor. Its hydrochloride salt is marketed under the tradename EFFEXOR® and used in the treatment of bipolar disorder. It has the chemical names ( ⁇ )-1-[2-(dimethylamino)-1-(4-methyoxyphenyl)ethyl]cyclohexanol; N,N-dimethyl-2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethylaminel and venlafexine. Its prepration is described in U.S. Pat. No. 4,535,186. A review of its pharmacology and clinical efficacy can be found in the Journal of Clinical Psychiatry (Montgomery, S. A. J. Clin. Psychiatry 1993, 54, 119-126.)
  • Venlafaxine is a representative of a new class of antidepressants (SNRIs) which inhibit selectively the uptake of serotonin and noradrenaline, but—in contrast to tricyclics—show no affinity for neurotransmitter receptors.
  • SNRIs antidepressants
  • Sedative Agent GABA Receptor Modulating Agents
  • GABA ⁇ -Aminobutyric acid
  • Receptors for GABA have traditionally been divided into GABA A and GABA B receptor subtypes.
  • the GABA A receptor is the more prominent GABA receptor subtype, and is a ligand-gated chloride ion channel that is opened after release of GABA from presynaptic neurons.
  • the GABA B receptor is a member of the G protein-coupled receptor family coupled both to biochemical pathways and to regulation of ion channels. See Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y., 9 th Edition, (1996) and Kerr, D. I. B. and Ong, J. Pharmac. Ther. 1995, 67, 187-246.
  • GABA By gating negative chloride ions into the interior of cells, GABA inhibits the presynaptic release of neurotransmitter due to a positive voltage polarization pulse. This form of inhibition is extremely common.
  • GABA receptors can be found in 60-80% of central nervous system neurons. Subtypes of GABA receptors can be activated by the mushroom toxin muscimol (at GABA A ) as well as the antispasmodic amino acid baclofen (GABA B ). These compounds directly mimic the action of GABA at the receptor. Allosteric facilitation of GABA receptors occurs at several distinct sites; compounds that bind there are used as sedatives and anxiolytics.
  • a characteristic property of GABA A receptors is the presence of a number of modulatory sites, one of which is the benzodiazepine (BZ) binding site.
  • the BZ binding site is the most explored of the GABA A -receptor modulatory sites, and is the site through which anxiolytic drugs such as temazepam exert their effect.
  • the benzodiazepine binding site was historically subdivided into two subtypes, BZ1 and BZ2, on the basis of radioligand binding studies.
  • the BZ1 subtype has been shown to be pharmacologically equivalent to a GABA A -receptor comprising the ⁇ 1-subunit in combination with a ⁇ -subunit and ⁇ 2. This is the most abundant GABA A -receptor subtype, and is believed to represent almost half of all GABA A receptors in the brain.
  • a dose of the GABA-receptor modulating agent or a pharmaceutically acceptable salt thereof suitable for administration to a human will be in the range of 0.01 to 50 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 3 mg per kilogram body weight per day. Unless otherwise stated all weights of active ingredients are calculated in terms of drug per se.
  • the desired dose is presented as two, three, four, five or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing about 5 to 50 mg.
  • the affinity of a compound to bind to a GABA receptor can be measured using procedures known in the art.
  • assay kits for determining GABA-receptor binding affinity can be purchased from MDS Pharma Services.
  • procedures to determine GABA-receptor binding affinity see Enna, S. J.; Snyder, S. H. Mol. Pharmacol. 1976, 13, 442; C. Martini et al. J. Neurochem. 1983, 41, 1183; Lewin, A. H. et al. Mol. Pharmacol. 1989, 35, 189; Schwartz, R. D.; Mindlin, M. C. J. Pharmacol. Exp. Ther. 1988, 244, 963; Facklam, M.; Bowery, N. G. Br. J.
  • the affinity of a compound at GABA A -receptor subtypes can be measured by competition for [ 3 H]flumazenil (85 Ci/mmol; Amersham) binding to SF9 cells expressing rat receptors of composition ⁇ 1 ⁇ 3 ⁇ 2, ⁇ 2 ⁇ 3 ⁇ 2, ⁇ 3 ⁇ 3 ⁇ 2 and ⁇ 5 ⁇ 3 ⁇ 2 .
  • Krebs-tris buffer 4.8 mM KCl, 1.2 mM CaCl 2 , 1.2 mM MgCl 2 , 120 mM NaCl, 15 mM Tris; pH 7.5; binding assay buffer
  • Radioligand binding assays are carried out in a volume of 200 ⁇ L (96-well plates) which contained 100 ⁇ L of cells, [ 3 H]flumazenil at a concentration of 1 nM for ⁇ 1 ⁇ 2 ⁇ 3 subunits and 0.5 nM for ⁇ 5 subunits and the test compound in the range of 10 ⁇ 10 to 3 ⁇ 10 ⁇ 6 M. In certain instances, nonspecific binding is defined by 10 ⁇ 5 M diazepam.
  • Assays are incubated to equilibrium for 1 hour at 4° C. and harvested onto GF/C uni-filters (Packard) by filtration using a Packard harvester and washing with ice-cold wash buffer (50 mM Tris; pH 7.5). After drying, filter-retained radioactivity was detected by liquid scintillation counting. K i values are calculated using Excel-Fit (Microsoft) and are the means of two determinations.
  • a large number of compounds are known to bind to the GABA receptor and modulate the activity of the receptor. Modulation of the GABA receptor can be agonistic or antagonistic. The compound can bind to any part of the GABA receptor sufficient to modulate the activity of the receptor. In certain instances, the GABA-receptor modulating compound binds to a GABA A receptor. In certain instances, the GABA-receptor modulating compound binds to a GABA B receptor. In certain embodiments, the GABA-receptor modulating compound has a K i of less than about 750 nM in a GABA-receptor binding assay.
  • the GABA-receptor modulating compound has a K i of less than about 500 nM in a GABA-receptor binding assay. In certain embodiments, the GABA-receptor modulating compound has a K i of less than about 250 nM in a GABA-receptor binding assay. In certain embodiments, the GABA-receptor modulating compound has a K i of less than about 100 nM in a GABA-receptor binding assay. In certain embodiments, the GABA-receptor modulating compound has a K i of less than about 75 nM in a GABA-receptor binding assay.
  • the GABA-receptor modulating compound has a K i of less than about 50 nM in a GABA-receptor binding assay. In certain embodiments, the GABA-receptor modulating compound has a K i of less than about 25 nM in a GABA-receptor binding assay. In certain embodiments, the GABA-receptor modulating compound has a K i of less than about 15 nM in a GABA-receptor binding assay. In certain embodiments, said GABA-receptor binding assay is a GABA A -receptor binding assay. In certain embodiments, said GABA-receptor binding assay is a GABA A -agonist receptor binding assay.
  • said GABA-receptor binding assay is a GABA A -antagonist receptor binding assay. In certain embodiments, said GABA-receptor binding assay is a GABA A -benzodiazepine receptor binding assay. In certain embodiments, said GABA-receptor binding assay is a GABA B -receptor binding assay. In certain embodiments, said GABA-receptor binding assay is a GABA B -agonist receptor binding assay.
  • GABA analogs with pharmaceutical activity have been synthesized and described in U.S. Pat. Nos. 4,024,175; 5,563,175; 6,020,370; 6,028,214; 6,103,932; and 6,117,906; and International Patent Applications WO 92/09560, WO 93/23383, WO 97/29101, WO 97/33858, WO 97/33859, WO 98/17627, WO 99/08671, WO 99/21824, WO 99/31057, WO 99/31074, WO 99/31075, WO 99/61424, WO 00/15611, WO 00/31020, and WO 00/50027, each of which is hereby incorporated by reference.
  • GABA B receptor agonists are disclosed in EP 0356128; EP 0181833, EP 0399949, EP 0463969
  • Zopiclone is the first of a chemically distinct class of hypnotic and anxiolytic compounds that offers a psychotherapeutic profile of efficacy and side effects similar to the benzodiazepines. This class of compounds, the cyclopyrrolones, appears to cause less residual sedation and slowing of reaction times than the benzodiazepines, and it offers the promise of an improved therapeutic index over benzodiazepines.
  • zopiclone The pharmacology of zopiclone has been shown both preclinically and clinically to be characterized by five distinct elements. It is predominantly a hypnotic-sedative, offering significant activity on first treatment in the absence of respiratory or cardiac depression. Additionally, zopiclone is an anticonvulsant, and it further exhibits muscle relaxant, anti-aggressive, and anxiolytic activities.
  • the compound binds to the benzodiazepine receptor complex, or to a site linked closely to this receptor complex.
  • benzodiazepine receptor complex See Goa, K. L. and Heel, R. C. Drugs, 32:48-65, (1986); Brun, J. P., Pharmacology, Biochemistry and Behavior, 29:831-832, (1988); Julou, L. et al., Pharmacology, Biochemistry and Behavior, 23:653-659, (1985); Verma, A. and Snyder S. H., Annu. Rev. Pharmacol. Toxicol, 29:307-322, (1989).
  • the central benzodiazepine receptor is a macromolecular complex that includes a site for the binding of gamma-aminobutyric acid (GABA), the inhibitory neurotransmitter, suggesting that benzodiazepines and chemically unrelated agonists including zopiclone may exert their effects by facilitating the synaptic effects of GABA. While it interacts with the benzodiazepine receptor, zopiclone apparently has minimal effects on memory, no interaction with alcohol, and little or no abuse or dependence potential.
  • GABA gamma-aminobutyric acid
  • the pharmacologic activity of zopiclone is predominantly that of a sedative or hypnotic, particularly at low doses. Accordingly, the drug may improve sleep in adults and geriatric patients with several types of sleep disorders, and situational, transient, primary, and secondary insomnia. Following a bedtime dose of zopiclone, there is minimal impairment of psychomotor skills and mental acuity the following morning. The drug is well absorbed from the stomach, and it is not highly bound to plasma proteins.
  • racemic mixture of zopiclone is presently used outside the United States primarily as an hypnotic, improving sleep patterns in chronic insomniacs and providing sleep induction before surgical procedures in hospitalized patients.
  • Insomnia is characterized by difficulty in sleeping or disturbed sleep patterns. Insomnia may be of a primary nature with little apparent relationship to immediate somatic or psychic events, or secondary to some acquired pain, anxiety or depression. Where possible, treatment is directed to the underlying cause of the condition; hypnotic medication such as zopiclone is generally reserved for insomnia of emotional disturbances and for refractory cases due to more common causes. In these cases, zopiclone provides sedative-hypnotic effects from the first day of-treatment, an activity that is maintained following subsequent doses over long treatment periods. There appears to be no diminution or potentiation of activity in adult or geriatric patients, and little or no effect on alertness and performance some ten hours following the bedtime dose. (Brun, J. P. Pharmacology, Biochemistry and Behavior 1988, 29, 831-832).
  • racemic mixture of zopiclone may be useful in treating other disorders such as convulsive states like epilepsy.
  • Seizure disorder or epilepsy represents a broad group of central nervous system disorders of function that are characterized by recurrent, sudden, often brief attacks, which may alter consciousness, motor activity, sensory phenomena, and autonomic responses, and which may prompt inappropriate behavior.
  • Recurrent seizure patterns of either an idiopathic or symptomatic etiology are termed epilepsy.
  • the most common form of these recurrent but transient episodes are convulsive seizures, which may include loss of consciousness, motor function and control, and which may produce tonic or clonic jerking of the extremities.
  • benzodiazepine receptors which can be located both within the central nervous system and peripherally (e.g., in the endocrine system), are comprised of macromolecular complexes characterized by sites for binding of the benzodiazepines, GABA, and zopiclone.
  • the benzodiazepine receptor complex is further associated with, and interacts with, a transmembrane channel for chloride ion transport.
  • zopiclone The effect of zopiclone's interaction with the benzodiazepine receptor/GABA receptor/chloride channel complex is to cause GABA to inhibit cerebral neuronal discharge, presumably by increasing membrane conductance of chloride ion, thus stabilizing membrane potentials and dampening excitatory input. (See Meldrum, B. S., Brit. J. Clin. Pharm., 27 (suppl. 1): 3S-11S, (1989)). It is believed that through mediation of this process zopiclone may be useful in treating epilepsy and a number of other conditions in which GABA is believed to exert a physiologic role.
  • racemic mixture of zopiclone may be useful in the treatment of the above-described disorders, it has a low therapeutic index and also causes adverse effects. These adverse effects include, but are not limited to, the development of a bitter taste due to the salivary secretion of the drug, dry mouth, drowsiness, morning tiredness, headache, dizziness, impairment of psychomotor skills and related effects.
  • Eszopiclone (or (+)-Zopiclone or (S)-zopiclone) is a potent drug useful for the treatment of sleep disorders, convulsive disorders, and disorders that are affected by the binding of agonists to central nervous system or peripheral benzodiazepine receptors.
  • Administration of isomerically pure or substantially isomerically pure (e.g., 90%, 95%, or 99% isomeric purity) (+)-zopiclone is generally preferred because this isomer possesses potent activity in treating sleep disorders while avoiding adverse effects including but not limited to drowsiness, next day effects, such as tiredness in the morning, inability to concentrate and headache.
  • Eszopiclone is a cyclopyrrolone that has the chemical name (+) 6-(5-chloro-pyri-2-dyl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3-4b]pyrazin or (+) 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate.
  • the chemical structure of zopiclone is shown below:
  • Eszopiclone is an optical isomer, the (+)-isomer, of the compound zopiclone, which is described in U.S. Pat. Nos. 6,319,926 and 6,444,673, and in Goa and Heel, [Drugs, 32:48-65 (1986)] and in U.S. Pat. Nos. 3,862,149 and 4,220,646.
  • This isomer which will hereinafter be referred to as eszopiclone, includes optically pure and the substantially optically pure (e.g., 90%, 95% or 99% optical purity) (+)-zopiclone isomer.
  • Racemic zopiclone is commercially available and can be made using various methods, such as those disclosed in U.S. Pat. Nos. 3,862,149 and 4,220,646.
  • Eszopiclone may be prepared from racemic zopiclone using standard methods, such as chiral-phase chromatography, resolution of an optically active salt, stereoselective enzymatic catalysis by means of an appropriate microorganism, or asymmetric synthesis.
  • U.S. Pat. No. 6,319,926 discloses methods for making eszopiclone, including resolution from racemic zopiclone by means of an optically active acid, such as D(+)-O,O′-dibenzoyltartaric acid.
  • Another method for making eszopiclone is by synthesis from racemic zopiclone (or (RS)-zopiclone) by chemical resolution via the D-malate salt as shown in the following synthesis schematic.
  • (RS)-Zopiclone and D-malic acid are dissolved in a mixture of acetone and methanol to form (S)-zopiclone D-malate and (R)-zopiclone D-malate.
  • the two diastereomeric salts are resolved in-situ by selective crystallization, filtration and rinsing to produce highly (S)-enriched zopiclone D-malate salt.
  • the majority of (R)-zopiclone D-malate remains in the mother liquors.
  • this stage of the process may also include cooling the reaction mixture during the isolation step to a temperature in the inclusive range of about 10° C. to 15° C., and washing or rinsing the wet cake obtained after filtration with cold solvent, such as cold methanol.
  • the resulting (S)-zopiclone D-malate salt is converted to optically pure eszopiclone free base by treatment with aqueous potassium carbonate and ethyl acetate, followed by phase separation and crystallization.
  • additional enantiomeric enrichment typically 1 to 4%) can be achieved by crystallization from ethyl acetate of low water content.
  • the water content can be controlled, e.g., by azeotropic distillation, and incorporating an in-process control of water content into the crystallization process can further improve the robustness of enantiomeric purity.
  • the water level during this step is 2% or less, more preferably 1% or less, and most preferably 0.6% or less.
  • the resulting optically pure eszopiclone free base can then be milled to a desired size for use as an active ingredient in a pharmaceutical composition according to or for use in methods of the present invention.
  • This two-stage process is depicted in the diagrams of FIGS. 1 and 2 .
  • Eszopiclone possess potent activity in treating sleep disorders such as insomnia. Eszopiclone also possess potent activity in treating sleep disorders while avoiding the usual adverse effects including but not limited to drowsiness, next day effects tiredness in the morning, inability to concentrate and headache, which are associated with the administration of the racemic mixture of zopiclone. Eszopiclone also possess potent activity in treating convulsive disorders such as epilepsy while avoiding the adverse effects which are associated with the administration of the racemic mixture of zopiclone.
  • compositions containing optically pure eszopiclone are useful in treating disorders that are affected by the binding of agonists to central nervous system and peripheral benzodiazepine receptors.
  • disorders include but are not limited to aggressive behavior, muscle tension, behavioral disorders, depression, schizophrenia, and disorders associated with abnormal plasma hormone levels such as endocrine disorders.
  • compositions are useful in treating disorders that are affected by the binding of agonists to central nervous system and peripheral benzodiazepine receptors.
  • the size of a prophylactic or therapeutic dose of eszopiclone in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 0.25 mg to about 15 mg.
  • a daily dose range should be between about 0.5 mg to about 10 mg.
  • a daily dose range should be between about 1.0 mg to about 5.0 mg.
  • the therapy may be initiated at a lower dose, perhaps about 0.5 mg to about 3 mg and increased up to about 5 mg or higher depending-on the patient's global response. It is further recommended that children and patients over 65 years, and those with impaired renal or hepatic function, initially receive low doses, and that they be titrated based on global response and blood level. It may be necessary to use dosages outside these ranges in some cases.
  • a suitable dosage range for use is from about 0.25 mg to about 15.0 mg with, in the usual case, the lower doses serving more common insomnia, and the higher doses, presented in divided dosing, reserved for control of psychiatric disorders.
  • a dose range of between about 0.5 mg to about 10 mg is given as a once daily administration or in divided doses if required; most preferably, a dose range of from about 1.0 mg to about 5 mg is given, either as a once daily administration or in divided doses if required.
  • Patients may be upward titrated from below to within this dose range to a satisfactory control of symptoms as appropriate.
  • each agent that is capable of inhibiting by 50% (the ID 50 or ED 50 ) an induced response in rodents, for example, provides the basis for comparison.
  • pentylenetetrazole-induced convulsions, picrotoxin convulsions, and electrically-induced convulsions can be used to demonstrate the anti-convulsant activity of zopiclone (Haefely, W., Psychotropic Agents, eds. Hofmeister, F. and Stille, G., Springer Verlag, Berlin, Part 11, 12-262, (1981)).
  • Indiplon is a potent sedative, anxiolytic and anti-convulsant agent, and possesses an improved profile of side effects, as compared to other benzodiazepine agents.
  • Indiplon shows a reduced tolerance to sedation, a lowered potential for abuse and a reduced tendency to potentiate the deleterious effects of ethanol.
  • Indiplon appears to be substantially devoid of next-day hangover effects and to have a considerably reduced amnesic potential compared to currently marketed sedative-hypnotic agents.
  • the half-life of indiplon in vivio is approximately 1.3 hours.
  • Indiplon occurs as an off-white to yellow, non-free flowing powder with little static charge.
  • Indiplon may be prepared using chemical synthesis techniques known to those skilled in this field. For example, Indiplon may generally be made by the synthetic procedures disclosed in U.S. Pat. Nos. 4,521,422 and 4,900,836. These patents, particularly U.S. Pat. No. 4,521,422, disclose a genus encompassing certain aryl and heteroaryl[7-(aryl and heteroaryl)-pyrazolo[1,5-a]pyrimidin-3-yl]methanones.
  • the size of a prophylactic or therapeutic dose of Indiplon in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 1 mg to about 75 mg.
  • a daily dose range should be between about 5 mg to about 50 mg.
  • a daily dose range should be between about 10 mg to about 35 mg.
  • the daily dose range should be about 10, 25, 30, or 35 mg.
  • the therapy may be initiated at a lower dose, perhaps about 2 mg to about 5 mg and increased up to about 10 mg or higher depending-on the patient's global response.
  • the mean plasma half-life of a sedative-hypnotic compound may be determined using well known techniques. Terminal half-life may be determined using standard pharmacokinetic calculations, such as those presented by Rolland and Tozer (Clinical Pharmacokinetics Concepts and Applications, 3 rd Ed., Chap. 3, 1995). in addition, software is commercially available which performs this calculation, such as the product sold under the tradename “WinNinlinTM” (Prof. Ver. 1.5).
  • a sedative-hypnotic effect of a compound may be readily established using, for example, standard tests that monitor the effects of a drug on motor activity, muscle relaxation and motor coordination (see, e.g., Beer et al., CNS Drug Reviews 3:207-224, 1997; Sanger et al., Eur. J. Pharmacol. 313:35-42, 1996, and references cited therein).
  • a sedative-hypnotic compound should have a statistically significant sedative effect within at least one, and preferably all, of the following assays: (a) assays to detect a reduction in locomotor activity, as described by Sanger et al., European J Pharmacol.
  • Zolpidem is a hypnotic agent that is known to induce or maintain sleep.
  • Zolpidem is an imidazopyridine having IUPAC chemical nomenclature N,N,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-s]pyridine-3-acetamide. The structure of zolpidem is presented below.
  • zolpidem free base was disclosed generically in EP 50563 of Synthelabo.
  • Zolpidem tartrate was subsequently disclosed in EP 251859 (U.S. Pat. No. 4,794,185). More recently, zolpidem has been suggested as useful in treating Parkinson's disease, parkinsonian symptoms, obsessive-compulsive disorder and certain forms of dementia in U.S. Pat. No. 5,891,891.
  • Zolpidem has been marketed as an immediate release tablet for oral application under the trade marks AMBIEN® and STILNOX®.
  • zolpidem is present as a salt with L(+)tartaric acid wherein the molar ratio of zolpidem to tartaric acid is 2:1.
  • This salt is conventionally called zolpidem hemitartrate but a more correct denomination thereof, which will be used hereinafter, is zolpidem tartrate.
  • zolpidem tartrate is characterized as a white or almost white crystalline powder, hygroscopic, slightly soluble in water, sparingly soluble in methanol, and practically insoluble in methylene chloride.
  • Commercially available zolpidem tablets are conventional film coated tablets for immediate release of the active substance after ingestion and they contain 5 or 10 mg of zolpidem tartrate.
  • the inactive ingredients are: lactose, microcrystalline cellulose, sodium starch glycolate, hydroxypropylmethylcellulose and magnesium stearate.
  • the film coating layer consists of hydroxypropylmethylcellulose, polyethylene glycol and colorants.
  • Zolpidem is generally administrated orally by means of a tablet or other solid dosage form. Indeed pharmacokinetic and pharmacodynamic data show that zolpidem has both a rapid absorption and onset of hypnotic action. Its bioavailability is 70% following oral administration and demonstrates linear kinetics in the therapeutical dose range, which lies between 5 and 10 mg in conventional forms, peak plasma concentration is reached at between 0.5 and 3 hours, the elimination half-life is short, with a mean of 2.4 hours and a duration of action of up to 6 hours. Generally, the dosage of zolpidem is between 1 and 50 mg.
  • the pharmacological effect of the zolpidem can be evaluated using the biological assays described in U.S. Pat. No. 4,382,938.
  • the toxicity of a compound can be determined on mice by intraperitoneal administration using LD 50 ranges from 500 to 1,000 mg/kg.
  • the anxiolytic activity can be determined according to the eating test (R. J. Stephens, (1973), Brit. J. Pharmac., 49, 146 P). In this test, the doses which increases the food consumption of the mice vary from 0.1 to 10 mg/kg, administered intraperitoneally.
  • the activity of the compounds in the area of cerebral circulation can be determined in the test for the hypoxia caused by pressure reduction.
  • Mice of the CD1 strain are kept in an oxygen-depleted atmosphere produced by creating a partial vacuum (190 mm of mercury, corresponding to 5.25% of oxygen).
  • the survival time of the animals is noted. This time is increased by agents which are capable of assisting the oxygenation of tissues and in particular of the brain.
  • the compounds studied are administered intraperitoneally in several doses, 10 minutes before the experiment. The percentage increases in the survival time, relative to the values obtained for control animals, are calculated.
  • the mean active dose (MAD) that is to say the dose which increases the survival time by 100%, is determined graphically.
  • the anticonvulsant activity can be determined in accordance with the test for the antagonism towards the mortality induced by bicuculline in mice (P. Worms, H. Depoortere and K. G. Lloyd, (1979) Life Sci., 25, 607-614).
  • the products to be studied are injected intraperitoneally, 30 minutes before the bicuculline (0.9 mg/kg, administered intravenously). With death being the criterion selected for this test, the percentage mortalities are noted for each batch, 2 hours after administration of the bicuculline (control batch: 100% mortality).
  • the 50% active dose is determined graphically.
  • the sedative or hypnotic activity can be determined by observing the action of the compounds on the EEG of curarised rats and also on the wake-sleep states in freely moving, implanted rats and cats (H. Depoortere, Rev. E. E. G. Neurophysiol., (1980) 10, 3, 207-214; L. M. Da Costa, H. Depoortere and R. Naquet, Rev. E. E. G. Neurophysiol., (1977), 7, 2, 158-164).
  • the products to be studied are injected intraperitoneally or orally at doses increasing from 0.1 to 30 mg/kg.
  • the products to be studied were injected intraperitoneally or orally at a single dose ranging from 1 to 10 mg/kg.
  • the products to be studied were injected intraperitoneally or orally at a single dose of 10 mg/kg.
  • results of these various tests can be used to determine the anti-anoxic, sleep-inducing, hypnotic and anticonvulsant properties of a pharmaceutical composition.
  • Zaleplon (Wyeth-Ayerst), also known as “Sonata”, is a nonbenzodiazipine recently approved by the FDA as sedative-hypnotic (see U.S. Pat. No. 4,626,538).
  • Zaleplon is a pyrazolopyrimidine that has the chemical name N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide.
  • Zaleplon is a white powder that has very low solubility in water and limited solubility in alcohol or propylene glycol. The structure of Zaleplon is given below.
  • Zaleplon binds to the gamma-aminobutyric acid benzodiazepine (GABA-BZ) receptor complex. Binding studies have revealed that Zaleplon binds selectively to the brain omega-I receptor located on alpha subunit of the GABA A /chloride ion channel receptor complex. This interaction modulates the binding of t-butylbicyclophosphorothionate binding. Importantly, the pharmacological properties of benzodiazepines, e.g. sedative, anxiolytic, muscle relaxant, and anticonvulsive effects in animals, are linked to modulation of the GABA-BZ receptor chloride channel complex.
  • GABA-BZ gamma-aminobutyric acid benzodiazepine
  • Zaleplon The pharmacokinetic profile of Zaleplon has been investigated in trials using a 60 mg single dose and once-daily administration of a 15 or 30 mg dose for up to 10 days. The data indicate that pharmacokinetics are proportional to the dose throughout the therapeutic range.
  • Zaleplon does not accumulate in once-daily administration treatment regimes. Zaleplon is rapidly absorbed when administered orally; however, Zaleplon is subject to substantial presystemic metabolism resulting in only 30% bioavailability. The majority of the metabolism is attributed to an aldehyde oxidase which converts Zaleplon to 5-oxo-Zaleplon. Consequently, peak plasma concentrations following oral administration typically occur 1 hour after administration.
  • the size of a prophylactic or therapeutic dose of Zaleplon in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 1 mg to about 50 mg.
  • a daily dose range should be between about 1 mg to about 25 mg.
  • a daily dose range should be between about 5 mg to about 20 mg.
  • the daily dose range should be about 5, 10, 15, or 20 mg.
  • the therapy may be initiated at a lower dose, perhaps about 2 mg to about 5 mg and increased up to about 10 mg or higher depending-on the patient's global response.
  • Zaleplon should be taken just prior to bedtime or immediately if a patient the patient has already gone to bed is having diffuculty falling asleep.
  • the dose of Zaleplon should be adjusted in accord with diet or special needs of the patient.
  • the dosage of Zaleplon should be approximately 5 mg for elderly or debilitated patients whom are likely to be particularly sensitive to hypnotic medications.
  • patients suffering from mild to moderate hepatic impairment should be administered only a 5 mg dose because systemic removal of drug is reduced in such patients.
  • Gaboxadol is a GABA-receptor agonist that has been shown to improve sleep-quality in both human and animal studies. Procedures for the preparation of gaboxadol have been described. U.S. Pat. No. 4,278,676; and P. Krogsgaard-Larsen, Acta. Chem. Scand. 1977, 31, 584.
  • Gaboxadol also known as THIP, is a crystalline, colorless solid that is soluble in water and methanol.
  • the chemical name for gaboxadol is 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol.
  • Gaboxadol is known to exist in two isomeric forms (Form A and Form B, shown below) and the term “gaboxadol” as used herein encompasses both forms separately, a mixture comprising both isomeric forms, and the pharmaceutically acceptable salts of any of them.
  • gaboxadol The GABA-receptor binding affinity and pharmacological properties of gaboxadol have been described. U.S. Pat. No. 4,278,676. In order to study the interactions of gaboxadol with the central GABA receptors in vitro, gaboxadol was tested in affinity binding experiments. See S. J. Enna and S. H. Snyder, Brain Res. 1975, 100, 81-97. The IC 50 value of gaboxadol was determined to be 0.13 ⁇ 0.005 ⁇ M based on experiments using five different concentrations of gaboxadol. Each experiment was conducted in triplicate and the IC 50 value was determined by logprobit analysis.
  • gaboxadol was tested in microelectrophoretic experiments. See U.S. Pat. No. 4,278,676. Experiments were performed on lumbar dorsal horn interneurones and Renshaw cells of cats anaesthetized with pentobarbitone sodium. Gaboxadol was found to be relatively more potent than GABA on the basis of electrophoretic currents required to produce equal and submaximal inhibitions of the firing of the central neurones. The inhibitory action of gaboxadol on central neurones was reversibly antagonized by the specific GABA antagonist bicuculline methochloride (BMC).
  • BMC bicuculline methochloride
  • gaboxadol did not interact with the GABA uptake system at concentrations of 5 ⁇ 10 4 M, and it did not interact with the GABA metabolizing enzymes GABA:2-oxo-glutarate aminotransferase and L-glutamate 1-carboxylase at concentrations of 10 ⁇ 3 M. Based on the above-mentioned experiments, gaboxadol is a specific and very potent GABA agonist. For additional information regarding the GABA receptor binding properties of gaboxadol, see: P. Krogsgaard-Larsen et al. Nature 1977, 268, 53.
  • gaboxadol is less toxic than muscimol.
  • the hydrobromide salt of gaboxadol has a LD 50 (mg/kg) of 80 (i.v.), 145 (i.p.), and >320 (p.o.) in mice.
  • muscimol has a LD 50 (mg/kg) of 7 (i.v.), 12 (i.p.), and 22 (p.o.) in mice. See U.S. Pat. No. 4,278,676.
  • the size of a prophylactic or therapeutic dose of gaboxadol will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein, is from about 1 mg to about 90 mg.
  • a daily dose range should be between about 2 mg to about 40 mg.
  • a daily dose range should be between about 5 mg to about 30 mg.
  • the daily dose range should be about 10, 15, 20, or 25 mg.
  • the therapy may be initiated at a lower dose, perhaps about 2 mg to about 4 mg and increased up to about 10 mg or higher depending-on the patient's global response.
  • Baclofen is a GABA-receptor agonist that has the chemical name ⁇ -(aminomethyl)-4-chlorobenzenepropanoic acid.
  • Procedures for the preparation of baclofen are described in U.S. Pat. No. 3,471,548.
  • the pharmacological properties are described in Hudgson, Weightman Brit. Med. J. 1971, 4, 15 and S. Ahuja in Analytical Profiles of Drug Substances vol. 14, K. Florey, Ed. (Academic Press, New York, 1985) pp 527-548.
  • the structure of baclofen is presented below.
  • a prophylactic or therapeutic dose of baclofen, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 5 mg to about 250 mg.
  • a daily dose range should be between about 20 mg to about 150 mg.
  • a daily dose range should be between about 30 mg to about 100 mg.
  • the daily dose range should be about 40, 50, 60, 70, or 80 mg.
  • the therapy may be initiated at a lower dose, perhaps about 5 mg to about 15 mg and increased up to about 35 mg or higher depending on the patient's global response.
  • children are administered a dosage in the range of about 40, 50 or 60 mg per day, often times in divided dosages.
  • Bicuculline is a naturally occurring GABA antagonist. Procedures for the preparation of bicuculline are described in Groenewoud, Robinson J. Chem. Soc. 1936, 199 and Haworth et al. Nature 1950, 165, 529. The pharmacological properties are described in Curtis et al. Nature 1970, 226, 1222.
  • the total daily dose range is from about 1 mg to about 2000 mg. Preferably, a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • Bicuculline has the chemical name (6R)-6-[(5S)-5,6,7,8-tetahydro-6-methyl-1,3-dioxolo[4,5-g]isoquinolin-5-yl]furo[3,4-e]1,3-benzodioxol-8(6H)-one and the structure is presented below.
  • CACA is a GABA receptor agonist that has the chemical name cis-4-aminocrotonic acid.
  • CACA can be purchased from Tocris Cookson Inc. in Ellisville, Mo. The pharmacological properties are described in J. Ulloor et al. J. Neurophysiol. 2004, 91(4), 1822-31.
  • the total daily dose range is from about 1 mg to about 2000 mg.
  • a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • the structure of CACA is presented below. ⁇ -CCP
  • ⁇ -CCP is an inverse agonist of the GABA receptor.
  • ⁇ -CCP can be purchased from Tocris Cookson Inc. in Ellisville, Mo. The pharmacological properties are described in P. Polc et al. Epilepsia 1996, 37(10), 1007-14.
  • the total daily dose range is from about 1 mg to about 2000 mg.
  • a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • the structure of ⁇ -CCP is presented below. CGP 35348
  • CGP 35348 is a GABA-receptor antagonist that has the chemical name 3-(aminopropyl)(diethoxymethyl)phosphinic acid.
  • CGP 35348 can be purchased from Tocris Cookson Inc. in Ellisville, Mo. The pharmacological properties are described in Olpe et al. Eur. J. Pharmacol. 1990, 187, 27; Hao et al. Neurosci. Lett. 1994, 182, 299; and Froestl et al. Pharmacol. Rev. Comm. 1996, 8, 127.
  • the total daily dose range is from about 1 mg to about 2000 mg.
  • a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • the structure of CGP 35348 is presented below.
  • CGP 46381 is a GABA-receptor antagonist that has the chemical name 3-(aminopropyl)(diethoxymethyl)phosphinic acid.
  • CGP 46381 is a GABA-receptor antagonist that has the chemical name (3-aminopropyl)(cyclohexylmethyl)phosphinic acid.
  • CGP 46381 can be purchased from KOMA Biotech, Inc. The pharmacological properties are described in Lingenhoehl, Olpe Pharmacol. Comm. 1993, 3, 49.
  • the total daily dose range is from about 1 mg to about 2000 mg.
  • a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • the structure of CGP 46381 is presented below.
  • CGP 52432 has the chemical name (3-aminopropyl)(cyclohexylmethyl)phosphinic acid.
  • CGP 46381 can be purchased from KOMA Biotech, Inc. The pharmacological properties are described in Lingenhoehl, Olpe Pharmacol. Comm. 1993, 3, 49.
  • the total daily dose range is
  • CGP 52432 is a GABA-receptor antagonist that has the chemical name 3-[[(3,4-dichlorophenyl)methyl]amino]propyl]diethoxymethyl)phosphinic acid.
  • CGP 52432 can be purchased from KOMA Biotech, Inc. The pharmacological properties are described in Lanza et al. Eur. J Pharmacol. 1993, 237, 191; Froestl et al. Pharmacol. Rev. Comm. 1996, 8, 127; Bonanno et al. Eur. J. Pharmacol. 1998, 362, 143; and Libri et al. Naunyn - Schmied. Arch. Pharmacol. 1998, 358, 168.
  • the total daily dose range is from about 1 mg to about 2000 mg.
  • a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • the structure of CGP 52432 is presented below.
  • CGP 54626 is a GABA-receptor antagonist that has the chemical name [S-(R*,R*)]-[3-[[1-(3,4-dichlorophenyl)ethyl]amino]-2-hydroxypropyl](cyclohexylmethyl)phosphinic acid.
  • CGP 52432 can be purchased from KOMA Biotech, Inc. The pharmacological properties are described in Brugger et al. Eur. J Pharmacol. 1993, 235, 153; Froestl et al. Pharmacol. Rev. Comm. 1996, 8, 127; and Kaupmann et al. Nature 1998, 396, 683.
  • the total daily dose range is from about 1 mg to about 2000 mg.
  • a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • the structure of CGP 54626 is presented below.
  • CGP 55845 has the chemical name
  • CGP 55845 is a GABA-receptor antagonist that has the chemical name (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl)phosphinic acid.
  • CGP 55845 can be purchased from KOMA Biotech, Inc. The pharmacological properties are described in Davies et al. Neuropharmacology 1993, 32, 1071; Froestl et al. Pharmacol. Rev. Comm. 1996, 8, 127; and Deisz Neuroscience 1999, 93, 1241.
  • the total daily dose range is from about 1 mg to about 2000 mg.
  • a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • the structure of CGP 55845 is presented below. Clonazepam
  • Clonazepam is an antianxiety agent marketed under the tradename KLONOPIN®. Procedures for the preparation of clonazepam are described in U.S. Pat. Nos. 3,121,076 and 3,116,203. The pharmacological properties are described in Guerrero-Figueroa et al. Curr. Ther. Res. Clin. Exp. 1969, 11, 40 and W. C. Winslow Anal. Profiles Drug Subs. 1977, 6, 61-81. Clonazepam has the chemical name 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one and the structure is presented below.
  • a prophylactic or therapeutic dose of clonazepam, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 1 mg to about 40 mg.
  • a daily dose range should be between about 2 mg to about 30 mg.
  • a daily dose range should be between about 4 mg to about 20 mg.
  • the daily dose range should be about 8, 12, or 16 mg.
  • the therapy may be initiated at a lower dose, perhaps about 1.5 mg to about 3.0 mg and increased up to about 6 mg or higher depending on the patient's global response.
  • Diazepam is a benzodiazepine used to relieve anxiety, nervousness, and tension associated with anxiety disorders.
  • diazepam is used to treat certain seizure disorders and muscle spasms. Procedures for the preparation of diazepam are described in U.S. Pat. Nos. 3,371,085; 3,109,843; and 3,136,815. The pharmacological properties are described in Hudson, Wolpert Arch. Int. Pharmacodyn. Ther. 1970, 186, 388; M. Mandelli et al. Clin. Pharmacokinet. 1978, 3, 72; and A. MacDonald et al. Anal. Profiles Drug Subs. 1972, 1, 79-99. Diazepam has the chemical name 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and the structure is presented below.
  • a prophylactic or therapeutic dose of diazepam, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose,.and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 0.5 mg to about 200 mg.
  • a daily dose range should be between about 1 mg to about 100 mg.
  • a daily dose range should be between about 5 mg to about 40 mg.
  • the daily dose range should be about 10, 15, 20, 25, 30 or 35 mg.
  • the therapy may be initiated at a lower dose, perhaps about 3 mg to about 4 mg and increased up to about 12 mg or higher depending on the patient's global response.
  • Flumazenil is a imidazodiazepine marketed under the tradename ROMAZICON®. Procedures for the preparation of flumazenil are described in U.S. Pat. No. 4,316,839. The pharmacological properties are described in W. Hunkeler et al. Nature 1981, 290, 514; S. E. File et al. Psychopharmacol. 1986, 89, 113; and A. Darragh et al. Lancet 1981, 2, 8.
  • Flumazenil has the chemical name 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester and the structure is presented below.
  • a prophylactic or therapeutic dose of flumazenil, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 0.01 mg to about 4.0 mg.
  • a daily dose range should be between about 0.1 mg to about 2.0 mg.
  • a daily dose range should be between about 0.2 mg to about 1.0 mg.
  • the daily dose range should be about 0.4, 0.6, or 0.8 mg.
  • the therapy may be initiated at a lower dose, perhaps about 0.15 mg to about 0.17 mg and increased up to about 0.5 mg or higher depending on the patient's global response.
  • Gabapentin is a GABA-receptor agonist marketed under the tradename NEURONTIN®. Procedures for the preparation of gabapentin are described in U.S. Pat. No. 4,024,175. The pharmacological properties are described in K. O. Vollmer et al. Arzneistoff - Forsch. 1986, 36, 830 and The US Gabapentin Study Group No. 5 Neurology 1993, 43, 2292. Gabapentin has the chemical name 1-(aminomethyl)cyclohexaneacetic acid and the structure is presented below.
  • a prophylactic or therapeutic dose of gabapentin, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 100 mg to about 3000 mg.
  • a daily dose range should be between about 450 mg to about 2400 mg.
  • a daily dose range should be between about 900 mg to about 1800 mg.
  • the daily dose range should be about 1100, 1300, 1500, or 1700 mg.
  • the therapy may be initiated at a lower dose, perhaps about 500 mg to about 700 mg and increased up to about 1400 mg or higher depending on the patient's global response.
  • a lower dose perhaps about 500 mg to about 700 mg and increased up to about 1400 mg or higher depending on the patient's global response.
  • children ages 3-12 years old are given a smaller dosage.
  • a child between the age of 3-12 years old may be given a dose in the range of about 10-15 mg/kg/day up to about 25-35 mg/kg/day.
  • 2-Hydroxysaclofen is a GABA-receptor antagonist that has the chemical name (RS)-3-amino-2-(4-chlorophenyl)-2-hydroxypropyl-sulphonic acid.
  • 2-Hydroxysaclofen can be purchased from KOMA Biotech, Inc. The pharmacological properties are described in Kerr et al. Neurosci. Lett. 1988, 92, 92; Curtis et al. Neurosci. Lett. 1988, 92, 97.
  • the total daily dose range is from about 1 mg to about 2000 mg.
  • a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • the structure of 2-hydroxysaclofen is presented below. Isoguvacine
  • Isoguvacine is a GABA receptor agonist.
  • the pharmacological properties of isoguvacine are described in Chebib, M.; Johnston, G. A. Clin. Exp. Pharamacol. Physiol. 1999, 26, 937-940; X. Leinekugel et al. J. Physiol. 1995, 487, 319-29; and White, W. F.; Snodgrass, S. R. J. Neurochem. 1983, 40(6), 1701-8.
  • the total daily dose range is from about 1 mg to about 2000 mg.
  • a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • Lamotrigine (LAMICTAL®)
  • Lamotrigine is a GABA-receptor agonist marketed under the tradename LAMICTAL®. Procedures for the preparation of lamotrigine are described in U.S. Pat. No. 4,602,017 and EP 21,121. The pharmacological properties are described in A. F. Cohen et al. Clin. Pharmacol. Ther. 1987, 42, 535; Epilepsia 1991, 32( Supp. 2), S9-S21; and K. L. Goa et al. Drugs 1993, 46, 152-157. Lamotrigine has the chemical name 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine and the structure is presented below.
  • a prophylactic or therapeutic dose of lamotrigine, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 5 mg to about 1000 mg.
  • a daily dose range should be between about 25 mg to about 750 mg.
  • a daily dose range should be between about 50 mg to about 500 mg.
  • the daily dose range should be about 100, 200, 300 or 400 mg.
  • the therapy may be initiated at a lower dose, perhaps about 40 mg to about 75 mg and increased up to about 250 mg or higher depending on the patient's global response.
  • Lorazepam is an antianxiety agent marketed under the tradename ATIVAN®. Procedures for the preparation of lorazepam are described in U.S. Pat. No. 3,296,249. The pharmacological properties are described in Arzneistoff - Forsch. 1971, 21, 1047-1102 and Ameer, B.; Greenblatt, D. J. Drugs 1981, 21, 161-200. Lorazepam has the chemical name 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one and the structure is presented below.
  • a prophylactic or therapeutic dose of lorazepam, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 0.1 mg to about 20 mg.
  • a daily dose range should be between about 0.5 mg to about 13 mg.
  • a daily dose range should be between about 1 mg to about 6 mg.
  • the daily dose range should be about 2, 3, 4, or 5 mg.
  • the therapy may be initiated at a lower dose, perhaps about 0.6 mg to about 0.8 mg and increased up to about 1.5 mg or higher depending on the patient's global response.
  • L-655708 is a benzodiazepine that binds selectively to the GABA A receptor.
  • L-655708 has the chemical name 11,12,13,13a-tetrahydro-7-methoxy-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid, ethyl ester.
  • L-655708 can be purchased from KOMA Biotech, Inc. The pharmacological properties are described in Quirk et al. Neuropharmacology 1996, 35, 1331; Sur et al. Mol. Pharmacol. 1998, 54, 928; and Sur et al. Brain Res. 1999, 822, 265.
  • the total daily dose range is from about 1 mg to about 2000 mg.
  • a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • the structure of L-655708 is presented below. Midazolam
  • Midazolam is a short-acting derivative of diazepam. Procedures for the preparation of midazolam are described in U.S. Pat. No. 4,280,957. The pharmacological properties are described in Brit. J. Clin. Pharmacol. 1983, 16 ( Suppl. 1), IS-199S; J. W. Dundee et al. Drugs 1984, 28, 519-543; and E. Lahat et al. Brit. Med. J. 2000, 321, 83. Midazolam has the chemical name 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine and the structure is presented below.
  • a prophylactic or therapeutic dose of midazolam, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 0.5 mg to about 100 mg.
  • a daily dose range should be between about 1 mg to about 40 mg.
  • a daily dose range should be between about 4 mg to about 20 mg.
  • the daily dose range should be about 8, 12, or 16 mg.
  • the therapy may be initiated at a lower dose, perhaps about 2 mg to about 3 mg and increased up to about 6 mg or higher depending on the patient's global response.
  • Muscimol is a GABA-receptor agonist that has the chemical name 5-(aminomethyl)-3(2H)-isoxazolone. Procedures for the preparation of muscimol are described in Nakamura Chem. Pharm. Bull. 1971, 19, 46 and McCarry, B. E.; Savard, M. Tetrahedron Letters 1981, 22, 5153. The pharmacological properties are described in Theobald et al. Arzneistoff - Forsch. 1968, 18, 311 and F. V. DeFeudis Neurochem. Res. 1980, 5, 1047-1068. For additional information see U.S. Pat. Nos. 3,242,190 and 3,397,209.
  • the total daily dose range is from about 1 mg to about 2000 mg.
  • a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • the structure of muscimol is presented below. Phaclofen
  • Phaclofen is a GABA-receptor antagonist that has the chemical name 3-amino-2-(4-chlorophenyl)propylphosphonic acid. Phaclofen can be purchased from KOMA Biotech, Inc. The pharmacological properties are described in Kerr et al. Brain Res. 1987, 405, 150; Karlsson et al. Eur. J. Pharmacol. 1988, 148, 485; and Hasuo, Gallagher Neurosci. Lett. 1988, 86, 77. In general, the total daily dose range is from about 1 mg to about 2000 mg. Preferably, a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg. The structure of phaclofen is presented below. Phenytoin (DILANTIN®)
  • Phenytoin is a GABA-receptor agonist marketed under the tradename DILANTIN®. Procedures for the preparation of phenytoin are described in U.S. Pat. No. 2,409,754. The pharmacological properties are described in Gillis et al. J. Pharmacol. Exp. Ther. 1971, 179, 599 and J. Philip et al. Anal. Profiles Drug Subs. 1984, 13, 417-445. In certain instances, the sodium salt of phenytoin is preferred. Phenytoin has the chemical name 5,5-diphenyl-2,4-imidazolidinedione and the structure is presented below.
  • a prophylactic or therapeutic dose of phenytoin, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 5 mg to about 600 mg.
  • a daily dose range should be between about 15 mg to about 450 mg.
  • a daily dose range should be between about 25 mg to about 300 mg.
  • the daily dose range should be about 50, 100, 150, 200, or 250 mg.
  • the therapy may be initiated at a lower dose, perhaps about 10 mg to about 20 mg and increased up to about 75 mg or higher depending on the patient's global response.
  • Pregabalin is an isobutyl analog of GABA developed by Pfizer in collaboration with researchers at Northwestern University. Pregabalin has a more linear relationship between drug plasma levels and the dosage of the drug compared to gabapentin. Procedures for the preparation of pregabalin are described in M. J. Burk et al. J. Org. Chem. 2003, 68, 5731-5734. The pharmacological properties are described in Bayes, M.; Rabasseda, X.; Prous, J. R. Methods Find Exp. Clin. Pharmacol. 2004, 26(3), 211-44 and A. C. Pande et al. J. Clin. Psychopharmacol. 2004, 24(2), 141-9. For additional information see U.S. Pat. No. 6,028,214. Pregabalin has the chemical name (S)-(+)-3-aminomethyl-5-methylhexanoic acid and the structure is presented below.
  • a prophylactic or therapeutic dose of pregabalin, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 5 mg to about 1200 mg.
  • a daily dose range should be between about 30 mg to about 800 mg.
  • a daily dose range should be between about 75 mg to about 600 mg.
  • the daily dose range should be about 100, 150, 250, 400, or 500 mg.
  • the therapy may be initiated at a lower dose, perhaps about 50 mg to about 65 mg and increased up to about 125 mg or higher depending on the patient's global response.
  • Progabide is a GABA receptor antagonist marketed under the tradename GABRENE®. Procedures for the preparation of progabide are described in U.S. Pat. No. 4,094,992. The pharmacological properties are described in I. Johno et al. J. Pharm. Sci. 1982, 71, 633 and U.S. Pat. No. 4,361,583. Progabide has the chemical name 4-[[(4-chlorophenyl)-(5-fluoro-2-hydroxyphenyl)methylene]amino]butanamide and the structure is presented below.
  • a prophylactic or therapeutic dose of progabide, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 5 mg/kg/day to about 75 mg/kg/day.
  • a daily dose range should be between about 15 mg/kg/day to about 55 mg/kg/day.
  • a daily dose range should be between about 25 mg/kg/day to about 45 mg/kg/day.
  • the daily dose range should be about about 30, 35, or 40 mg/kg/day.
  • the therapy may be initiated at a lower dose, perhaps about 10 mg/kg/day to about 15 mg/kg/day and increased up to about 30 mg/kg/day or higher depending on the patient's global response.
  • Riluzole is a benzothiazole derivative marketed by Rhone Poulenc Rorer. Procedures for the preparation of riluzole are described in U.S. Pat. No. 4,370,338 and EP 50,551. The pharmacological properties are described in J. Mizoule et al. Neuropharmacology 1985, 24, 767 amd M. W. Debono et al. Eur. J Pharmacol. 1993, 235, 283. Riluzole has the chemical name 6-(trifluoromethoxy)benzothiazolamine and the structure is presented below.
  • a prophylactic or therapeutic dose of riluzole, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 5 mg to about 250 mg.
  • a daily dose range should be between about 50 mg to about 175 mg.
  • a daily dose range should be between about 80 mg to about 120 mg.
  • the daily dose range should be about 90, 100, or 110 mg.
  • the therapy may be initiated at a lower dose, perhaps about 60 mg to about 70 mg and increased up to about 100 mg or higher depending on the patient's global response.
  • Saclofen is a GABA-receptor antagonist that has the chemical name (RS)-3-amino-2-(4-chlorophenyl)propylsulphonic acid.
  • Saclofen can be purchased from KOMA Biotech, Inc. The pharmacological properties are described in Bowery TiPS. 1989, 10, 401; Kerr et al. Neurosci. Lett. 1989, 107, 239; and Jane et al. in GABA B Receptors in Mammalian Function. Eds. Bowery et al., p 42b, John Wiley & Sons, 1990, Chichester, U. K.
  • the total daily dose range is from about 1 mg to about 2000 mg.
  • a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • the structure of saclofen is presented below. SCH50911
  • SCH 50911 is a GABA-receptor antagonist that has the chemical name (2S)-5,5-dimethyl-2-morpholineacetic acid.
  • SCH 50911 can be purchased from KOMA Biotech, Inc. The pharmacological properties are described in Bolser et al. J. Pharmacol. Exp. Ther. 1996, 274, 1393; Hosford et al. J. Pharmacol. Exp. Ther. 1996, 274, 1399; and Ong et al. Eur. J. Pharmacol. 1998, 362, 35.
  • the total daily dose range is from about 1 mg to about 2000 mg.
  • a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • the structure of SCH 50911 is presented below. SKF 97541
  • SKF 97541 is a GABA-receptor agonist with the chemical name 3-aminopropyl(methyl)phosphinic acid.
  • SKF 97541 is a white solid that is readily soluble in sater and dilute aqueous base.
  • SKF 97541 can be purchased from A.G. Scientific, Inc. located in San Diego, Calif. The pharmacological properties are described in Hoskison, M. M.; Connor, J. A.; Shuttleworth, C. W. Neurosci. Lett. 2004, 365(1), 48-53 and Hue, B.; Amat, C. J Insect Physiol. 1997, 43(12), 1125-1131. In certain instances, the hydrochloride salt is preferred.
  • the total daily dose range is from about 1 mg to about 2000 mg.
  • a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • the structure of SKF 97541 is presented below. SR 95531
  • SR 95531 is a GABA-receptor antagonist.
  • SR 95531 can be purchased from Tocris Cookson Inc. in Ellisville, Mo. The pharmacological properties are described in B. M. Stell et al. J. Neurosci. 2002, 22(10), RC223.
  • the total daily dose range is from about 1 mg to about 2000 mg.
  • a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • the structure of SR 95531 is presented below. Tiagabine (GABITIRIL®)
  • Tiagabine is a GABA uptake inhibitor marketed under the tradename GABITIRIL®. Procedures for the preparation of tiagabine are described in U.S. Pat. No. 5,010,090 and K. E. Andersen et al. J. Med. Chem. 1993, 36, 1716. The pharmacological properties are described in C. L. Faingold et al. Exp. Neurology 1994, 126, 225 and W. J. Giardina J. Epilepsy 1994, 7, 161-166. Tiagabine has the chemical name (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid and the structure is presented below.
  • a prophylactic or therapeutic dose of tiagabine, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 1 mg to about 100 mg.
  • a daily dose range should be between about 15 mg to about 50 mg.
  • a daily dose range should be between about 30 mg to about 35 mg.
  • the daily dose range should be about 32 or 34 mg.
  • the therapy may be initiated at a lower dose, perhaps about 5 mg to about 10 mg and increased up to about 20 mg or higher depending on the patient's global response.
  • TPMPA is a GABA-receptor antagonist.
  • TPMPA can be purchased from Tocris Cookson Inc. in Ellisville, Mo. The pharmacological properties of TPMPA are described in K. Schlicker et al. Brain Res. Bull. 2004, 63(2), 91-7.
  • the total daily dose range is from about 1 mg to about 2000 mg.
  • a daily dose range should be between about 5 mg to about 1000 mg. More preferably, a daily dose range should be between about 10 mg to about 250 mg.
  • the structure of isoguvacine is presented below. Topiramate (TOPAMAX®)
  • Topiramate is a fructopyranose derivative marketed under the tradename TOPAMAX®. Procedures for the preparation of topiramate are described in U.S. Pat. No. 4,513,006. The pharmacological properties are described in M. Bialer Clin. Pharmacokinet. 1993, 24, 441 and B. E. Maryanoff et al J. Med. Chem. 1987, 30, 880. Topiramate has the chemical name 2,3:4,5-bis-O-(1-methylethylidene)- ⁇ -D-fructopyranose sulfamate and the structure is presented below.
  • a prophylactic or therapeutic dose of topiramate, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 5 mg to about 400 mg.
  • a daily dose range should be between about 100 mg to about 300 mg.
  • a daily dose range should be between about 170 mg to about 230 mg.
  • the daily dose range should be about 180, 190, 200, 210, or 220 mg.
  • the therapy may be initiated at a lower dose, perhaps about 125 mg to about 150 mg and increased up to about 175 mg or higher depending on the patient's global response. In general, children a given a smaller dosage.
  • Valproic acid has the chemical name 2-propylpentanoic acid and is used to treat migraine headaches and prevent seizures in people suffering from epilepsy. Procedures for the preparation of valproic acid are described in Weimann, Thuan Bull. Soc. Chim. France 1958, 199. The pharmacological properties are described in Rimmer, E. M.; Richens, A. Pharmacother. 1985, 5, 171-184 and Z. L. Chang in Analytical Profiles of Drug Substances vol. 8, K. Florey, Ed. (Academic Press, New York, 1979) pp 529-556. The structure of valproic acid is presented below.
  • a prophylactic or therapeutic dose of valproic acid, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 5 mg to about 900 mg.
  • a daily dose range should be between about 25 mg to about 700 mg.
  • a daily dose range should be between about 50 mg to about 500 mg.
  • the daily dose range should be about 100, 200, 300 or 400 mg.
  • the therapy may be initiated at a lower dose, perhaps about 20 mg to about 40 mg and increased up to about 75 mg or higher depending on the patient's global response.
  • Vigabatrin has the chemical name 4-amino-5-hexenoic acid and is used to prevent seizures in people suffering from epilepsy. Procedures for the preparation of vigabatrin are described in U.S. Pat. No. 3,960,927. The pharmacological properties are described in K. D. Haegele et al. Clin. Pharmacol. Ther. 1986, 40, 581 and Grant, S. M.; Heel, R. C. Drugs 1991, 41, 889-926. The structure of vigabatrin is presented below.
  • a prophylactic or therapeutic dose of vigabatrin, or one of its salts, in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose ranges, for the conditions described herein is from about 100 mg to about 5000 mg.
  • a daily dose range should be between about 500 mg to about 4000 mg.
  • a daily dose range should be between about 1000 mg to about 3000 mg.
  • the daily dose range should be about 1200, 1500, 2000, or 2500 mg.
  • the therapy may be initiated at a lower dose, perhaps about 700 mg to about 900 mg and increased up to about 1300 mg or higher depending on the patient's global response.
  • GABA receptor modulating compounds amenable to the present invention include the GABA receptor agonists described in U.S. patent application 20030162754 and WO 02/06786, which are hereby incorporated by reference.
  • compounds amenable to the present invention include 4-amino-3-phenylbutanoic acid, 4-amino-3-hydroxybutanoic acid, 4-amino-3-(4-chlorophenyl)-3-hydroxyphenylbutanoic acid, 4-amino-3-(thien-2-yl)butanoic acid, 4-amino-3-(5-chlorothien-2-yl)butanoic acid, 4-amino-3-(5-bromothien-2-yl)butanoic acid, 4-amino-3-(5-methylthien-2-yl)butanoic acid, 4-amino-3-(2-imidazolyl)butanoic acid, 4-guanidino-3-(4-chlorophenyl)butanoic acid
  • GABA receptor modulating compounds amenable to the present invention include the GABA receptors agonsits described in U.S. Pat. No. 6,399,608; which is hereby incorporated by reference.
  • compounds amenable to the present invention include 3,7-diphenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[4,3-b]pyridazine; 7,8-dimethyl-3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[4,3-b]pyridazine; 7-methyl-3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[4,3-b]pyridazine; b 7-ethyl-3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[4,3-b]pyridazine; 8-methyl-3,7-diphenyl-6-(2-pyridy
  • Additional GABA modulating agents for use in the present invention are 3-amino-propyl phosphinic acid and (1S,2R)-(+)-2-(aminomethyl)-cyclopropane-1-carboxylate.
  • the structure of 3-amino-propyl phosphinic acid is presented below.
  • One aspect of the present invention relates to combination therapy.
  • This type of therapy is advantageous because the co-administration of active ingredients achieves a therapeutic effect that is greater than the therapeutic effect achieved by administration of only a single therapeutic agent.
  • the co-administration of two or more therapeutic agents achieves a synergistic effect, i.e., a therapeutic affect that is greater than the sum of the therapeutic effects of the individual components of the combination.
  • the co-administration of two or more therapeutic agents achieves an augmentation effect.
  • the active ingredients that comprise a combination therapy may be administered together via a single dosage form or by separate administration of each active agent.
  • the first and second therapeutic agents are administered in a single dosage form.
  • the agents may be formulated into a single tablet, pill, capsule, or solution for parenteral administration and the like.
  • the first therapeutic agent and the second therapeutic agents may be administered as separate compositions, e.g., as separate tablets or solutions.
  • the first active agent may be administered at the same time as the second active agent or the first active agent may be administered intermittently with the second active agent.
  • the length of time between administration of the first and second therapeutic agent may be adjusted to achieve the desired therapeutic effect.
  • the second therapeutic agent may be administered only a few minutes (e.g., 1, 2, 5, 10, 30, or 60 min) after administration of the first therapeutic agent.
  • the second therapeutic agent may be administered several hours (e.g., 2, 4, 6, 10, 12, 24, or 36 hr) after administration of the first therapeutic agent.
  • the second therapeutic agent may be administered at 2 hours and then again at 10 hours following administration of the first therapeutic agent.
  • the therapeutic effects of each active ingredient overlap for at least a portion of the duration of each therapeutic agent so that the overall therapeutic effect of the combination therapy is attributable in part to the combined or synergistic effects of the combination therapy.
  • the dosage of the active agents will generally be dependent upon a number of factors including pharmacodynamic characteristics of each agent of the combination, mode and route of administration of active agent(s), the health of the patient being treated, the extent of treatment desired, the nature and kind of concurrent therapy, if any, and the frequency of treatment and the nature of the effect desired.
  • dosage ranges of the active agents often range from about 0.001 to about 250 mg/kg body weight per day. For example, for a normal adult having a body weight of about 70 kg, a dosage in the range of from about 0.1 to about 25 mg/kg body weight is typically preferred. However, some variability in this general dosage range may be required depending upon the age and weight of the subject being treated, the intended route of administration, the particular agent being administered and the like.
  • the pharmaceutical combination may be advantageous for the pharmaceutical combination to have a relatively large amount of the first component compared to the second component.
  • the ratio of the first active agent to second active agent is 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, or 5:1.
  • the ratio of the first active agent to the second active agent is 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, or 1:4.
  • it may be advantageous for the pharmaceutical combination to have a relatively large amount of the second component compared to the first component.
  • the ratio of the second active agent to the first active agent is 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, or 5:1.
  • a composition comprising any of the above-identified combinations of first therapeutic agent and second therapeutic agent may be administered in divided doses 1, 2, 3, 4, 5, 6, or more times per day or in a form that will provide a rate of release effective to attain the desired results.
  • the dosage form contains both the first and second active agents.
  • the dosage form only has to be administered one time per day and the dosage form contains both the first and second active agents.
  • a formulation intended for oral administration to humans may contain from 0.1 mg to 5 g of the first therapeutic agent and 0.1 mg to 5 g of the second therapeutic agent, both of which are compounded with an appropriate and convenient amount of carrier material varying from about 5 to about 95 percent of the total composition.
  • Unit dosages will generally contain between from about 0.5 mg to about 1500 mg of the first therapeutic agent and 0.5 mg to about 1500 mg of the second therapeutic agent.
  • the dosage comprises 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg, etc., up to 1500 mg of the first therapeutic agent.
  • the dosage comprises 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg, etc., up to 1500 mg of the second therapeutic agent.
  • the optimal ratios of the first and second therapeutic agent can be determined by standard assays known in the art.
  • the phenyl-p-benzoquinone test may be used to establish analgesic effectiveness.
  • the phenyl-p-benzoquinone induced writhing test in mice H. Blumberg et al., 1965, Proc. Soc. Exp. Med. 118:763-766) and known modifications thereof is a standard procedure which may be used for detecting and comparing the analgesic activity of different classes of analgesic drugs with a good correlation with human analgesic activity.
  • Data for the mouse can be translated to other species where the orally effective analgesic dose of the individual compounds are known or can be estimated.
  • the method consists of reading the percent ED 50 dose for each dose ratio on the best fit regression analysis curve from the mouse isobologram, multiplying each component by its effective species dose, and then forming the ratio of the amount of COX-2 inhibitor and opioid analgesic. This basic correlation for analgesic properties enables estimation of the range of human effectiveness (E. W. Pelikan, 1959, The Pharmacologist 1:73).
  • an equieffective dose substitution model and a curvilinear regression analysis utilizing all the data for the individual compounds and various dose ratios for the combinations can be used to establish the existence of unexpectedly enhanced analgesic activity of combinations of active agents, i.e., the resulting activity is greater than the activity expected from the sum of the activities of the individual components.
  • the toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
  • Compounds which exhibit large therapeutic indices are preferred.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of RT production from infected cells compared to untreated control as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
  • Levels in plasma may be measured, for example, by high performance liquid chromatography (HPLC).
  • synergistic refers to a combination which is more effective than the additive effects of any two or more single agents.
  • a synergistic effect permits the effective treatment of a disease using lower amounts (doses) of either individual therapy. The lower doses result in lower toxicity without reduced efficacy.
  • a synergistic effect can result in improved efficacy, e.g., improved antiviral activity.
  • synergy may result in an improved avoidance or reduction of disease as compared to any single therapy.
  • Combination therapy can allow for the use of lower doses of the first therapeutic or the second therapeutic agent (referred to as “apparent one-way synergy” herein), or lower doses F both therapeutic agents (referred to as “two-way synergy” herein) than would normally be required when either drug is used alone.
  • the synergism exhibited between the second therapeutic agent and the first therapeutic agent is such that the dosage of the first therapeutic agent would be sub-therapeutic if administered without the dosage of the second therapeutic agent.
  • the synergism exhibited between the second therapeutic agent and the first therapeutic agent is such that the dosage of the second therapeutic agent would be sub-therapeutic if administered without the dosage of the first therapeutic agent.
  • augmentation refers to combination where one of the compounds increases or enhances therapeutic effects of another compound or compounds administered to a patient. In some instances, augmentation can result in improving the efficacy, tolerability, or safety, or any combination thereof, of a particular therapy.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of a first therapeutic agent together with a dose of a second therapeutic agent effective to augment the therapeutic effect of the first therapeutic agent.
  • the present invention relates to methods of augmenting the therapeutic effect in a patient of a first therapeutic agent by administering the second therapeutic agent to the patient.
  • the present invention relates to a pharmaceutical composition comprising an therapeutically effective dose of a second therapeutic agent together with a dose of a first therapeutic agent effective to augment the therapeutic effect of the second therapeutic agent.
  • the present invention relates to methods of augmenting the therapeutic effect in a patient of a second therapeutic agent by administering the first therapeutic agent to the patient.
  • the invention is directed in part to synergistic combinations of the first therapeutic agent in an amount sufficient to render a therapeutic effect together with a second therapeutic agent.
  • a therapeutic effect is attained which is at least about 2 (or at least about 4, 6, 8, or 10) times greater than that obtained with the dose of the first therapeutic agent alone.
  • the synergistic combination provides a therapeutic effect which is up to about 20, 30 or 40 times greater than that obtained with the dose of first therapeutic agent alone.
  • the synergistic combinations display what is referred to herein as an “apparent one-way synergy”, meaning that the dose of second therapeutic agent synergistically potentiates the effect of the first therapeutic agent, but the dose of first therapeutic agent does not appear to significantly potentiate the effect of the second therapeutic agent.
  • the combination of active agents exhibit two-way synergism, meaning that the second therapeutic agent potentiates the effect of the first therapeutic agent, and the first therapeutic agent potentiates the effect of the second therapeutic agent.
  • other embodiments of the invention relate to combinations of a second therapeutic agent and a first therapeutic agent where the dose of each drug is reduced due to the synergism between the drugs, and the therapeutic effect derived from the combination of drugs in reduced doses is enhanced.
  • the two-way synergism is not always readily apparent in actual dosages due to the potency ratio of the first therapeutic agent to the second therapeutic agent. For instance, two-way synergism can be difficult to detect when one therapeutic agent displays much greater therapeutic potency relative to the other therapeutic agent.
  • the synergistic effects of combination therapy may be evaluated by biological activity assays.
  • the therapeutic agents are be mixed at molar ratios designed to give approximately equipotent therapeutic effects based on the EC 90 values. Then, three different molar ratios are used for each combination to allow for variability in the estimates of relative potency. These molar ratios are maintained throughout the dilution series.
  • the corresponding monotherapies are also evaluated in parallel to the combination treatments using the standard primary assay format. A comparison of the therapeutic effect of the combination treatment to the therapeutic effect of the monotherapy gives a measure of the synergistic effect. Further details on the design of combination analyses can be found in B E Korba (1996) Antiviral Res. 29:49.
  • Analysis of synergism, additivity, or antagonism can be determined by analysis of the aforementioned data using the CalcuSynTM program (Biosoft, Inc.). This program evaluates drug interactions by use of the widely accepted method of Chou and Talalay combined with a statistically evaluation using the Monte Carlo statistical package.
  • the data are displayed in several different formats including median-effect and dose-effects plots, isobolograms, and combination index [CI] plots with standard deviations. For the latter analysis, a CI greater than 1.0 indicates antagonism and a CI less than 1.0 indicates synergism.
  • compositions of the invention present the opportunity for obtaining relief from moderate to severe cases of disease. Due to the synergistic and/or additive effects provided by the inventive combination of the first and second therapeutic agent, it may be possible to use reduced dosages of each of therapeutic agent. By using lesser amounts of other or both drugs, the side effects associated with each may be reduced in number and degree. Moreover, the inventive combination avoids side effects to which some patients are particularly sensitive.
  • One aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a serotonin reuptake inhibitor.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a serotonin reuptake inhibitor, wherein said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, or ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said serotonin reuptake inhibitor is fluoxetine, fluvoxamine, milnacipran, or paroxetine, or a pharmaceutically acceptable salt, solvate,.clathrate, polymorph, or co-crystal of any one of them.
  • said serotonin reuptake inhibitor is fluoxetine, fluvoxamine, milnacipran, or paroxetine, or a pharmaceutically acceptable salt, solvate,.clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said serotonin reuptake inhibitor is fluoxetine, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said serotonin reuptake inhibitor is fluoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said fluoxetine is fluoxetine hydrochloride, or a pharmaceutically acceptable solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a pharmaceutical composition consisting essentially of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a serotonin reuptake inhibitor; and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a pharmaceutical composition consisting essentially of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a serotonin reuptake inhibitor, wherein said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, or ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said serotonin reuptake inhibitor is fluoxetine, fluvoxamine, milnacipran, or paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said serotonin reuptake inhibitor is fluoxetine, fluvoxamine, milnacipran, or paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said serotonin reuptake inhibitor is fluoxetine, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said serotonin reuptake inhibitor is fluoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said fluoxetine is fluoxetine hydrochloride, or a pharmaceutically acceptable solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a serotonin reuptake inhibitor.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a serotonin reuptake inhibitor, wherein said serotonin reuptake inibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, or ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, fluvoxamine, milnacipran, or paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein said fluoxetine is fluoxetine hydrochloride, or a pharmaceutically acceptable solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a serotonin reuptake inhibitor; and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a serotonin reuptake inhibitor, wherein said serotonin reuptake inibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, or ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, fluvoxamine, milnacipran, or paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein said fluoxetine is fluoxetine hydrochloride, or a pharmaceutically acceptable solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein said sleep abnormality is difficulty falling asleep, difficulty staying asleep, or waking up too early.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a serotonin reuptake inhibitor.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a serotonin reuptake inhibitor, wherein said serotonin reuptake inibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, or ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, fluvoxamine, milnacipran, or paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein said fluoxetine is fluoxetine hydrochloride, or a pharmaceutically acceptable solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a serotonin reuptake inhibitor; and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a serotonin reuptake inhibitor, wherein said serotonin reuptake inibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, or ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and at least one pharmaceutically acceptable carrier.
  • a serotonin reuptake inhibitor where
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, fluvoxamine, milnacipran, or paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein said fluoxetine is fluoxetine hydrochloride, or a pharmaceutically acceptable solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein said insomnia is transient insomnia.
  • the present invention relates to the aforementioned method, wherein said insomnia is short-term insomnia.
  • the present invention relates to the aforementioned method, wherein said insomnia is chronic insomnia.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a serotonin reuptake inhibitor.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a serotonin reuptake inhibitor, wherein said serotonin reuptake inibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, or ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, fluvoxamine, milnacipran, or paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein said fluoxetine is fluoxetine hydrochloride, or a pharmaceutically acceptable solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a serotonin reuptake inhibitor; and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a serotonin reuptake inhibitor, wherein said serotonin reuptake inibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, or ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and at least one pharmaceutically acceptable carrier.
  • a serotonin reuptake inhibitor where
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, fluvoxamine, milnacipran, or paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said serotonin reuptake inhibitor is fluoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein said fluoxetine is fluoxetine hydrochloride, or a pharmaceutically acceptable solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein said depression is a major depressive disorder.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a norepinephrine reuptake inhibitor.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a norepinephrine reuptake inhibitor, wherein said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, or (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, or (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said norepinephrine reuptake inhibitor is (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a pharmaceutical composition consisting essentially of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a norepinephrine reuptake inhibitor; and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a pharmaceutical composition consisting essentially of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a norepinephrine reuptake inhibitor, wherein said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, or (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, or (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said norepinephrine reuptake inhibitor is (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of norepinephrine reuptake inhibitor.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of norepinephrine reuptake inhibitor, wherein said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, or (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, or (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said norepinephrine reuptake inhibitor is (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of norepinephrine reuptake inhibitor; and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of norepinephrine reuptake inhibitor, wherein said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, or (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned method, wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, or (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said norepinephrine reuptake inhibitor is (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein said sleep abnormality is difficulty falling asleep, difficulty staying asleep, or waking up too early.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of norepinephrine reuptake inhibitor.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of norepinephrine reuptake inhibitor, wherein said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, or (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, or (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said norepinephrine reuptake inhibitor is (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of norepinephrine reuptake inhibitor; and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of norepinephrine reuptake inhibitor, wherein said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, or (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned method, wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, or (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said norepinephrine reuptake inhibitor is (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said insomnia is transient insomnia.
  • the present invention relates to the aforementioned method, wherein said insomnia is short-term insomnia.
  • the present invention relates to the aforementioned method, wherein said insomnia is chronic insomnia.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of norepinephrine reuptake inhibitor.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of norepinephrine reuptake inhibitor, wherein said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, or (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, or (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said norepinephrine reuptake inhibitor is (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of norepinephrine reuptake inhibitor; and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of norepinephrine reuptake inhibitor, wherein said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, or (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned method, wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, or (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said norepinephrine reuptake inhibitor is (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said depression is a major depressive disorder.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a dopamine reuptake inhibitor.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a dopamine reuptake inhibitor
  • said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, desmethylvenlafaxine, or 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said dopamine reuptake inhibitor is bupropion, or GBR-12935, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said dopamine reuptake inhibitor is bupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said dopamine reuptake inhibitor is venlafaxine, desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said desmethylvenlafaxine is racemic desmethylvenlafaxine, (+)-desmethylvenlafaxine, or ( ⁇ )-desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a pharmaceutical composition consisting essentially of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a dopamine reuptake inhibitor; and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a pharmaceutical composition consisting essentially of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a dopamine reuptake inhibitor, said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, desmethylvenlafaxine, or 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said dopamine reuptake inhibitor is bupropion, or GBR-12935, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said dopamine reuptake inhibitor is bupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said dopamine reuptake inhibitor is venlafaxine, desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said desmethylvenlafaxine is racemic desmethylvenlafaxine, (+)-desmethylvenlafaxine, or ( ⁇ )-desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a dopamine reuptake inhibitor.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a dopamine reuptake inhibitor, wherein said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, desmethylvenlafaxine, or 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is bupropion, or GBR-12935, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is bupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is venlafaxine, desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said desmethylvenlafaxine is racemic desmethylvenlafaxine, (+)-desmethylvenlafaxine, or ( ⁇ )-desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, a therapeutically effective amount of a dopamine reuptake inhibitor; and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a dopamine reuptake inhibitor, wherein said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, desmethylvenlafaxine, or 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and at least one pharmaceutically acceptable carrier.
  • a dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, desmethylvenlafaxine, or 2 ⁇
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is bupropion, or GBR-12935, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is bupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is venlafaxine, desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said desmethylvenlafaxine is racemic desmethylvenlafaxine, (+)-desmethylvenlafaxine, or ( ⁇ )-desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said sleep abnormality is difficulty falling asleep, difficulty staying asleep, or waking up too early.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a dopamine reuptake inhibitor.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a dopamine reuptake inhibitor, wherein said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, desmethylvenlafaxine, or 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is bupropion, or GBR-12935, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is bupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is venlafaxine, desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said desmethylvenlafaxine is racemic desmethylvenlafaxine, (+)-desmethylvenlafaxine, or ( ⁇ )-desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a dopamine reuptake inhibitor; and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a dopamine reuptake inhibitor, wherein said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, desmethylvenlafaxine, or 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and at least one pharmaceutically acceptable carrier.
  • a dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, desmethylvenlafaxine, or 2 ⁇ -propano
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is bupropion, or GBR-12935, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is bupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is venlafaxine, desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said desmethylvenlafaxine is racemic desmethylvenlafaxine, (+)-desmethylvenlafaxine, or ( ⁇ )-desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said insomnia is transient insomnia.
  • the present invention relates to the aforementioned method, wherein said insomnia is short-term insomnia.
  • the present invention relates to the aforementioned method, wherein said insomnia is chronic insomnia.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a dopamine reuptake inhibitor.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a dopamine reuptake inhibitor, wherein said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, desmethylvenlafaxine, or 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • a dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, desmethylvenlafaxine, or 2 ⁇ -propanoyl-3 ⁇ -(4-
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is bupropion, or GBR-12935, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is bupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is venlafaxine, desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said desmethylvenlafaxine is racemic desmethylvenlafaxine, (+)-desmethylvenlafaxine, or ( ⁇ )-desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a dopamine reuptake inhibitor; and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a dopamine reuptake inhibitor, wherein said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, desmethylvenlafaxine, or 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and at least one pharmaceutically acceptable carrier.
  • a dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, desmethylvenlafaxine, or 2 ⁇ -propano
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is bupropion, or GBR-12935, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is bupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein said dopamine reuptake inhibitor is venlafaxine, desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • the present invention relates to the aforementioned method, wherein said desmethylvenlafaxine is racemic desmethylvenlafaxine, (+)-desmethylvenlafaxine, or ( ⁇ )-desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said depression is a major depressive disorder.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a 5-HT 2A modulator.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein the 5-HT 2A modulator is a 5-HT 2A antagonist.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein the 5-HT 2A modulator is a 5-HT 2A inverse agonist.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a 5-HT 2A modulator, wherein said 5 HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, or azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, or phenylindole compounds A, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, or fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said 5-HT 2A modulator, wherein said 5-HT 2A modulator is piperidinyl compounds B, spiroazacyclic compounds C, or azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a pharmaceutical composition consisting essentially of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a 5-HT 2A modulator; and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein the 5-HT 2A modulator is a 5-HT 2A antagonist.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein the 5-HT 2A modulator is a 5-HT 2A inverse agonist.
  • Another aspect of the present invention relates to a pharmaceutical composition consisting essentially of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a 5-HT 2A modulator, wherein said 5 HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, or azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, or phenylindole compounds A, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, or fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said 5-HT 2A modulator, wherein said 5 HT 2A modulator is piperidinyl compounds B, spiroazacyclic compounds C, or azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a 5-HT 2A modulator.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is a 5-HT 2A antagonist.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is a 5-HT 2A inverse agonist.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a 5-HT 2A modulator, wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, or phenylindole compounds A, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, or fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a 5-HT 2A modulator; and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is a 5-HT 2A antagonist.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is a 5-HT 2A inverse agonist.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a 5-HT 2A modulator, wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, or phenylindole compounds A, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, or fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said sleep abnormality is difficulty falling asleep, difficulty staying asleep, or waking up too early.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a 5-HT 2A modulator.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is a 5-HT 2A antagonist.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is a 5-HT 2A inverse agonist.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a 5-HT 2A modulator, wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, or phenylindole compounds A, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, or fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a 5-HT 2A modulator; and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is a 5-HT 2A antagonist.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is a 5-HT 2A inverse agonist.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a 5-HT 2A modulator, wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, or phenylindole compounds A, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, or fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said insomnia is transient insomnia.
  • the present invention relates to the aforementioned method, wherein said insomnia is short-term insomnia.
  • the present invention relates to the aforementioned method, wherein said insomnia is chronic insomnia.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a 5-HT 2A modulator.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is a 5-HT 2A antagonist.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is a 5-HT 2A inverse agonist.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of a 5-HT 2A modulator, wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, or phenylindole compounds A, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, or fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a 5-HT 2A modulator; and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is a 5-HT 2A antagonist.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is a 5-HT 2A inverse agonist.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a 5-HT 2A modulator, wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, or phenylindole compounds A, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, or fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the 5-HT 2A modulator is piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein said depression is a major depressive disorder.
  • Another aspect of the present invention relates to a method for augmentation of antidepressant therapy in a patient comprising administering to the patient in need thereof, undergoing antidepressant therapy, a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method for eliciting a dose sparing effect in a patient undergoing treatment with an antidepressant, comprising administering to the patient in need thereof, undergoing antidepressant therapy, a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method for reducing depression relapse in a patient who received antidepressant treatment, comprising administering to the patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein the eszopiclone is administered chronically or long-term.
  • Another aspect of the present invention relates to a method for improving the tolerability of antidepressant therapy in a patient suffering from depression, comprising administering to the patient in need thereof, undergoing antidepressant therapy, a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein the antidepressant is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the antidepressant is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the antidepressant is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S) hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the antidepressant is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S) hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the antidepressant is bupropion, venlafaxine, or desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the desmethylvenlafaxine is racemic desmethylvenlafaxine, (+)-desmethylvenlafaxine, or ( ⁇ )-desmethylvenlafaxine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned method, wherein the antidepressant is a dopamine reuptake inhibitor or an atypical antidepressant.
  • the present invention relates to a pharmaceutical composition, comprising a sedative agent and an antidepressant.
  • the antidepressant is a serotonin reuptake inhibitor, including without limitation selective serotonin reuptake inhibitors, a norepinephrine reuptake inhibitor, including without limitation a selective norepinephrine reuptake inhibitor, a dopamine reuptake inhibitor, or an atypical antidepressant.
  • the antidepressant is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising a sedative agent and a serotonin reuptake inhibitor; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 150 nM.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 75 nM.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 30 nM.
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising a sedative agent and a serotonin reuptake inhibitor; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is racemic zo
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said sedative agent is eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said serotonin reuptake inhibitor is fluoxetine, fluvoxamine, milnacipran, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said serotonin reuptake inhibitor is fluoxetine, fluvoxamine, milnacipran, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising a sedative agent and a serotonin reuptake inhibitor; wherein said sedative agent is racemic zopiclone, eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them; and said serotonin reuptake inhibitor is fluoxetine, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising a sedative agent and a serotonin reuptake inhibitor; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and said serotonin reuptake inhibitor is fluoxetine or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof and fluoxetine hydrochloride or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising a sedative agent and a norepinephrine reuptake inhibitor; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 150 nM.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 75 nM.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 30 nM.
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising a sedative agent and a norepinephrine reuptake inhibitor; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is racemic zopiclone, eszopiclone, indiplon,
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising a sedative agent and a norepinephrine reuptake inhibitor; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof
  • said norepinephrine reuptake inhibitor is desipramine, maprotiline,
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a norepinephrine reuptake inhibitor; wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising a sedative agent and a 5-HT 2 receptor modulator.
  • the 5-HT 2 receptor modulator is a 5-HT 2A receptor antagonist or a 5-HT 2A inverse agonist.
  • the pharmaceutical composition comprises a sedative agent and a 5-HT 2 receptor modulator, wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said said 5-HT 2 receptor modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay
  • said 5-HT 2 receptor modulator is MDL 100907, SR 46349B, YM 992, fanans
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 150 nM.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 75 nM.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 30 nM.;
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising a sedative agent and a 5-HT 2A modulator; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolp
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising a sedative agent and a 5-HT 2A modulator; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising eszopiclone and a 5-HT 2A modulator; wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • a pharmaceutical composition comprising eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and a 5-HT 2A inverse agonist.
  • the 5-HT 2A inverse agonist is piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising a sedative agent and a dopamine reuptake inhibitor; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay
  • said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 150 nM.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 75 nM.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 30 nM.
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising a sedative agent and a dopamine reuptake inhibitor; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising a sedative agent and a dopamine reuptake inhibitor; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof
  • said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said dopamine reuptake inhibitor is bupropion, GBR-12935, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • Another aspect of the present invention relates to a pharmaceutical composition, comprising eszopiclone and bupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of a sedative agent, a serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 150 nM.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 75 nM.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 30 nM.
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of a sedative agent, a serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said serotonin reuptake inhibitor is fluoxetine, fluvoxamine, milnacipran, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said serotonin reuptake inhibitor is fluoxetine, fluvoxamine, milnacipran, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of a sedative agent, a serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them; and said serotonin reuptake inhibitor is fluoxetine, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of a sedative agent, a serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said serotonin reuptake inhibitor is fluoxetine or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, fluoxetine hydrochloride or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal therof, and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of a sedative agent, a norepinephrine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 150 nM.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 75 nM.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 30 nM.
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of a sedative agent, a norepinephrine reuptake inhibitor, and at least one pharmaceutically acceptable carrier, wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is racemic zopiclone, e
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of a sedative agent, a norepinephrine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, a norepinephrine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of a sedative agent, a 5-HT 2A modulator, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 150 nM.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 75 nM.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 30 nM.
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of a sedative agent, a 5-HT 2A modulator, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is racemic zopiclone, eszo
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of a sedative agent, a 5-HT 2A modulator, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof
  • said 5-HT 2A modulator is MDL 100907,
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them, a 5-HT 2A modulator, and at least one pharmaceutically acceptable carrier; wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of a sedative agent, a dopamine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal-of any one of them.
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay
  • said dopamine reuptake inhibitor is amineptine, bupropion, GBR
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 150 nM.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 75 nM.
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said K i is less than about 30 nM.
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of a sedative agent, a dopamine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, za
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of a sedative agent, a dopamine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof
  • said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2
  • the present invention relates to the aforementioned pharmaceutical composition, wherein said dopamine reuptake inhibitor is bupropion, GBR-12935, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • Another aspect of the present invention relates to a pharmaceutical composition, consisting essentially of eszopiclone and bupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them, and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative and a therapeutically effective amount of an antidepressant; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said antidepressant is a serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, 5HT 2A modulator, or dopamine reuptake inhibitor.
  • the present invention relates to the aforementioned method, wherein said sedative is racemic zopiclone, (S)-zopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them; and said antidepressant is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, MDL 100907, SR 46349B, YM 992, fananserin, o
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a serotonin reuptake inhibitor;
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a serotonin reuptake inhibitor; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutical
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a serotonin reuptake inhibitor; wherein said sedative agent is racemic zopiclone, eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them; and said serotonin reuptake inhibitor is fluoxetine, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a serotonin reuptake inhibitor; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said serotonin reuptake inhibitor is fluoxetine or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and a therapeutically effective amount of fluoxetine hydrochloride or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a norepinephrine reuptake inhibitor; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a norepinephrine reuptake inhibitor; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a norepinephrine reuptake inhibitor; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate,
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal; and a therapeutically effective amount of a norepinephrine reuptake inhibitor; wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a 5-HT 2A modulator; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a 5-HT 2A modulator; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-cry
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a 5-HT 2A modulator; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clath
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone and a therapeutically effective amount of a 5-HT 2A modulator; wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a dopamine reuptake inhibitor; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a dopamine reuptake inhibitor; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is racemic
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a dopamine reuptake inhibitor; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and a therapeutically effective amount of bupropion or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier;
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay;
  • said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine,
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them; and said serotonin reuptake inhibitor is fluoxetine, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said serotonin reuptake inhibitor is fluoxetine or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of fluoxetine hydrochloride or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a norepinephrine reuptake inhibitor, and at least one pharmaceutically acceptable carrier;
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a norepinephrine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate,
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a norepinephrine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, a therapeutically effective amount of a norepinephrine reuptake inhibitor; and at least one pharmaceutically acceptable carrier; wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a 5-HT 2A modulator, and at least one pharmaceutically acceptable carrier;
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay
  • said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a 5-HT 2A modulator, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a 5-HT 2A modulator, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; a therapeutically effective amount of a 5-HT 2A modulator; and at least one pharmaceutically acceptable carrier; wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a dopamine reuptake inhibitor, and at least one pharmaceutically acceptable carrier;
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a dopamine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a dopamine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-
  • Another aspect of the present invention relates to a method of treating a patient suffering from a sleep abnormality, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and a therapeutically effective amount of bupropion or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned methods, wherein said sleep disturbance is difficulty falling asleep, difficulty staying asleep, or waking up too early.
  • Another aspect of the present invention relates generally to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative and a therapeutically effective amount of an antidepressant; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said antidepressant is a serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, 5HT 2A modulator, or dopamine reuptake inhibitor.
  • the present invention relates to the aforementioned method, wherein said sedative is racemic zopiclone, (S)-zopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them; and said antidepressant is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, MDL 100907, SR 46349B, YM 992, fananserin, o
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a serotonin reuptake inhibitor; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a serotonin reuptake inhibitor; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt,
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a serotonin reuptake inhibitor; wherein said sedative agent is racemic zopiclone, eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them; and said serotonin reuptake inhibitor is fluoxetine, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a serotonin reuptake inhibitor; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said serotonin reuptake inhibitor is fluoxetine or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and a therapeutically effective amount of fluoxetine hydrochloride or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a norepinephrine reuptake inhibitor; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a norepinephrine reuptake inhibitor; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a norepinephrine reuptake inhibitor; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal; and a therapeutically effective amount of a norepinephrine reuptake inhibitor; wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, (S,S)-hydroxybupropion, or a-pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a 5-HT 2A modulator; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a 5-HT 2A modulator; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a 5-HT 2A modulator; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone and a therapeutically effective amount of a 5-HT 2A modulator; wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a dopamine reuptake inhibitor; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a dopamine reuptake inhibitor; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is racemic zopic
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a dopamine reuptake inhibitor; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and a therapeutically effective amount of bupropion or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier;
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay;
  • said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them; and said serotonin reuptake inhibitor is fluoxetine, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said serotonin reuptake inhibitor is fluoxetine or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of fluoxetine hydrochloride or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a norepinephrine reuptake inhibitor, and at least one pharmaceutically acceptable carrier;
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a norepinephrine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate,
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a norepinephrine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a norepinephrine reuptake inhibitor; and at least one pharmaceutically acceptable carrier; wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a 5-HT 2A modulator, and at least one pharmaceutically acceptable carrier;
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay;
  • said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a 5-HT 2A modulator, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph,
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a 5-HT 2A modulator, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solv
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; a therapeutically effective amount of a 5-HT 2A modulator; and at least one pharmaceutically acceptable carrier; wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a dopamine reuptake inhibitor, and at least one pharmaceutically acceptable carrier;
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a dopamine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a dopamine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof
  • Another aspect of the present invention relates to a method of treating a patient suffering from insomnia, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and a therapeutically effective amount of bupropion or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and at least one pharmaceutically acceptable carrier.
  • the present invention relates to the aforementioned methods, wherein said insomnia is transient insomnia.
  • the present invention relates to the aforementioned methods, wherein said insomnia is short-term insomnia.
  • the present invention relates to the aforementioned methods, wherein said insomnia is chronic insomnia.
  • Another aspect of the present invention relates generally to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative and a therapeutically effective amount of an antidepressant; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said antidepressant is a serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, 5HT 2A modulator, or dopamine reuptake inhibitor.
  • the present invention relates to the aforementioned method, wherein said sedative is racemic zopiclone, (S)-zopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, or hydrate of any one of them; and said antidepressant is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, MDL 100907, SR 46349B, YM 992, fananserin, o
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a serotonin reuptake inhibitor;
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a serotonin reuptake inhibitor; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt,
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a serotonin reuptake inhibitor; wherein said sedative agent is racemic zopiclone, eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them; and said serotonin reuptake inhibitor is fluoxetine, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a serotonin reuptake inhibitor; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said serotonin reuptake inhibitor is fluoxetine or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and a therapeutically effective amount of fluoxetine hydrochloride or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a norepinephrine reuptake inhibitor; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a norepinephrine reuptake inhibitor; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a norepinephrine reuptake inhibitor; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal; and a therapeutically effective amount of a norepinephrine reuptake inhibitor; wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a 5-HT 2A modulator; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a 5-HT 2A modulator; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a 5-HT 2A modulator; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone and a therapeutically effective amount of a 5-HT 2A modulator; wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a dopamine reuptake inhibitor; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a dopamine reuptake inhibitor; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is racemic zopic
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a therapeutically effective amount of a dopamine reuptake inhibitor; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and a therapeutically effective amount of bupropion or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier;
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay;
  • said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said serotonin reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them; and said serotonin reuptake inhibitor is fluoxetine, paroxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of either of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a serotonin reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said serotonin reuptake inhibitor is fluoxetine or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of fluoxetine hydrochloride or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a norepinephrine reuptake inhibitor, and at least one pharmaceutically acceptable carrier;
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a norepinephrine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate,
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a norepinephrine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; a therapeutically effective amount of a norepinephrine reuptake inhibitor; and at least one pharmaceutically acceptable carrier; wherein said norepinephrine reuptake inhibitor is desipramine, reboxetine, oxaprotiline, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a 5-HT 2A modulator, and at least one pharmaceutically acceptable carrier;
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay
  • said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a 5-HT 2A modulator, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph,
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a 5-HT 2A modulator, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole compounds A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic compounds D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solv
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; a therapeutically effective amount of a 5-HT 2A modulator; and at least one pharmaceutically acceptable carrier; wherein said 5-HT 2A modulator is MDL 100907, SR 46349B, YM 992, fananserin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a dopamine reuptake inhibitor, and at least one pharmaceutically acceptable carrier;
  • said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a dopamine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent, a therapeutically effective amount of a dopamine reuptake inhibitor, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and said dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935, venlafaxine, 2 ⁇ -propanoyl-3 ⁇ -(4-tolyl)-tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • said sedative agent is eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof
  • Another aspect of the present invention relates to a method of treating a patient suffering from depression, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof; and a therapeutically effective amount of bupropion or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a method of augmentation of antidepressant therapy in a patient, comprising the step of administering to a patient in need thereof, undergoing antidepressant therapy, a therapeutically effective amount of a sedative agent; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay.
  • Another aspect of the present invention relates to a method of augmentation of antidepressant therapy in a patient, comprising the step of administering to a patient in need thereof, undergoing antidepressant therapy, a therapeutically effective amount of a sedative agent; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • a sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method for augmentation of antidepressant therapy in a patient comprising administering to the patient in need thereof, undergoing antidepressant therapy, a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method for eliciting a dose sparing effect in a patient undergoing treatment with an antidepressant, comprising the step of administering to a patient in need thereof, undergoing antidepressant therapy, a therapeutically effective amount of a sedative agent; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay.
  • Another aspect of the present invention relates to a method for eliciting a dose sparing effect in a patient undergoing treatment with an antidepressant, comprising the step of administering to a patient in need thereof, undergoing antidepressant therapy, a therapeutically effective amount of a sedative agent; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method for eliciting a dose sparing effect in a patient undergoing treatment with an antidepressant, comprising administering to the patient in need thereof, undergoing antidepressant therapy, a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method for reducing depression relapse in a patient who received antidepressant treatment, comprising the step of administering to a patient in need thereof, receiving antidepressant treatment, a therapeutically effective amount of a sedative agent; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay.
  • Another aspect of the present invention relates to a method for reducing depression relapse in a patient who received antidepressant treatment, comprising the step of administering to a patient in need thereof, receiving antidepressant treatment, a therapeutically effective amount of a sedative agent; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method for reducing depression relapse in a patient who received antidepressant treatment, comprising administering to the patient in need thereof receiving antidepressant treatment, a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned method, wherein the eszopiclone is administered chronically or long-term.
  • Another aspect of the present invention relates to a method for improving the efficacy of antidepressant therapy in a patient suffering from depression, comprising the step of administering to a patient in need thereof, undergoing antidepressant therapy, a therapeutically effective amount of a sedative agent; wherein said sedative agent is a compound that modulates the activity of a GABA receptor and has a K i less than about 300 nM in a GABA-receptor binding assay.
  • Another aspect of the present invention relates to a method for improving the efficacy of antidepressant therapy in a patient suffering from depression, comprising the step of administering to a patient in need thereof, undergoing antidepressant therapy, a therapeutically effective amount of a sedative agent; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method for improving the tolerability of antidepressant therapy in a patient suffering from depression, comprising administering to the patient in need thereof, undergoing antidepressant therapy, a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • Another aspect of the present invention relates to a method for improving the tolerability of antidepressant therapy in a patient suffering from depression, comprising the step of administering to a patient in need thereof, undergoing antidepressant therapy, a therapeutically effective amount of a sedative agent; wherein said sedative agent is racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • Another aspect of the present invention relates to a method for improving the tolerability of antidepressant therapy in a patient suffering from depression, comprising administering to the patient in need thereof, undergoing antidepressant therapy, a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.
  • the present invention relates to the aforementioned methods, wherein the antidepressant is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the antidepressant is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned methods, wherein the antidepressant is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the antidepressant is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one of them.
  • the present invention relates to the aforementioned methods, wherein the antidepressant is a dopamine reuptake inhibitor or an atypical antidepressant.
  • the combination therapy may be formulated in an immediate release dosage form or a sustained release dosage form.
  • the present invention relates to immediate release dosage forms of the first and second therapeutic agents.
  • An immediate release dosage form may be formulated as a tablet or multiparticulate which may be encapsulated.
  • Other immediate release dosage forms known in the art can be employed.
  • the combination of therapeutic agents may be formulated to provide for an increased duration (sustained release) of therapeutic action.
  • the combination therapy can be formulated to delivery the therapeutic agents at the same time or at separate times.
  • the first and second therapeutic agents are administered via an oral solid dosage form that includes a sustained release carrier causing the sustained release of the first therapeutic agent, or both the first therapeutic agent and the second therapeutic agent when the dosage form contacts gastrointestinal fluid.
  • the sustained release dosage form may comprise a plurality of substrates which include the drugs.
  • the substrates may comprise matrix spheroids or may comprise inert pharmaceutically acceptable beads which are coated with the drugs. The coated beads are then preferably overcoated with a sustained release coating comprising the sustained release carrier.
  • the matrix spheroid may include the sustained release carrier in the matrix itself; or the matrix may comprise a normal release matrix containing the drugs, the matrix having a coating applied thereon which comprises the sustained release carrier.
  • the oral solid dosage form comprises a tablet core containing the drugs within a normal release matrix, with the tablet core being coated with a sustained release coating comprising the sustained release carrier.
  • the tablet contains the drugs within a sustained release matrix comprising the sustained release carrier.
  • the tablet contains the first therapeutic agent within a sustained release matrix and the second therapeutic agent coated into the tablet as an immediate release layer.
  • sustained release is defined for purposes of the present invention as the release of the therapeutic agent from the formulation at such a rate that blood (e.g., plasma) concentrations (levels) are maintained within the therapeutic range (above the minimum effective analgesic concentration or “MEAC”) but below toxic levels over a period of time of about 12 hours or longer.
  • blood e.g., plasma
  • concentrations levels
  • MEAC minimum effective analgesic concentration
  • the first and second therapeutic agents can be formulated as a controlled or sustained release oral formulation in any suitable tablet, coated tablet or multiparticulate formulation known to those skilled in the art.
  • the sustained release dosage form may optionally include a sustained released carrier which is incorporated into a matrix along with the active agents, or which is applied as a sustained release coating.
  • the sustained release dosage form may include the first therapeutic agent in sustained release form and second therapeutic agent in the sustained release form or in immediate release form.
  • the first therapeutic agent may be incorporated into the sustained release matrix along with the second therapeutic agent; incorporated into the sustained release coating; incorporated as a separated sustained release layer or immediate release layer; or may be incorporated as a powder, granulation, etc., in a gelatin capsule with the substrates of the present invention.
  • the sustained release dosage form may have the first therapeutic agent in the sustained release form and the second therapeutic agent in the sustained release form or immediate release form.
  • An oral dosage form according to the invention may be provided as, for example, granules, spheroids, beads, pellets (hereinafter collectively referred to as “multiparticulates”) and/or particles.
  • An amount of the multiparticulates which is effective to provide the desired dose of the therapeutic agents over time may be placed in a capsule or may be incorporated in any other suitable oral solid form.
  • the sustained release dosage form comprises such particles containing or comprising the active ingredient, wherein the particles have diameter from about 0.1 mm to about 2.5 mm, preferably from about 0.5 mm to about 2 mm.
  • the particles comprise normal release matrixes containing the first therapeutic agent with the second therapeutic agent. These particles are then coated with the sustained release carrier in embodiments where the first therapeutic agent is immediately released, the first therapeutic agent may be included in separate normal release matrix particles, or may be co-administered in a different immediate release composition which is either enveloped within a gelatin capsule or is administered separately.
  • the particles comprise inert beads which are coated with the second therapeutic agent with the first therapeutic agents. Thereafter, a coating comprising the sustained release carrier is applied onto the beads as an overcoat.
  • the particles are preferably film coated with a material that permits release of the active agents at a sustained rate in an aqueous medium.
  • the film coat is chosen so as to achieve, in combination with the other stated properties, a desired in vitro release rate.
  • the sustained release coating formulations of the present invention should be capable of producing a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert, and tack-free.
  • the dosage forms of the present invention may optionally be coated with one or more materials suitable for the regulation of release or for the protection of the formulation.
  • coatings are provided to permit either pH-dependent or pH-independent release, e.g., when exposed to gastrointestinal fluid.
  • a pH-dependent coating serves to release the first active agent, second active agent, or both in the desired areas of the gastro-intestinal (GI) tract, e.g., the stomach or small intestine, such that an absorption profile is provided which is capable of providing at least about twelve hours and preferably up to twenty-four hours of therapeutic benefit to a patient.
  • GI gastro-intestinal
  • the coating is designed to achieve optimal release regardless of pH-changes in the environmental fluid, e.g., the GI tract.
  • compositions which release a portion of the dose in one desired area of the GI tract, e.g., the stomach, and release the remainder of the dose in another area of the GI tract, e.g., the small intestine.
  • the first therapeutic agent is released in one area of the GI tract and the second therapeutic agent is released in a second area of the GI tract.
  • the first and second therapeutic agents are released in nearly equal amounts at the same location in the GI tract.
  • Formulations according to the invention that utilize pH-dependent coatings to obtain formulations may also impart a repeat-action effect whereby unprotected drug is coated over the enteric coat and is released in the stomach, while the remainder, being protected by the enteric coating, is released further down the gastrointestinal tract.
  • Coatings which are pH-dependent may be used in accordance with the present invention include shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, and methacrylic acid ester copolymers, zein, and the like.
  • one aspect of the present invention relates to a formulation wherein the first therapeutic agent is coated over the enteric coat and released into the stomach while the second therapeutic agent is protected by the enteric coating and is released further down the GI tract.
  • one aspect of the present invention relates to a formulation wherein the second therapeutic agent is coated over the enteric coat and released into the stomach while the first therapeutic agent is protected by the enteric coating and is released further down the GI tract.
  • the substrate e.g., tablet core bead, matrix particle
  • the substrate containing the first therapeutic agent (with or without the second therapeutic agent) is coated with a hydrophobic material selected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof.
  • the coating may be applied in the form of an organic or aqueous solution or dispersion. The coating may be applied to obtain a weight gain from about 2 to about 25% of the substrate in order to obtain a desired sustained release profile.
  • the invention relates to instances wherein the substrate (e.g., tablet core bead, matrix particle) containing the second therapeutic agent (with or without the first therapeutic agent) is coated with a hydrophobic material.
  • sustained release formulations and coatings which may be used in accordance with the present invention include U.S. Pat. Nos. 5,324,351; 5,356,467, and 5,472,712.
  • Cellulosic materials and polymers including alkylcelluloses, provide hydrophobic materials well suited for coating the formulations according to the invention.
  • one preferred alkylcellulosic polymer is ethylcellulose, although the artisan will appreciate that other cellulose and/or alkylcellulose polymers may be readily employed, singly or in any combination, as all or part of a hydrophobic coating.
  • Aquacoat® One commercially-available aqueous dispersion of ethylcellulose is Aquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the same in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. The plasticizer is not incorporated in the pseudolatex during the manufacturing phase. Thus, prior to using the same as a coating, it is necessary to intimately mix the Aquacoat® with a suitable plasticizer prior to use.
  • aqueous dispersion of ethylcellulose is commercially available as Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product is prepared by incorporating plasticizer into the dispersion during the manufacturing process. A hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly onto substrates.
  • Surelease® Colorcon, Inc., West Point, Pa., U.S.A.
  • the hydrophobic material comprising the controlled release coating is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • acrylic acid and methacrylic acid copolymers including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic
  • the acrylic polymer is comprised of one or more ammonio methacrylate copolymers.
  • Ammonio methacrylate copolymers are well known in the art, and are copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. In order to obtain a desirable dissolution profile, it may be necessary to incorporate in a coating two or more ammonio methacrylate copolymers having differing physical properties, such as different molar ratios of the quaternary ammonium groups to the neutral (meth)acrylic esters.
  • methacrylic acid ester-type polymers are useful for preparing pH-dependent coatings which may be used in accordance with the present invention.
  • methacrylic acid copolymer or polymeric methacrylates commercially available as Eudragit® from Rohm Tech, Inc.
  • Eudragit® E is an example of a methacrylic acid copolymer which swells and dissolves in acidic media.
  • Eudragit® L is a methacrylic acid copolymer which does not swell at about pH ⁇ 5.7 and is soluble at about pH>6.
  • Eudragit® S does not swell at about pH ⁇ 6.5 and is soluble at about pH>7.
  • Eudragit® RL and Eudragit® RS are water swellable, and the amount of water absorbed by these polymers is pH-dependent, however, dosage forms coated with Eudragit® RL and RS are pH-independent.
  • the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D, respectively.
  • Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D.
  • the mean molecular weight is about 150,000.
  • the code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents.
  • Eudragit® RL/RS mixtures are insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids.
  • the Eudragit® RL/RS dispersions of the present invention may be mixed together in any desired ratio in order to ultimately obtain a sustained release formulation having a desirable dissolution profile. Desirable sustained release formulations may be obtained, for instance, from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Of course, one skilled in the art will recognize that other acrylic polymers may also be used, such as, for example, Eudragit® L.
  • the inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic material will further improve the physical properties of the sustained release coating.
  • a plasticizer into an ethylcellulose coating containing sustained release coating before using the same as a coating material.
  • the amount of plasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 percent by weight of the film-former. Concentration of the plasticizer, however, can only be properly determined after careful experimentation with the particular coating solution and method of application.
  • plasticizers for ethylcellulose include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although it is possible that other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) may be used.
  • Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.
  • plasticizers for the acrylic polymers of the present invention include, but are not limited to citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol.
  • Other plasticizers which have proved to be suitable for enhancing the elasticity of the films formed from acrylic films such as Eudragit® RL/RS lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin.
  • Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.
  • aqueous dispersion of hydrophobic material When the aqueous dispersion of hydrophobic material is used to coat inert pharmaceutical beads such as nu pariel 18/20 beads, a plurality of the resultant stabilized solid controlled release beads may thereafter be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and contacted by an environmental fluid, e.g., gastric fluid or dissolution media.
  • an environmental fluid e.g., gastric fluid or dissolution media.
  • the stabilized controlled release bead formulations of the present invention slowly release the therapeutically active agent, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids.
  • the controlled release profile of the formulations of the invention can be altered, for example, by varying the amount of overcoating with the aqueous dispersion of hydrophobic material, altering the manner in which the plasticizer is added to the aqueous dispersion of hydrophobic material, by varying the amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc.
  • the dissolution profile of the ultimate product may also be modified, for example, by increasing or decreasing the thickness of the retardant coating.
  • Spheroids or beads coated with a therapeutically active agent are prepared, e.g., by dissolving the therapeutically active agent in water and then spraying the solution onto a substrate, for example, nu pariel 18/20 beads, using a Wuster insert.
  • additional ingredients are also added prior to coating the beads in order to assist the binding of the active agents to the beads, and/or to color the solution, etc.
  • a product which includes hydroxypropylmethylcellulose, etc. with or without colorant e.g., Opadry®, commercially available from Colorcon, Inc.
  • the resultant coated substrate in this example beads, may then be optionally overcoated with a barrier agent, to separate the therapeutically active agent from the hydrophobic controlled release coating.
  • a barrier agent is one which comprises hydroxypropylmethylcellulose.
  • any film-former known in the art may be used. It is preferred that the barrier agent does not affect the dissolution rate of the final product.
  • the beads may then be overcoated with an aqueous dispersion of the hydrophobic material.
  • the aqueous dispersion of hydrophobic material preferably further includes an effective amount of plasticizer, e.g. triethyl citrate.
  • plasticizer e.g. triethyl citrate.
  • pre-formulated aqueous dispersions of acrylic polymers such as Eudragit® can be used.
  • the coating solutions of the present invention preferably contain, in addition to the film-former, plasticizer, and solvent system (i.e., water), a colorant to provide elegance and product distinction.
  • Color may be added to the solution of the therapeutically active agent instead, or in addition to the aqueous dispersion of hydrophobic material.
  • color be added to Aquacoat® via the use of alcohol or propylene glycol based color dispersions, milled aluminum lakes and opacifiers such as titanium dioxide by adding color with shear to water soluble polymer solution and then using low shear to the plasticized Aquacoat®.
  • any suitable method of providing color to the formulations of the present invention may be used.
  • Suitable ingredients for providing color to the formulation when an aqueous dispersion of an acrylic polymer is used include titanium dioxide and color pigments, such as iron oxide pigments. The incorporation of pigments, may, however, increase the retard effect of the coating.
  • the plasticized aqueous dispersion of hydrophobic material may be applied onto the substrate comprising the therapeutically active agent by spraying using any suitable spray equipment known in the art.
  • a Wurster fluidized-bed system is used in which an air jet, injected from underneath, fluidizes the core material and effects drying while the acrylic polymer coating is sprayed on.
  • a further overcoat of a film-former such as Opadry®, is optionally applied to the beads. This overcoat is provided, if at all, in order to substantially reduce agglomeration of the beads.
  • the release of the therapeutically active agent from the controlled release formulation of the present invention can be further influenced, i.e., adjusted to a desired rate, by the addition of one or more release-modifying agents, or by providing one or more passageways through the coating.
  • the ratio of hydrophobic material to water soluble material is determined by, among other factors, the release rate required and the solubility characteristics of the materials selected.
  • the release-modifying agents which function as pore-formers may be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use.
  • the pore-formers may comprise one or more hydrophilic materials such as hydroxypropylmethylcellulose.
  • the sustained release coatings of the present invention can also include erosion-promoting agents such as starch and gums.
  • the sustained release coatings of the present invention can also include materials useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain.
  • the release-modifying agent may also comprise a semi-permeable polymer.
  • the release-modifying agent is selected from hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing.
  • the sustained release coatings of the present invention may also include an exit means comprising at least one passageway, orifice, or the like.
  • the passageway may be formed by such methods as those disclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864.
  • the passageway can have any shape such as round, triangular, square, elliptical, irregular, etc.
  • the controlled release formulation is achieved via a matrix having a controlled release coating as set forth above.
  • the present invention may also utilize a controlled release matrix that affords in-vitro dissolution rates of the active agent within the preferred ranges and that releases the active agent in a pH-dependent or pH-independent manner.
  • the materials suitable for inclusion in a controlled release matrix will depend on the method used to form the matrix.
  • a matrix in addition to the first active agent and (optionally) the second active agent may include: (1) Hydrophilic and/or hydrophobic materials, such as gums, cellulose ethers, acrylic resins, protein derived materials; the list is not meant to be exclusive, and any pharmaceutically acceptable hydrophobic material or hydrophilic material which is capable of imparting controlled release of the active agent and which melts (or softens to the extent necessary to be extruded) may be used in accordance with the present invention.
  • Hydrophilic and/or hydrophobic materials such as gums, cellulose ethers, acrylic resins, protein derived materials; the list is not meant to be exclusive, and any pharmaceutically acceptable hydrophobic material or hydrophilic material which is capable of imparting controlled release of the active agent and which melts (or softens to the extent necessary to be extruded) may be used in accordance with the present invention.
  • C 8 -C 50 especially C 12 -C 40
  • substituted or unsubstituted hydrocarbons such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes, and stearyl alcohol
  • polyalkylene glycols such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes, and stearyl alcohol.
  • the hydrophobic material is preferably selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, or mixtures thereof.
  • the hydrophobic material is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • the hydrophobic material is a pharmaceutically acceptable acrylic
  • hydrophobic materials are water-insoluble with more or less pronounced hydrophilic and/or hydrophobic trends.
  • the hydrophobic materials useful in the invention have a melting point from about 30 to about 200 C., preferably from about 45 to about 90 C.
  • the hydrophobic material may comprise natural or synthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or preferably cetostearyl alcohol), fatty acids, including but not limited to fatty acid esters, fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic aid, stearyl alcohol and hydrophobic and hydrophilic materials having hydrocarbon backbones.
  • Suitable waxes include, for example, beeswax, glycowax, castor wax and carnauba wax.
  • a wax-like substance is defined as any material which is normally solid at room temperature and has a melting point of from about 30 to about 100 C.
  • Suitable hydrophobic materials which may be used in accordance with the present invention include digestible, long chain (C 8 -C 50 , especially C 12 -C 40 ), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and natural and synthetic waxes. Hydrocarbons having a melting point of between 25 and 90 C. are preferred. Of the long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred in certain embodiments.
  • the oral dosage form may contain up to 60% (by weight) of at least one digestible, long chain hydrocarbon.
  • hydrophobic materials are included in the matrix formulations. If an additional hydrophobic material is included, it may be selected from natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures of the same. Examples include beeswax, carnauba wax, stearic acid and stearyl alcohol. This list is not meant to be exclusive.
  • One particular suitable matrix comprises at least one water soluble hydroxyalkyl cellulose, at least one C 12 -C 36 , preferably C 14 -C 22 , aliphatic alcohol and, optionally, at least one polyalkylene glycol.
  • the at least one hydroxyalkyl cellulose is preferably a hydroxy (C 1 to C 6 ) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, especially, hydroxyethylcellulose.
  • the amount of the at least one hydroxyalkyl cellulose in the present oral dosage form will be determined, inter alia, by the precise rate of release desired for the therapeutic agent.
  • the at least one aliphatic alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. In certain embodiments of the present oral dosage form, however, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol.
  • the amount of the at least one aliphatic alcohol in the present oral dosage form will be determined, as above, by the precise rate of release desired for the therapeutic agent. It will also depend on whether at least one polyalkylene glycol is present in or absent from the oral dosage form. In the absence of at least one polyalkylene glycol, the oral dosage form preferably contains between 20% and 50% (by wt) of the at least one aliphatic alcohol. When at least one polyalkylene glycol is present in the oral dosage form, then the combined weight of the at least one aliphatic alcohol and the at least one polyalkylene glycol preferably constitutes between 20% and 50% (by wt) of the total dosage.
  • the ratio of, e.g., the at least one hydroxyalkyl cellulose or acrylic resin to the at least one aliphatic alcohol/polyalkylene glycol determines, to a considerable extent, the release rate of the active agent from the formulation.
  • a ratio of the at least one hydroxyalkyl cellulose to the at least one aliphatic alcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with a ratio of between 1:3 and 1:4 being particularly preferred.
  • the at least one polyalkylene glycol may be, for example, polypropylene glycol or, which is preferred, polyethylene glycol.
  • the number average molecular weight of the at least one polyalkylene glycol is preferred between 1,000 and 15,000 especially between 1,500 and 12,000.
  • Another suitable controlled release matrix would comprise an alkylcellulose (especially ethyl cellulose), a C 12 to C 36 aliphatic alcohol and, optionally, a polyalkylene glycol.
  • the matrix includes a pharmaceutically acceptable combination of at least two hydrophobic materials.
  • a controlled release matrix may also contain suitable quantities of other materials, e.g. diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art.
  • the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example
  • terapéuticaally-effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, 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 carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • solvent encapsulating material involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its 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 glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
  • sulfate bisulfate
  • phosphate nitrate
  • acetate valerate
  • oleate palmitate
  • stearate laurate
  • benzoate lactate
  • phosphate tosylate
  • citrate maleate
  • fumarate succinate
  • tartrate napthylate
  • mesylate glucoheptonate
  • lactobionate lactobionate
  • laurylsulphonate salts and the like See, for example,
  • the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra)
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a 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 mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxa
  • pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow 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 be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • 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.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating 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.
  • suitable nonirritating 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.
  • Formulations of the present invention which are suitable for vaginal administration 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 the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, 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.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as 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.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • the therapeutic agent alone or on combination with other therapeutic agents can be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art.
  • conventional excipients i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelate, carbohydrates such as lactose, amylose or starch, magnesium stearate talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, etc.
  • the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They can also be combined where desired with other active agents, e.g., other analgesic agents.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.
  • other active agents e.g., other analgesic agents.
  • particularly suitable are oily or
  • compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients which are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • Aqueous suspensions contain the above-identified combination of drugs and that mixture has one or more excipients suitable as suspending agents, for example pharmaceutically acceptable synthetic gums such as hydroxypropylmethylcellulose or natural gums.
  • Oily suspensions may be formulated by suspending the above-identified combination of drugs in a vegetable oil or mineral oil.
  • the oily suspensions may contain a thickening agent such as beeswax or cetyl alcohol.
  • a syrup, elixir, or the like can be used wherein a sweetened vehicle is employed.
  • Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. It is also possible to freeze-dry the active compounds and use the obtained lyophilized compounds, for example, for the preparation of products for injection.
  • One aspect of combination therapy pertains to a method for providing effective therapeutic treatment in humans, comprising administering an effective or sub-therapeutic amount of a first therapeutic agent; and administering an effective amount of a second therapeutic agent in an amount effective to augment the therapeutic effect provided by said first therapeutic agent.
  • the second therapeutic agent can be administered before, simultaneously with, or after administration of the first therapeutic agent, as long as the dosing interval of the second therapeutic agent overlaps with the dosing interval of the first therapeutic agent (or its therapeutic effect).
  • the second therapeutic agent need not be administered in the same dosage form or even by the same route of administration as the first therapeutic agent.
  • the method is directed to the surprising synergistic and/or additive benefits obtained in humans, when therapeutically effective levels of a first therapeutic agent have been administered to a human, and, prior to or during the dosage interval for the second therapeutic agent or while the human is experiencing the therapeutic effect, an effective amount of a second therapeutic agent to augment the therapeutic effect of the first therapeutic agent is administered.
  • the second therapeutic agent is administered prior to the administration of the first therapeutic agent, it is preferred that the dosage intervals for the two drugs overlap, i.e., such that the therapeutic effect over at least a portion of the dosage interval of the first therapeutic agent is at least partly attributable to the second therapeutic agent.
  • the surprising synergistic and/or additive benefits obtained in the patient are achieved when therapeutically effective levels of the second therapeutic agent have been administered to the patient, and, during the dosage interval for the second therapeutic agent or while the patient is experiencing the therapeutic effect by virtue of the administration of a second therapeutic agent, an effective amount of a first therapeutic agent to augment the therapeutic effect of the second therapeutic agent is administered.
  • combination therapy relates to an oral solid dosage form comprising an therapeutically effective amount of a first therapeutic agent together with an amount of a second therapeutic agent or pharmaceutically acceptable salt thereof which augments the effect of the first therapeutic agent.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • 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, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
  • composition While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).
  • the compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals.
  • the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the subject compounds, as described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin, lungs, or mucous membranes; or (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually or buccally; (6)
  • treatment is intended to encompass also prophylaxis, therapy, management and cure.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.
  • the compound of the invention can be administered as such or in admixtures with pharmaceutically acceptable carriers and can also be administered in conjunction with antimicrobial agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides.
  • Conjunctive therapy thus includes sequential, simultaneous and separate administration of the active compound in a way that the therapeutical effects of the first administered one is not entirely disappeared when the subsequent is administered.
  • the addition of the active compound of the invention to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the complete ration.
  • an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed.
  • feed premixes and complete rations are described in reference books (such as “Applied Animal Nutrition”, W. H. Freedman and CO., San Francisco, U.S.A., 1969 or “Livestock Feeds and Feeding” O and B books, Corvallis, Ore., U.S.A., 1977).
  • microemulsification technology to improve bioavailability of some lipophilic (water insoluble) pharmaceutical agents.
  • examples include Trimetrine (Dordunoo, S. K., et al., Drug Development and Industrial Pharmacy, 17(12), 1685-1713, 1991 and REV 5901 (Sheen, P. C., et al., J Pharm Sci 80(7), 712-714, 1991).
  • microemulsification provides enhanced bioavailability by preferentially directing absorption to the lymphatic system instead of the circulatory system, which thereby bypasses the liver, and prevents destruction of the compounds in the hepatobiliary circulation.
  • the formulations contain micelles formed from a compound of the present invention and at least one amphiphilic carrier, in which the micelles have an average diameter of less than about 100 nm. More preferred embodiments provide micelles having an average diameter less than about 50 nm, and even more preferred embodiments provide micelles having an average diameter less than about 30 nm, or even less than about 20 nm.
  • amphiphilic carriers While all suitable amphiphilic carriers are contemplated, the presently preferred carriers are generally those that have Generally-Recognized-as-Safe (GRAS) status, and that can both solubilize the compound of the present invention and microemulsify it at a later stage when the solution comes into a contact with a complex water phase (such as one found in human gastro-intestinal tract).
  • GRAS Generally-Recognized-as-Safe
  • amphiphilic ingredients that satisfy these requirements have HLB (hydrophilic to lipophilic balance) values of 2-20, and their structures contain straight chain aliphatic radicals in the range of C-6 to C-20. Examples are polyethylene-glycolized fatty glycerides and polyethylene glycols.
  • Particularly preferred amphiphilic carriers are saturated and monounsaturated polyethyleneglycolyzed fatty acid glycerides, such as those obtained from fully or partially hydrogenated various vegetable oils.
  • oils may advantageously consist of tri- di- and mono-fatty acid glycerides and di- and mono-polyethyleneglycol esters of the corresponding fatty acids, with a particularly preferred fatty acid composition including capric acid 4-10, capric acid 3-9, lauric acid 40-50, myristic acid 14-24, palmitic acid 4-14 and stearic acid 5-15%.
  • amphiphilic carriers includes partially esterified sorbitan and/or sorbitol, with saturated or mono-unsaturated fatty acids (SPAN-series) or corresponding ethoxylated analogs (TWEEN-series).
  • SPAN-series saturated or mono-unsaturated fatty acids
  • TWEEN-series corresponding ethoxylated analogs
  • amphiphilic carriers are particularly contemplated, including Gelucire-series, Labrafil, Labrasol, or Lauroglycol (all manufactured and distributed by Gattefosse Corporation, Saint Priest, France), PEG-mono-oleate, PEG-di-oleate, PEG-mono-laurate and di-laurate, Lecithin, Polysorbate 80, etc (produced and distributed by a number of companies in USA and worldwide).
  • Hydrophilic polymers suitable for use in the present invention are those which are readily water-soluble, can be covalently attached to a vesicle-forming lipid, and which are tolerated in vivo without toxic effects (i.e., are biocompatible).
  • Suitable polymers include polyethylene glycol (PEG), polylactic (also termed polylactide), polyglycolic acid (also termed polyglycolide), a polylactic-polyglycolic acid copolymer, and polyvinyl alcohol.
  • PEG polyethylene glycol
  • polylactic also termed polylactide
  • polyglycolic acid also termed polyglycolide
  • a polylactic-polyglycolic acid copolymer a polyvinyl alcohol.
  • Preferred polymers are those having a molecular weight of from about 100 or 120 daltons up to about 5,000 or 10,000 daltons, and more preferably from about 300 daltons to about 5,000 daltons.
  • the polymer is polyethyleneglycol having a molecular weight of from about 100 to about 5,000 daltons, and more preferably having a molecular weight of from about 300 to about 5,000 daltons.
  • the polymer is polyethyleneglycol of 750 daltons (PEG(750)).
  • Polymers may also be defined by the number of monomers therein; a preferred embodiment of the present invention utilizes polymers of at least about three monomers, such PEG polymers consisting of three monomers (approximately 150 daltons).
  • hydrophilic polymers which may be suitable for use in the present invention include polyvinylpyrrolidone, polymethoxazoline, polyethyloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide, polydimethylacrylamide, and derivatized celluloses such as hydroxymethylcellulose or hydroxyethylcellulose.
  • a formulation of the present invention comprises a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and co-polymers thereof, celluloses, polypropylene, polyethylenes, polystyrene, polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid), poly(lactide-co-caprolactone), polysaccharides, proteins, polyhyaluronic acids, polycyanoacrylates, and blends, mixtures, or copolymers thereof.
  • a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and
  • Cyclodextrins are cyclic oligosaccharides, consisting of 6, 7 or 8 glucose units, designated by the Greek letter .alpha., .beta. or .gamma., respectively. Cyclodextrins with fewer than six glucose units are not known to exist. The glucose units are linked by alpha-1,4-glucosidic bonds. As a consequence of the chair conformation of the sugar units, all secondary hydroxyl groups (at C-2, C-3) are located on one side of the ring, while all the primary hydroxyl groups at C-6 are situated on the other side. As a result, the external faces are hydrophilic, making the cyclodextrins water-soluble.
  • the cavities of the cyclodextrins are hydrophobic, since they are lined by the hydrogen of atoms C-3 and C-5, and by ether-like oxygens.
  • These matrices allow complexation with a variety of relatively hydrophobic compounds, including, for instance, steroid compounds such as 17.beta.-estradiol (see, e.g., van Uden et al. Plant Cell Tiss. Org. Cult. 38:1-3-113 (1994)).
  • the complexation takes place by Van der Waals interactions and by hydrogen bond formation.
  • the physico-chemical properties of the cyclodextrin derivatives depend strongly on the kind and the degree of substitution. For example, their solubility in water ranges from insoluble (e.g., triacetyl-beta-cyclodextrin) to 147% soluble (w/v) (G-2-beta-cyclodextrin). In addition, they are soluble in many organic solvents.
  • the properties of the cyclodextrins enable the control over solubility of various formulation components by increasing or decreasing their solubility.
  • Parmeter (I), et al. (U.S. Pat. No. 3,453,259) and Gramera, et al. (U.S. Pat. No. 3,459,731) described electroneutral cyclodextrins.
  • Other derivatives include cyclodextrins with cationic properties [Parmeter (II), U.S. Pat. No. 3,453,257], insoluble crosslinked cyclodextrins (Solms, U.S. Pat. No. 3,420,788), and cyclodextrins with anionic properties [Parmeter (III), U.S. Pat. No. 3,426,011].
  • cyclodextrin derivatives with anionic properties carboxylic acids, phosphorous acids, phosphinous acids, phosphonic acids, phosphoric acids, thiophosphonic acids, thiosulphinic acids, and sulfonic acids have been appended to the parent cyclodextrin [see, Parmeter (III), supra]. Furthermore, sulfoalkyl ether cyclodextrin derivatives have been described by Stella, et al. (U.S. Pat. No. 5,134,127).
  • Liposomes consist of at least one lipid bilayer membrane enclosing an aqueous internal compartment. Liposomes may be characterized by membrane type and by size. Small unilamellar vesicles (SUVs) have a single membrane and typically range between 0.02 and 0.05 ⁇ m in diameter; large unilamellar vesicles (LUVS) are typically larger than 0.05 ⁇ m Oligolamellar large vesicles and multilamellar vesicles have multiple, usually concentric, membrane layers and are typically larger than 0.1 ⁇ m. Liposomes with several nonconcentric membranes, i.e., several smaller vesicles contained within a larger vesicle, are termed multivesicular vesicles.
  • SUVs Small unilamellar vesicles
  • LUVS large unilamellar vesicles
  • Oligolamellar large vesicles and multilamellar vesicles have multiple, usually concentric
  • One aspect of the present invention relates to formulations comprising liposomes containing a compound of the present invention, where the liposome membrane is formulated to provide a liposome with increased carrying capacity.
  • the compound of the present invention may be contained within, or adsorbed onto, the liposome bilayer of the liposome.
  • the compound of the present invention may be aggregated with a lipid surfactant and carried within the liposome's internal space; in these cases, the liposome membrane is formulated to resist the disruptive effects of the active agent-surfactant aggregate.
  • the lipid bilayer of a liposome contains lipids derivatized with polyethylene glycol (PEG), such that the PEG chains extend from the inner surface of the lipid bilayer into the interior space encapsulated by the liposome, and extend from the exterior of the lipid bilayer into the surrounding environment.
  • PEG polyethylene glycol
  • Active agents contained within liposomes of the present invention are in solubilized form. Aggregates of surfactant and active agent (such as emulsions or micelles containing the active agent of interest) may be entrapped within the interior space of liposomes according to the present invention.
  • a surfactant acts to disperse and solubilize the active agent, and may be selected from any suitable aliphatic, cycloaliphatic or aromatic surfactant, including but not limited to biocompatible lysophosphatidylcholines (LPCs) of varying chain lengths (for example, from about C 14 to about C 20 ).
  • LPCs biocompatible lysophosphatidylcholines
  • Polymer-derivatized lipids such as PEG-lipids may also be utilized for micelle formation as they will act to inhibit micelle/membrane fusion, and as the addition of a polymer to surfactant molecules decreases the CMC of the surfactant and aids in micelle formation.
  • Liposomes according to the present invention may be prepared by any of a variety of techniques that are known in the art. See, e.g., U.S. Pat. No. 4,235,871; Published PCT applications WO 96/14057; New RRC, Liposomes: A practical approach, IRL Press, Oxford (1990), pages 33-104; Lasic DD, Liposomes from physics to applications, Elsevier Science Publishers BV, Amsterdam, 1993.
  • liposomes of the present invention may be prepared by diffusing a lipid derivatized with a hydrophilic polymer into preformed liposomes, such as by exposing preformed liposomes to micelles composed of lipid-grafted polymers, at lipid concentrations corresponding to the final mole percent of derivatized lipid which is desired in the liposome.
  • Liposomes containing a hydrophilic polymer can also be formed by homogenization, lipid-field hydration, or extrusion techniques, as are known in the art.
  • the active agent is first dispersed by sonication in a lysophosphatidylcholine or other low CMC surfactant (including polymer grafted lipids) that readily solubilizes hydrophobic molecules.
  • a lysophosphatidylcholine or other low CMC surfactant including polymer grafted lipids
  • the resulting micellar suspension of active agent is then used to rehydrate a dried lipid sample that contains a suitable mole percent of polymer-grafted lipid, or cholesterol.
  • the lipid and active agent suspension is then formed into liposomes using extrusion techniques as are known in the art, and the resulting liposomes separated from the unencapsulated solution by standard column separation.
  • the liposomes are prepared to have substantially homogeneous sizes in a selected size range.
  • One effective sizing method involves extruding an aqueous suspension of the liposomes through a series of polycarbonate membranes having a selected uniform pore size; the pore size of the membrane will correspond roughly with the largest sizes of liposomes produced by extrusion through that membrane. See e.g., U.S. Pat. No. 4,737,323 (Apr. 12, 1988).
  • release characteristics of a formulation of the present invention depend on the encapsulating material, the concentration of encapsulated drug, and the presence of release modifiers.
  • release can be manipulated to be pH dependent, for example, using a pH sensitive coating that releases only at a low pH, as in the stomach, or a higher pH, as in the intestine.
  • An enteric coating can be used to prevent release from occurring until after passage through the stomach.
  • Multiple coatings or mixtures of cyanamide encapsulated in different materials can be used to obtain an initial release in the stomach, followed by later release in the intestine.
  • Release can also be manipulated by inclusion of salts or pore forming agents, which can increase water uptake or release of drug by diffusion from the capsule.
  • Excipients which modify the solubility of the drug can also be used to control the release rate.
  • Agents which enhance degradation of the matrix or release from the matrix can also be incorporated. They can be added to the drug, added as a separate phase (i.e., as particulates), or can be co-dissolved in the polymer phase depending on the compound. In all cases the amount should be between 0.1 and thirty percent (w/w polymer).
  • Types of degradation enhancers include inorganic salts such as ammonium sulfate and ammonium chloride, organic acids such as citric acid, benzoic acid, and ascorbic acid, inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, zinc carbonate, and zinc hydroxide, and organic bases such as protamine sulfate, spermine, choline, ethanolamine, diethanolamine, and triethanolamine and surfactants such as Tween® and Pluronic®.
  • Pore forming agents which add microstructure to the matrices i.e., water soluble compounds such as inorganic salts and sugars
  • the range should be between one and thirty percent (w/w polymer).
  • Uptake can also be manipulated by altering residence time of the particles in the gut. This can be achieved, for example, by coating the particle with, or selecting as the encapsulating material, a mucosal adhesive polymer.
  • a mucosal adhesive polymer examples include most polymers with free carboxyl groups, such as chitosan, celluloses, and especially polyacrylates (as used herein, polyacrylates refers to polymers including acrylate groups and modified acrylate groups such as cyanoacrylates and methacrylates).
  • any method of preparing a matrix formulation known to those skilled in the art may be used.
  • incorporation in the matrix may be effected, for example, by (a) forming granules comprising at least one water soluble hydroxyalkyl cellulose and the active agent; (b) mixing the hydroxyalkyl cellulose containing granules with at least one C.sub.12 -C.sub.36 aliphatic alcohol; and (c) optionally, compressing and shaping the granules.
  • the granules are formed by wet granulating the hydroxyalkyl cellulose/active agent with water.
  • the amount of water added during tie wet granulation step is preferably between 1.5 and 5 times, especially between 1.75 and 3.5 times, the dry weight of the active agent.
  • a spheronizing agent together with the active ingredient can be spheronized to form spheroids.
  • Microcrystalline cellulose is preferred.
  • a suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (Trade Mark, FMC Corporation).
  • the spheroids may also contain a binder. Suitable binders, such as low viscosity, water soluble polymers, will be well known to those skilled in the pharmaceutical art. However, water soluble hydroxy lower alkyl cellulose, such as hydroxypropylcellulose, are preferred.
  • the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.
  • the sustained release coating will generally include a hydrophobic material such as (a) a wax, either alone or in admixture with a fatty alcohol; or (b) shellac or zein.
  • Sustained release matrices can also be prepared via melt-granulation or melt-extrusion techniques.
  • melt-granulation techniques involve melting a normally solid hydrophobic material, e.g. a wax, and incorporating a powdered drug therein.
  • an additional hydrophobic substance e.g. ethylcellulose or a water-insoluble acrylic polymer, into the molten wax hydrophobic material. Examples of sustained release formulations prepared via melt-granulation techniques are found in U.S. Pat. No. 4,861,598.
  • the additional hydrophobic material may comprise one or more water-insoluble wax-like thermoplastic substances possibly mixed with one or more wax-like thermoplastic substances being less hydrophobic than said one or more water-insoluble wax-like substances.
  • the individual wax-like substances in the formulation should be substantially non-degradable and insoluble in gastrointestinal fluids during the initial release phases.
  • Useful water-insoluble wax-like substances may be those with a water-solubility that is lower than about 1:5,000 (w/w).
  • a sustained release matrix may also contain suitable quantities of other materials, e.g., diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art. The quantities of these additional materials will be sufficient to provide the desired effect to the desired formulation.
  • a sustained release matrix incorporating melt-extruded multiparticulates may also contain suitable quantities of other materials, e.g. diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art in amounts up to about 50% by weight of the particulate if desired.
  • the preparation of a suitable melt-extruded matrix according to the present invention may, for example, include the steps of blending the active agent, together with at least one hydrophobic material and preferably the additional hydrophobic material to obtain a homogeneous mixture.
  • the homogeneous mixture is then heated to a temperature sufficient to at least soften the mixture sufficiently to extrude the same.
  • the resulting homogeneous mixture is then extruded to form strands.
  • the extrudate is preferably cooled and cut into multiparticulates by any means known in the art.
  • the strands are cooled and cut into multiparticulates.
  • the multiparticulates are then divided into unit doses.
  • the extrudate preferably has a diameter of from about 0.1 to about 5 mm and provides sustained release of the therapeutically active agent for a time period of from about 8 to about 24 hours.
  • An optional process for preparing the melt extrusions of the present invention includes directly metering into an extruder a hydrophobic material, a therapeutically active agent, and an optional binder; heating the homogenous mixture; extruding the homogenous mixture to thereby form strands; cooling the strands containing the homogeneous mixture; cutting the strands into particles having a size from about 0.1 mm to about 12 mm; and dividing said particles into unit doses.
  • a relatively continuous manufacturing procedure is realized.
  • the diameter of the extruder aperture or exit port can also be adjusted to vary the thickness of the extruded strands.
  • the exit part of the extruder need not be round; it can be oblong, rectangular, etc.
  • the exiting strands can be reduced to particles using a hot wire cutter, guillotine, etc.
  • melt extruded multiparticulate system can be, for example, in the form of granules, spheroids or pellets depending upon the extruder exit orifice.
  • melt-extruded multiparticulate(s)” and “melt-extruded multiparticulate system(s)” and “melt-extruded particles” shall refer to a plurality of units, preferably within a range of similar size and/or shape and containing one or more active agents and one or more excipients, preferably including a hydrophobic material as described herein.
  • melt-extruded multiparticulates will be of a range of from about 0.1 to about 12 mm in length and have a diameter of from about 0.1 to about 5 mm.
  • melt-extruded multiparticulates can be any geometrical shape within this size range.
  • the extrudate may simply be cut into desired lengths and divided into unit doses of the therapeutically active agent without the need of a spheronization step.
  • oral dosage forms are prepared to include an effective amount of melt-extruded multiparticulates within a capsule.
  • a plurality of the melt-extruded multiparticulates may be placed in a gelatin capsule in an amount sufficient to provide an effective sustained release dose when ingested and contacted by gastric fluid.
  • a suitable amount of the multiparticulate extrudate is compressed into an oral tablet using conventional tableting equipment using standard techniques. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described in Remington's Pharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980).
  • the extrudate can be shaped into tablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et. al.).
  • the sustained release melt-extruded multiparticulate systems or tablets can be coated, or the gelatin capsule can be further coated, with a sustained release coating such as the sustained release coatings described above.
  • a sustained release coating such as the sustained release coatings described above.
  • Such coatings preferably include a sufficient amount of hydrophobic material to obtain a weight gain level from about 2 to about 30 percent, although the overcoat may be greater depending upon the physical properties of the particular active agent utilized and the desired release rate, among other things.
  • the melt-extruded unit dosage forms of the present invention may further include combinations of melt-extruded multiparticulates containing one or more of the therapeutically active agents disclosed above before being encapsulated. Furthermore, the unit dosage forms can also include an amount of an immediate release therapeutically active agent for prompt therapeutic effect.
  • the immediate release therapeutically active agent may be incorporated, e.g., as separate pellets within a gelatin capsule, or may be coated on the surface of the multiparticulates after preparation of the dosage forms (e.g., controlled release coating or matrix-based).
  • the unit dosage forms of the present invention may also contain a combination of controlled release beads and matrix multiparticulates to achieve a desired effect.
  • the sustained release formulations of the present invention preferably slowly release the therapeutically active agent, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids.
  • the sustained release profile of the melt-extruded formulations of the invention can be altered, for example, by varying the amount of retardant, i.e., hydrophobic material, by varying the amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc.
  • the melt extruded material is prepared without the inclusion of the therapeutically active agent, which is added thereafter to the extrudate.
  • Such formulations typically will have the therapeutically active agent blended together with the extruded matrix material, and then the mixture would be tableted in order to provide a slow release formulation.
  • Such formulations may be advantageous, for example, when the therapeutically active agent included in the formulation is sensitive to temperatures needed for softening the hydrophobic material and/ or the retardant material.
  • sedative agents including without limitation, serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, and 5-HT 2A modulators are chiral compounds that can exist as a racemic mixture, a non-equal mixture of enantiomers, or as a single enantiomer.
  • the recitation of a compound that can exist as a racemic mixture, a non-equal mixture of enantiomers, or a single enantiomer is meant to encompass all three aforementioned forms, unless stated otherwise.
  • enantiomeric excess is related to the older term “optical purity” in that both are measures of the same phenomenon.
  • the value of e.e. will be a number from 0 to 100, zero being racemic and 100 being pure, single enantiomer.
  • a compound which in the past might have been called 98% optically pure is now more precisely described as 96% e.e.; in other words, a 90% e.e. reflects the presence of 95% of one enantiomer and 5% of the other in the material in question.
  • compositions comprising a specified enantiomer contain the specified enantiomer in at least 90% e.e. More preferably, such compositions comprising a specified enantiomer contain the specified enantiomer in at least 95% e.e. Even more preferably, such compositions comprising a specified enantiomer contain the specified enantiomer in at least 98% e.e. Most preferably, such compositions comprising a specified enantiomer contain the specified enantiomer in at least 99% e.e.
  • compositions comprising eszopiclone contain the S-enantiomer of zopiclone in at least 90% e.e. More preferably, compositions comprising eszopiclone contain the S-enantiomer of zopiclone in at least 95% e.e. Even more preferably, such compositions comprising eszopiclone contain the S-enantiomer of zopiclone in at least 98% e.e. Most preferably, such compositions comprising eszopiclone contain the S-enantiomer of zopiclone in at least 99% e.e.
  • serotonin reuptake inhibitor refers to a compound that at least partially inhibits the reuptake of serotonin.
  • the serotonin reuptake inhibitor is a selective serotonin reuptake inhibitor.
  • selective serotonin reuptake inhibitor refers to a compound that preferentially inhibits serotonin reuptake relative to its ability to modulate the activity of other receptors.
  • norepinephrine reuptake inhibitor refers to a compound that at least partially inhibits the reuptake of norepinephrine.
  • the norepinephrine reuptake inhibitor is a selective norepinephrine reuptake inhibitor.
  • selective norepinephrine reuptake inhibitor refers to a compound that preferentially inhibits norepinephrine reuptake relative to its ability to modulate the activity of other receptors.
  • 5-HT 2A modulator refers to a compound that modulates the activity of 5-HT 2A receptor.
  • the term “5-HT 2A modulator” includes 5-HT 2A antagonists and 5-HT 2A inverse agonists and 5-HT 2A partial agonists.
  • antagonist refers to a compound that binds to a receptor site, but does not cause any physiological changes.
  • inverse agonist and “negative antagonist” and “neutral antagonist” refer to compounds that inhibit an unoccupied, but active receptor.
  • a patient refers to a mammal in need of a particular treatment.
  • a patient is a primate, canine, feline, or equine.
  • a patient is a human.
  • co-administration and “co-administering” refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time varied administration (administration of one or more therapeutic agents at a time different from that of the administration of an additional therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent at the same time.
  • solvate refers to a pharmaceutically acceptable form of a specified compound, with one or more solvent molecules, that retains the biological effectiveness of such compound.
  • solvates include compounds of the invention in combination with solvents such, for example, water (to form the hydrate), isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or acetone.
  • solvents such as water (to form the hydrate), isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or acetone.
  • formulations of solvate mixtures such as a compound of the invention in combination with two or more solvents.
  • screened subject refers to any subject who signs the Informed Consent and completes at least one study related procedure.
  • screen failure subject refers to any subject who has signed the informed consent and completed at least one study related procedure and discontinues for any reason prior to receiving any study medication.
  • randomized subject refers to any subject who receives a randomization number.
  • completed subject refers to any subject who completes all study visits.
  • early termination subject refers to any subject who is assigned a randomization number but does not complete all study visits.
  • insomnia disorders or “sleep abnormality” refers to primary insomnia; secondary insomnia; situational insomnia; transient insomnia; short-term insomnia; chronic insomnia; acute insomnia; prolonged latency to sleep onset; difficulty falling asleep; difficulty staying asleep; sleep maintenance problems, including without limitation, frequent awakenings, an increase in time spent awake after initially falling asleep (wake time after sleep onset, or WASO), sleep fragmentation, transient microarousals, and unrefreshing sleep; increased time awake during the sleep period; waking up too early; and reduced total sleep time.
  • WASO wake time after sleep onset
  • depression refers to major depression, major depressive disorder, mild depression, moderate depression, severe depression without psychosis, severe depression with psychosis, dysthymia, bipolar disorder, or manic depression.
  • antidepressant refers to compounds used to treat depression, including without limitation: tricyclic antidepressents, such as clomipramine, amoxapine, nortriptyline, moprotilene, trimipramine, imipramine, or protriptyline; monoamine oxidase inhibitors; serotonin reuptake inhibitors, including selective serotonin reuptake inihibitors, such as citalopram, escitalopram, duloxetine, fluoxetine, sertraline, norsertraline, paroxetine, mirtrazepine, fluvoxamine, milnacipran, clominpramine, femoxetine, indapline, alaprolclate, cericlamine, or ifoxetine; norepinephrine reuptake inhibitors, including selective norepinephrine reuptake inhibitors, such as desipramine, maprotiline, lofepramine, re
  • DREAMDD Major Depressive Disorder
  • insomnia is the most disabling of the depressive symptom complex.
  • SSRIs selective serotonin re-uptake inhibitors
  • a primary objective of the present study was to evaluate subjective sleep efficacy during eight weeks of treatment with eszopiclone 3 mg nightly (at bed time) in subjects with insomnia related to major depressive disorder and treated concurrently with fluoxetine hydrochloride.
  • a secondary objective of the study was to evaluate the potential for eszopiclone 3 mg to augment the antidepressant effect of fluoxetine hydrochloride by investigating the differences in time to onset and amplitude of antidepressant responses over an 8-week treatment period.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Molecular Biology (AREA)
  • Anesthesiology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US11/007,795 2003-12-11 2004-12-08 Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression Abandoned US20050176680A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US11/007,795 US20050176680A1 (en) 2003-12-11 2004-12-08 Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
US11/761,235 US8097625B2 (en) 2003-12-11 2007-06-11 Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
US13/305,007 US20120122874A1 (en) 2003-12-11 2011-11-28 Combination of a sedative and a neurotransmitter modulator, and methods for treating depression
US14/448,499 US20140343069A1 (en) 2003-12-11 2014-07-31 Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US52915603P 2003-12-11 2003-12-11
US54161404P 2004-02-04 2004-02-04
US63321304P 2004-12-03 2004-12-03
US11/007,795 US20050176680A1 (en) 2003-12-11 2004-12-08 Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US11/761,235 Division US8097625B2 (en) 2003-12-11 2007-06-11 Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
US11/761,235 Continuation US8097625B2 (en) 2003-12-11 2007-06-11 Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression

Publications (1)

Publication Number Publication Date
US20050176680A1 true US20050176680A1 (en) 2005-08-11

Family

ID=34714379

Family Applications (4)

Application Number Title Priority Date Filing Date
US11/007,795 Abandoned US20050176680A1 (en) 2003-12-11 2004-12-08 Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
US11/761,235 Expired - Fee Related US8097625B2 (en) 2003-12-11 2007-06-11 Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
US13/305,007 Abandoned US20120122874A1 (en) 2003-12-11 2011-11-28 Combination of a sedative and a neurotransmitter modulator, and methods for treating depression
US14/448,499 Abandoned US20140343069A1 (en) 2003-12-11 2014-07-31 Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression

Family Applications After (3)

Application Number Title Priority Date Filing Date
US11/761,235 Expired - Fee Related US8097625B2 (en) 2003-12-11 2007-06-11 Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
US13/305,007 Abandoned US20120122874A1 (en) 2003-12-11 2011-11-28 Combination of a sedative and a neurotransmitter modulator, and methods for treating depression
US14/448,499 Abandoned US20140343069A1 (en) 2003-12-11 2014-07-31 Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression

Country Status (11)

Country Link
US (4) US20050176680A1 (ja)
EP (2) EP2343073A3 (ja)
JP (2) JP5646126B2 (ja)
AU (2) AU2004305563C1 (ja)
CA (1) CA2548917C (ja)
DK (1) DK1691811T3 (ja)
ES (1) ES2515092T3 (ja)
HK (1) HK1095279A1 (ja)
PL (1) PL1691811T3 (ja)
PT (1) PT1691811E (ja)
WO (1) WO2005060968A1 (ja)

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050234093A1 (en) * 2003-06-25 2005-10-20 H. Lundbeck A/S Treatment of depression and other affective disorders
US20070027213A1 (en) * 2005-06-27 2007-02-01 Biovail Laboratories International S.R.L. Modified release formulations of a bupropion salt
WO2007117581A2 (en) * 2006-04-06 2007-10-18 Collegium Pharmaceutical, Inc. Stabilized transdermal bupropion preparations
US20070250375A1 (en) * 2006-02-24 2007-10-25 Mcclellan William Dynamic Capture Rate Performance Metric
US20070299055A1 (en) * 2003-12-11 2007-12-27 Sepracor Inc. Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
US20080051429A1 (en) * 2006-04-19 2008-02-28 Van Kammen Daniel Use of 4-amino-piperidines for treating sleep disorders
US20080181943A1 (en) * 2005-08-19 2008-07-31 Sanofi-Aventis Combination of a long-acting hypnotic agent and a short-acting hypnotic agent and therapeutic use thereof
WO2008112968A1 (en) * 2007-03-14 2008-09-18 Caliper Life Sciences, Inc. Sydnonimines - specific dopamine reuptake inhibitors and their use in treating dopamine related disorders
US20080280885A1 (en) * 2005-04-07 2008-11-13 Hythiam, Inc. Methods for Treating Anxiety Related Disorders
US20080293726A1 (en) * 2005-07-06 2008-11-27 Sepracor Inc. Combinations of Eszopiclone and Trans 4-(3,4-Dichlorophenyl)-1,2,3,4-Tetrahydro-N-Methyl-1-Napthalenamine or Trans 4-(3,4-Dichlorophenyl)-1,2,3,4-Tetrahydro-1-Napthalenamine, and Methods of Treatment of Menopause and Mood, Anxiety, and Cognitive Disorders
US20090111817A1 (en) * 2005-07-06 2009-04-30 Sepracor Inc. Combinations of Eszopiclone and an Antidepressant
US20090111818A1 (en) * 2005-07-06 2009-04-30 Sepracor Inc. Combinations of Eszopiclone and O-Desmethylvenlafaxine, and Methods of Treatment of Menopause and Mood, Anxiety, and Cognitive Disorders
US20090209545A1 (en) * 2007-12-19 2009-08-20 Sepracor Inc. Besylate Salts of 6-(5-Chloro-2-Pyridyl)-5-[(4-Methyl-1-Piperazinyl)Carbonyloxy]-7-oxo-6,7-dihydro-5H-Pyrrolo[3,4-b]Pyrazine
US20090215784A1 (en) * 2007-12-19 2009-08-27 Sepracor Inc. Maleate Salts of 6-(5-Chloro-2-Pyridyl)-5-[(4-Methyl-1-Piperazinyl)Carbonyloxy]-7-oxo-6,7-dihydro-5H-Pyrrolo[3,4-b]Pyrazine
EP2123626A1 (en) * 2008-05-21 2009-11-25 Laboratorios del Dr. Esteve S.A. Co-crystals of duloxetine and co-crystal formers for the treatment of pain
US20100004251A1 (en) * 2004-02-18 2010-01-07 Sepracor Inc. Dopamine-Agonist Combination Therapy For Improving Sleep Quality
US20100009995A1 (en) * 2007-12-19 2010-01-14 Sepracor Inc. Maleate Salts of 6-(5-Chloro-2-Pyridyl)-5-[(4-Methyl-1-Piperazinyl)Carbonyloxy]-7-oxo-6,7-dihydro-5H-Pyrrolo[3,4-b]Pyrazine
US20100009994A1 (en) * 2007-12-19 2010-01-14 Sepracor Inc. L-Malate Salts of 6-(5-Chloro-2-Pyridyl)-5-[(4-Methyl-1-Piperazinyl)Carbonyloxy]-7-Oxo-6,7-Dihydro-5H-Pyrrolo[3,4-b]Pyrazine
US20100280038A1 (en) * 2004-04-05 2010-11-04 Sepracor Inc. Methods of treatment of chronic pain using eszopiclone
WO2010116385A3 (en) * 2009-04-08 2011-01-20 Rubicon Research Private Limited Pharmaceutical compositions for alleviating unpleasant taste
US20110053945A1 (en) * 2007-12-19 2011-03-03 Sepracor Inc. Salts of 6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihy-dro-5h-pyrrolo[3,4-b]pyrazine
EP2340818A1 (en) * 2009-12-23 2011-07-06 Laboratorios Del. Dr. Esteve, S.A. Co-crystals of venlafaxine and celecoxib
US20110224196A1 (en) * 2010-01-07 2011-09-15 Vivus, Inc. Treatment of obstructive sleep apnea syndrome with a combination of a carbonic anhydrase inhibitor and an additional active agent
US8198277B2 (en) 2007-12-19 2012-06-12 Sunovion Pharmaceuticals Inc. L-malate salts of 6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine
US20120238800A1 (en) * 2009-06-04 2012-09-20 Koninklijke Philips Electronics N.V. Method and system for providing behavioural therapy for insomnia
WO2013134080A2 (en) * 2012-03-05 2013-09-12 Knobler Robert L Improved method and compound for treatment of menopausal symptoms
WO2014052394A1 (en) * 2012-09-26 2014-04-03 Feuerstein Seth D Combination methods and compositions including sleep therapeutics for treating mood
US8691853B2 (en) 2007-03-14 2014-04-08 Caliper Life Sciences, Inc. Method of using dopamine reuptake inhibitors and their analogs for treating autoimmune conditions and delaying or preventing autoimmune related pathologic progressions
US9119843B2 (en) 2009-12-04 2015-09-01 Caliper Life Sciences, Inc. Method of using dopamine reuptake inhibitors and their analogs for treating diabetes symptoms and delaying or preventing diabetes-associated pathologic conditions
WO2017156266A1 (en) * 2016-03-10 2017-09-14 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists
CN112930179A (zh) * 2018-10-31 2021-06-08 爱普宁公司(特拉华) 治疗睡眠呼吸暂停的方法和组合物
US11059828B2 (en) 2009-10-23 2021-07-13 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-C]pyrroles as orexin receptor modulators
US11080484B1 (en) * 2020-10-08 2021-08-03 Omniscient Neurotechnology Pty Limited Natural language processing of electronic records
US12029714B2 (en) 2023-01-10 2024-07-09 Seth Feuerstein Combination methods and compositions including sleep therapeutics for treating mood

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7790905B2 (en) 2002-02-15 2010-09-07 Mcneil-Ppc, Inc. Pharmaceutical propylene glycol solvate compositions
US20030224006A1 (en) 2002-03-01 2003-12-04 Zaworotko Michael J. Multiple-component solid phases containing at least one active pharmaceutical ingredient
US7927613B2 (en) 2002-02-15 2011-04-19 University Of South Florida Pharmaceutical co-crystal compositions
JP2006500377A (ja) 2002-06-21 2006-01-05 トランスフォーム・ファーマシューティカルズ・インコーポレイテッド 改善された溶解性を有する医薬組成物
US8183290B2 (en) 2002-12-30 2012-05-22 Mcneil-Ppc, Inc. Pharmaceutically acceptable propylene glycol solvate of naproxen
GT200600397A (es) * 2005-09-07 2007-08-28 Formulas topicas conteniendo o-desmetil venlafaxina (odv) o sus sales
US9211212B2 (en) 2006-04-20 2015-12-15 Cerêve, Inc. Apparatus and method for modulating sleep
US11684510B2 (en) 2006-04-20 2023-06-27 University of Pittsburgh—of the Commonwealth System of Higher Education Noninvasive, regional brain thermal stimuli for the treatment of neurological disorders
US9492313B2 (en) 2006-04-20 2016-11-15 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Method and apparatus of noninvasive, regional brain thermal stimuli for the treatment of neurological disorders
US8425583B2 (en) 2006-04-20 2013-04-23 University of Pittsburgh—of the Commonwealth System of Higher Education Methods, devices and systems for treating insomnia by inducing frontal cerebral hypothermia
US20100227916A1 (en) * 2006-05-19 2010-09-09 Somaxon Pharmaceuticals, Inc N-desmethyl-doxepin and methods of using the same to treat sleep disorders
US20100179214A1 (en) 2006-05-19 2010-07-15 Somaxon Pharmaceuticals, Inc. Doxepin trans isomers and isomeric mixtures and methods of using the same to treat sleep disorders
US20100179215A1 (en) 2006-05-19 2010-07-15 Somaxon Pharmaceuticals, Inc. Doxepin isomers and isomeric mixtures and methods of using the same to treat sleep disorders
WO2007136845A2 (en) 2006-05-19 2007-11-29 Somaxon Pharmaceuticals, Inc. Low-dose doxepin for treatment of sleep disorders in elderly patients
WO2007142810A2 (en) 2006-05-19 2007-12-13 Somaxon Pharmaceuticals, Inc. Methods of using low-dose doxepin for the improvement of sleep
WO2008011150A1 (en) 2006-07-20 2008-01-24 Somaxon Pharmaceuticals, Inc. Methods of improving the pharmacokinetics of doxepin
WO2008052139A2 (en) 2006-10-25 2008-05-02 Somaxon Pharmaceuticals, Inc. Ultra low dose doxepin and methods of using the same to treat sleep disorders
US20110077200A1 (en) * 2006-12-06 2011-03-31 Somaxon Pharmaceuticals, Inc. Combination therapy using low-dose doxepin for the improvement of sleep
EP2148659A2 (en) 2007-04-13 2010-02-03 Somaxon Pharmaceuticals, Inc. Low-dose doxepin formulations
EP2020403A1 (en) 2007-08-02 2009-02-04 Esteve Quimica, S.A. Process for the resolution of zopiclone and intermediate compounds
CA2747000C (en) * 2007-12-19 2013-09-03 Sunovion Pharmaceuticals Inc. Maleate, besylate, and l-malate salts of 6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5h-pyrrolo[3,4-b]pyrazine
CN101607961B (zh) * 2008-06-18 2011-08-10 天津天士力集团有限公司 一种右佐匹克隆结晶及其组合物
US8583563B1 (en) * 2008-12-23 2013-11-12 Match.Com, L.L.C. System and method for providing enhanced matching based on personality analysis
EP2941292B1 (en) 2013-01-02 2021-02-24 EBB Therapeutics, Inc. Systems for enhancing sleep
WO2016123241A1 (en) * 2015-01-27 2016-08-04 Cerêve, Inc. Method and apparatuses for modulating sleep by chemical activation of temperature receptors
WO2017027249A1 (en) * 2015-08-11 2017-02-16 Ovid Therapeutics Inc. Methods of sedation and parenteral formulation for use during critical care treatment
EP4153549A2 (en) * 2020-05-20 2023-03-29 Certego Therapeutics Inc. Ring deuterated gaboxadol and its use for the treatment of psychiatric disorders
WO2023215338A1 (en) * 2022-05-03 2023-11-09 Wesana Health Inc. Compositions and methods for treating cluster headache

Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4278676A (en) * 1977-06-20 1981-07-14 H. Lundbeck & Co. A/S Heterocyclic compounds
US4419345A (en) * 1981-07-20 1983-12-06 Kinetic Systems, Inc. Sleep-inducing pharmaceutical composition and method
US4505914A (en) * 1982-07-29 1985-03-19 Merckle Gmbh Pharmaceutical for the treatment of sleep disorders
US5430029A (en) * 1991-05-13 1995-07-04 Iflo-Istituto Farmacologico Lombardo S.A.S. Di Giorgio E Ald. Laguzzi Pharmaceutical compositions active in the therapy of sleep disorders
US5786357A (en) * 1991-12-02 1998-07-28 Sepracor Inc. Methods and compositions for treating sleep disorders, convulsive seizures and other disorders using optically pure (+) zopiclone
US5929065A (en) * 1995-07-13 1999-07-27 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Method for treating sleep disorders
US6211173B1 (en) * 1997-03-12 2001-04-03 Cenes Limited Use of 2,3,4,5-tetrahydro-1H-3-benzazepines for the manufacture of a pharmaceutical composition for the treatment of sleep disorders
US6258814B1 (en) * 2000-10-13 2001-07-10 Schering Corporation Method of using cetirizine and pharmaceutical compositions containing the same for inducing sleep
US6341125B1 (en) * 1999-11-19 2002-01-22 Lg Electronics Inc. Method for improving TFCI transportation performance
US20020019398A1 (en) * 1999-05-14 2002-02-14 Sepracor, Inc. Methods of making and using N-desmethylzopiclone
US6348485B1 (en) * 1998-06-09 2002-02-19 Takeda Chemical Industries, Ltd. Method for treating or preventing sleep disorders
US20020193378A1 (en) * 1991-01-17 2002-12-19 Sepracor Inc. Optically active 5H-pyrrolo[3,4-b]pyrazine derivative, its preparation and pharmaceutical compositions containing it
US6640105B1 (en) * 1999-07-02 2003-10-28 Lg Electronics, Inc. Method for controlling a radio access bearer in a communication system
US20040122104A1 (en) * 2002-10-25 2004-06-24 Collegium Pharmaceutical, Inc. Modified release compositions of milnacipran
US20040147521A1 (en) * 2002-10-24 2004-07-29 Jerussi Thomas P. Compositions comprising zopiclone derivatives and methods of making and using the same
US6781970B1 (en) * 1999-08-27 2004-08-24 Telefonaktiebolaget Lm Ericsson (Publ) Transport format combination indicator mapping for telecommunications
US20050031688A1 (en) * 2003-08-04 2005-02-10 Ayala William J. Positive wakeup pharmaceutical sleep system with compatible pre-bedtime administration
US20050038042A1 (en) * 2002-11-15 2005-02-17 Jenet Codd Modified release composition comprising a short-acting hypnotic for treatment of sleep disorders

Family Cites Families (153)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2409754A (en) 1946-10-22 Method for obtaining hydantoins
US3109843A (en) 1963-11-05 Process for preparing
US3121076A (en) 1964-02-11 Benzodiazepinones and processes
NL110232C (ja) 1958-12-06
US3136815A (en) 1959-12-10 1964-06-09 Hoffmann La Roche Amino substituted benzophenone oximes and derivatives thereof
US3371085A (en) 1959-12-10 1968-02-27 Hoffmann La Roche 5-aryl-3h-1,4-benzodiazepin-2(1h)-ones
US3454554A (en) 1960-10-14 1969-07-08 Colgate Palmolive Co Aminoalkyliminodibenzyl compounds
NL127069C (ja) 1961-10-10
US3116203A (en) 1962-03-14 1963-12-31 Hoffmann La Roche Oleaginous systems
NL298071A (ja) 1963-06-04
CH449645A (de) 1963-07-09 1968-01-15 Ciba Geigy Verfahren zur Herstellung neuer Aminosäuren
CH427803A (de) 1963-12-06 1967-01-15 Geigy Ag J R Verfahren zur Herstellung eines neuen Isoxazolderivates
CH445129A (fr) 1964-04-29 1967-10-15 Nestle Sa Procédé pour la préparation de composés d'inclusion à poids moléculaire élevé
US3397209A (en) 1966-11-25 1968-08-13 Geigy Chem Corp 3-hydroxy-5-isoxazole-carboxamide
US3459731A (en) 1966-12-16 1969-08-05 Corn Products Co Cyclodextrin polyethers and their production
US3426011A (en) 1967-02-13 1969-02-04 Corn Products Co Cyclodextrins with anionic properties
US3453257A (en) 1967-02-13 1969-07-01 Corn Products Co Cyclodextrin with cationic properties
US3453259A (en) 1967-03-22 1969-07-01 Corn Products Co Cyclodextrin polyol ethers and their oxidation products
GB1177525A (en) 1967-04-13 1970-01-14 Leo Ab New Heterocyclic Aminoketones of Therapeutic Interest
BE759838A (fr) 1969-12-04 1971-06-03 Wellcome Found Cetones a activite biologique
US3885046A (en) 1969-12-04 1975-05-20 Burroughs Wellcome Co Meta chloro or fluoro substituted alpha-T-butylaminopropionphenones in the treatment of depression
US3821249A (en) 1970-03-13 1974-06-28 En Nom Collectif Science Union Dibenzothiazefin derivatives
US3758528A (en) 1970-03-13 1973-09-11 Science Union & Cie Tricyclic compounds
OA04285A (fr) 1972-01-07 1979-12-31 Rhone Poulenc Sa Nouveaux dérivés de la pyrrolo (3,4-b) pyrazine et leur préparation.
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
GB1422263A (en) 1973-01-30 1976-01-21 Ferrosan As 4-phenyl-piperidine compounds
US3916889A (en) 1973-09-28 1975-11-04 Sandoz Ag Patient ventilator apparatus
US4314081A (en) 1974-01-10 1982-02-02 Eli Lilly And Company Arloxyphenylpropylamines
US4280957A (en) 1974-09-11 1981-07-28 Hoffmann-La Roche Inc. Imidazodiazepines and processes therefor
AR208414A1 (es) 1974-11-07 1976-12-27 Rhone Poulenc Ind Procedimiento para obtener nuevos derivados de la((acil-4piperazinil-1)carboniloxi-5 pirrolinona-2)
GB1478759A (en) 1974-11-18 1977-07-06 Alza Corp Process for forming outlet passageways in pills using a laser
DE2460891C2 (de) 1974-12-21 1982-09-23 Gödecke AG, 1000 Berlin 1-Aminomethyl-1-cycloalkanessigsäuren und deren Ester, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel
US3960927A (en) 1975-03-18 1976-06-01 Richardson-Merrell Inc. Olefinic derivatives of amino acids
NL7503310A (nl) 1975-03-20 1976-09-22 Philips Nv Verbindingen met antidepressieve werking.
GB1497306A (en) 1975-07-03 1978-01-05 Leo Ab Preparation of lofepramine and its hydrochloride
FR2319338A1 (fr) 1975-08-01 1977-02-25 Synthelabo Nouveaux derives de a- phenyl benzylideniques des acides amines, leur preparation et les medicaments qui en contiennent
FR2334358A1 (fr) 1975-12-12 1977-07-08 Sogeras Nouveaux medicaments derives de l'indole
GB1526331A (en) 1976-01-14 1978-09-27 Kefalas As Phthalanes
US4063064A (en) 1976-02-23 1977-12-13 Coherent Radiation Apparatus for tracking moving workpiece by a laser beam
DE2657271C2 (de) 1976-12-17 1978-10-26 Werner & Pfleiderer, 7000 Stuttgart Verfahren zum Herstellen eines rohrförmigen Körpers aus verschleißfestem Metall
IL56369A (en) 1978-01-20 1984-05-31 Erba Farmitalia Alpha-phenoxybenzyl propanolamine derivatives,their preparation and pharmaceutical compositions comprising them
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
AU530999B2 (en) 1979-06-01 1983-08-04 Wellcome Foundation Limited, The Substituted amino triazines and their use in treatment of cns disorders
CA1143728A (en) 1979-10-04 1983-03-29 Max Gerecke Imidazodiazepine derivatives
US4536518A (en) 1979-11-01 1985-08-20 Pfizer Inc. Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine
US4361583A (en) 1980-08-19 1982-11-30 Synthelabo Analgesic agent
FR2492258A1 (fr) 1980-10-17 1982-04-23 Pharmindustrie Nouveau medicament a base d'amino-2 trifluoromethoxy-6 benzothiazole
FR2492382A1 (fr) 1980-10-22 1982-04-23 Synthelabo Derives d'imidazo (1,2-a) pyridine, leur preparation et leur application en therapeutique
FR2508035A1 (fr) 1981-06-23 1982-12-24 Fabre Sa Pierre Derives d'aryl-1-aminomethyl-2 cyclopropanes carboxamides (z), leur preparation et leur application en tant que medicaments utiles dans le traitement des troubles du systeme nerveux central
US4535186A (en) 1983-04-19 1985-08-13 American Home Products Corporation 2-Phenyl-2-(1-hydroxycycloalkyl or 1-hydroxycycloalk-2-enyl)ethylamine derivatives
US4521422A (en) 1983-06-23 1985-06-04 American Cyanamid Company Aryl and heteroaryl[7-(aryl and heteroaryl)pyrazolo[1,5-a]pyrimidin-3-yl]methanones
US4900836A (en) 1983-06-23 1990-02-13 American Cyanamid Company (3-amino-1H-pyrazol-4-yl) (aryl)methanones
US4654347A (en) 1983-06-23 1987-03-31 American Cyanamid Company Aryl and heteroaryl[[7-(3-disubstituted amino)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]methanones
US4626538A (en) 1983-06-23 1986-12-02 American Cyanamid Company [7-(3-disubstituted amino)phenyl]pyrazolo[1,5-a]pyrimidines
US4513006A (en) 1983-09-26 1985-04-23 Mcneil Lab., Inc. Anticonvulsant sulfamate derivatives
GB8425872D0 (en) 1984-10-12 1984-11-21 Ciba Geigy Ag Chemical compounds
GB2167407B (en) 1984-11-22 1988-05-11 Erba Farmitalia Enantiomers of phenoxy derivatives of benzyl morpholine and salts thereof
US4594358A (en) 1985-02-25 1986-06-10 Eli Lilly And Company Analgesic method
US4683235A (en) 1985-02-25 1987-07-28 Eli Lilly And Company Analgesic method
DK288385D0 (da) 1985-06-26 1985-06-26 Novo Industri As Aminosyrederivater
ZA864772B (en) 1985-07-02 1987-02-25 Merrell Dow Pharma Novel chemical compounds
US4647591A (en) 1985-10-07 1987-03-03 Eli Lilly And Company Method for improving memory
EP0223403B1 (en) 1985-10-25 1993-08-04 Beecham Group Plc Piperidine derivative, its preparation, and its use as medicament
FR2593499B1 (fr) 1986-01-30 1988-08-12 Jouveinal Sa Aminoalcools, leur procede de preparation et leurs applications, notamment en therapeutique
US4737323A (en) 1986-02-13 1988-04-12 Liposome Technology, Inc. Liposome extrusion method
FR2600650B1 (fr) 1986-06-27 1988-09-09 Synthelabo Procede de preparation d'imidazopyridines et composes intermediaires
US4861598A (en) 1986-07-18 1989-08-29 Euroceltique, S.A. Controlled release bases for pharmaceuticals
US4847256A (en) 1986-10-16 1989-07-11 American Cyanamid Company 4,5-dihydro and 4,5,6,7-tetrahydropyrazolo(1,5-A)-pyrimidines
FR2606410B1 (fr) 1986-11-07 1989-02-24 Synthelabo Imidazopyridines, leur preparation et leur application en therapeutique
US4956388A (en) 1986-12-22 1990-09-11 Eli Lilly And Company 3-aryloxy-3-substituted propanamines
US5446070A (en) 1991-02-27 1995-08-29 Nover Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
DE3812567A1 (de) 1988-04-15 1989-10-26 Basf Ag Verfahren zur herstellung pharmazeutischer mischungen
GB8820266D0 (en) 1988-08-26 1988-09-28 Smith Kline French Lab Compounds
US4999382A (en) 1988-10-26 1991-03-12 Massachusetts Institute Of Technology Compositions for treating tobacco withdrawal symptoms and methods for their use
FR2639942B1 (fr) 1988-12-02 1991-03-29 Sanofi Sa Ethers oximes de propenone, procede pour leur preparation et compositions pharmaceutiques les contenant
US4940585A (en) 1989-02-17 1990-07-10 Hapworth William E Method for the treatment of nicotine withdrawal syndrome
GB8911017D0 (en) 1989-05-13 1989-06-28 Ciba Geigy Ag Substituted aminoalkylphosphinic acids
KR0166088B1 (ko) 1990-01-23 1999-01-15 . 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도
US5356934A (en) 1990-03-29 1994-10-18 Eli Lilly And Company Selected serotonin subtype receptor agonist to treat sleep apnea
ES2067937T3 (es) 1990-06-01 1995-04-01 Merrell Dow Pharma (+)-alfa-(2,3-dimetoxifenil)-1-(2-(4-fluorofenil)etil)-4-piperidinametanol.
FR2663934B1 (fr) 1990-06-27 1994-06-03 Adir Nouveaux derives de l'acide 4 - amino butyrique, leur procede de preparation et les preparations pharmaceutiques qui les contiennent.
US5589511A (en) 1990-08-13 1996-12-31 Sepracor Inc. Method for treating migraine headaches using optically pure S(+) fluoxetine
US5104899A (en) 1990-08-13 1992-04-14 Sepracor, Inc. Methods and compositions for treating depression using optically pure fluoxetine
DK213290D0 (da) 1990-09-06 1990-09-06 Lundbeck & Co As H Treatment of cerebrovascular disorders
US6197819B1 (en) 1990-11-27 2001-03-06 Northwestern University Gamma amino butyric acid analogs and optical isomers
AU9137091A (en) 1990-11-27 1992-06-25 Northwestern University Gaba and l-glutamic acid analogs for antiseizure treatment
US5116852A (en) * 1990-12-03 1992-05-26 Bristol-Myers Squibb Co. Treatment of sleep disorders
AU1919592A (en) 1991-04-16 1992-11-17 National Institutes Of Health Method of treating trichotillomania and onychophagia
US5151448A (en) 1991-07-12 1992-09-29 Crenshaw Roger T Method for treating premature ejaculation
IL99316A (en) 1991-08-27 1995-03-15 Teva Pharma Production of fluoxetine and new intermediates
US5286493A (en) 1992-01-27 1994-02-15 Euroceltique, S.A. Stabilized controlled release formulations having acrylic polymer coating
US5273760A (en) 1991-12-24 1993-12-28 Euroceltigue, S.A. Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US5472712A (en) 1991-12-24 1995-12-05 Euroceltique, S.A. Controlled-release formulations coated with aqueous dispersions of ethylcellulose
US5760055A (en) 1992-03-13 1998-06-02 Wake Forest University Biologically active tropane derivatives
ES2165857T3 (es) 1992-05-20 2002-04-01 Univ Northwestern Analogos de gaba y acido l-glutamico para el tratamiento de trastornos del sistema nervioso central.
US5324351A (en) 1992-08-13 1994-06-28 Euroceltique Aqueous dispersions of zein and preparation thereof
IL111786A0 (en) 1993-12-01 1995-01-24 Max Planck Gesellschaft Methods of promoting the survival and differentiation of subclasses of cholinergic and serotonergic neurons using fibroblast growth factor-5
FR2722192A1 (fr) 1994-07-06 1996-01-12 Adir Nouveaux derives de l'acide 4-amino butyrique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
IL115849A0 (en) 1994-11-03 1996-01-31 Merz & Co Gmbh & Co Tangential filtration preparation of liposomal drugs and liposome product thereof
US5538977A (en) 1995-03-17 1996-07-23 American Cyanamid Company 3-Substituted-7-[3-(imidazol-1-yl)phenyl]-pyrazolo[1,5-a]pyrimidines
IT1276522B1 (it) 1995-04-07 1997-10-31 Elena Benincasa Uso dello zolpidem per il trattamento terapeudico di sindromi neuropsichiatriche associate a disfunsione e di circuiti neurali dei
US5714607A (en) 1995-12-01 1998-02-03 American Cyanamid Company Process improvement in the synthesis of N- 3-(3-cyano-pyrazolo 1,5-a!pyrimidin-7-yl)phenyl!-N-ethylacetamide
PT888325E (pt) 1996-02-07 2002-10-31 Warner Lambert Co Novos amino acidos ciclicos como agentes farmaceuiticos
SK282848B6 (sk) 1996-03-14 2002-12-03 Warner-Lambert Company Premostené cyklické aminokyseliny, farmaceutická kompozícia obsahujúca tieto aminokyseliny
ES2167717T3 (es) 1996-03-14 2002-05-16 Warner Lambert Co Nuevos aminoacidos ciclicos sustituidos como agentes farmaceuticos.
ATE361909T1 (de) 1996-10-23 2007-06-15 Warner Lambert Co Substituierte gamma-aminobuttersäurederivate als arzneimittel
DE19707628A1 (de) 1997-02-26 1998-08-27 Merck Patent Gmbh Oxazolidinone
FR2761686B1 (fr) 1997-04-07 1999-05-14 Sipsy Sa Nouveau procede de preparation du (+/-)3-(3,4- dichlorophenyl)-2-dimethylamino-2-methyl-propan-1-ol ou cericlamine (inn)
EP0994872B9 (en) 1997-06-10 2001-12-05 Synthon B.V. 4-phenylpiperidine compounds
US6028083A (en) 1997-07-25 2000-02-22 Hoechst Marion Roussel, Inc. Esters of (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol
AU8668598A (en) 1997-08-20 1999-03-08 University Of Oklahoma, The Gaba analogs to prevent and treat gastrointestinal damage
GB9718833D0 (en) 1997-09-04 1997-11-12 Merck Sharp & Dohme Therapeutic agents
US6989435B2 (en) * 1997-09-11 2006-01-24 Cambridge University Technical Services Ltd. Compounds and methods to inhibit or augment an inflammatory response
AU9214498A (en) 1997-09-23 1999-04-12 Eli Lilly And Company Treatment of attention-deficit/hyperactivity disorder
UA57107C2 (uk) 1997-09-23 2003-06-16 Елі Ліллі Енд Компані Спосіб лікування розладу поведінки
EP1032555B1 (en) 1997-10-27 2006-04-12 Warner-Lambert Company Llc Cyclic amino acids and derivatives thereof useful as pharmaceutical agents
TR200001794T2 (tr) 1997-12-16 2000-10-23 Warner-Lambert Company Farmasötik maddeler olarak yeni aminler
US6545022B1 (en) 1997-12-16 2003-04-08 Pfizer Inc. 4(3)substituted-4(3)-aminomethyl-(thio)pyran or piperidine derivatives (=gabapentin analogues), their preparation and their use in the treatment of neurological disorders
AU765802B2 (en) 1997-12-16 2003-10-02 Warner-Lambert Company 1-substituted-1-aminomethyl-cycloalkane derivatives (=gabapentin analogues), their preparation and their use in the treatment of neurological disorders
GB9801538D0 (en) * 1998-01-23 1998-03-25 Merck Sharp & Dohme Pharmaceutical product
SE9801516D0 (sv) 1998-04-30 1998-04-30 Maria Carlsson M100907/4-Piperidinemethanol derivatives for autism
US6316638B1 (en) 1998-05-26 2001-11-13 Warner-Lambert Company Conformationally constrained amino acid compounds having affinity for the alpha2delta subunit of a calcium channel
US6974838B2 (en) 1998-08-24 2005-12-13 Sepracor Inc. Methods of treating or preventing pain using sibutramine metabolites
US6277864B1 (en) 1998-08-28 2001-08-21 Aventis Pharmaceuticals Inc. Use of R- +)-α-(2,3-dimethoxyphenyl-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol for the treatment of sleep disorders
ATE280154T1 (de) 1998-09-14 2004-11-15 Warner Lambert Co Verzweigte alkylpyrrolidin-3-carbonsäuren
WO2000031020A1 (en) 1998-11-25 2000-06-02 Warner-Lambert Company Improved gamma amino butyric acid analogs
US6342533B1 (en) * 1998-12-01 2002-01-29 Sepracor, Inc. Derivatives of (−)-venlafaxine and methods of preparing and using the same
EP1005863A1 (en) 1998-12-04 2000-06-07 Synthelabo Controlled-release dosage forms comprising a short acting hypnotic or a salt thereof
EP1031350A1 (en) 1999-02-23 2000-08-30 Warner-Lambert Company Use of a gabapentin-analog for the manufacture of a medicament for preventing and treating visceral pain
US6342496B1 (en) 1999-03-01 2002-01-29 Sepracor Inc. Bupropion metabolites and methods of use
IL151164A0 (en) 2000-03-06 2003-04-10 Acadia Pharm Inc Azacyclic compounds for use in the treatment of serotonin related diseases
AU5066101A (en) 2000-04-13 2001-10-30 Synthon B.V. Modified release formulations containing a hypnotic agent
KR20030053501A (ko) 2000-07-13 2003-06-28 미쓰비시덴키 가부시키가이샤 압력 센서
TWI239333B (en) 2000-11-16 2005-09-11 Hoffmann La Roche Benzodiazepine derivatives as GABA A receptor modulators
CA2445843A1 (en) * 2001-05-01 2002-11-07 H. Lundbeck A/S The use of enantiomeric pure escitalopram
US20030162754A1 (en) 2001-12-17 2003-08-28 Tufts University Use of GABA and GABAB agonists
KR20100008799A (ko) 2001-12-28 2010-01-26 아카디아 파마슈티칼스 인코포레이티드 모노아민 수용체 조정자로서의 스피로아자사이클릭 화합물
EP2177601A1 (en) * 2002-04-12 2010-04-21 Medical College of Georgia Research Institute, Inc Antigen-presenting cell populations and their use as reagents for enhancing or reducing immune tolerance
US20050288355A1 (en) * 2002-06-20 2005-12-29 Arne Mork Combination therapy wherein a serotonin reuptake inhibitor is used
US7253186B2 (en) 2002-06-24 2007-08-07 Carl-Magnus Andersson N-substituted piperidine derivatives as serotonin receptor agents
AU2003272460B2 (en) * 2002-09-16 2009-12-17 Sepracor Inc. Treatment of CNS disorders with trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine and its formamide
PL1641456T3 (pl) 2003-06-25 2010-08-31 H Lundbeck As Gaboksadol do leczenia depresji i innych zaburzeń afektywnych
PL1691811T3 (pl) * 2003-12-11 2014-12-31 Sunovion Pharmaceuticals Inc Skojarzenie leku uspokajającego i modulatora neuroprzekaźnikowego oraz sposoby poprawy jakości snu i leczenia depresji
US20050215521A1 (en) * 2003-12-22 2005-09-29 Karim Lalji Modafinil combination therapy for improving sleep quality
WO2005063297A2 (en) 2003-12-24 2005-07-14 Sepracor Inc. Melatonin combination therapy for improving sleep quality
DE602005018763D1 (de) * 2004-02-18 2010-02-25 Sepracor Inc Dopamin-agonisten-kombinationstherapie mit sedativa zur verbesserung der schlafqualität
WO2005097132A2 (en) * 2004-04-05 2005-10-20 Sepracor Inc. Methods of treatment using eszopiclone
US7465729B2 (en) * 2004-04-05 2008-12-16 Sepracor Inc. Methods of treatment of menopause and perimenopause using eszopiclone
JP2009500420A (ja) * 2005-07-06 2009-01-08 セプラコア インコーポレーテッド エスゾピクロン及びｏ−デスメチルベンラファキシンの組み合わせ、並びに閉経期並びに気分、不安、及び認知障害の治療方法
WO2007005940A2 (en) * 2005-07-06 2007-01-11 Sepracor Inc. Combinations of eszopiclone and didesmethylsibutramine, and methods of treatment of menopause and mood, anxiety, and cognitive disorders
CN101257907A (zh) * 2005-07-06 2008-09-03 塞普拉科公司 左旋佐匹克隆和抗抑郁剂的组合
CA2957667A1 (en) * 2005-07-06 2007-01-11 Sepracor Inc. Combinations of eszopiclone and trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-n-methyl-1-napthalenamine or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, and methods of treatment of menopause and mood, anxiety, and cognitive disorders
CA2670593A1 (en) * 2006-12-01 2008-06-12 Sepracor Inc. Treatment of anxiety with eszopiclone

Patent Citations (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4278676A (en) * 1977-06-20 1981-07-14 H. Lundbeck & Co. A/S Heterocyclic compounds
US4419345A (en) * 1981-07-20 1983-12-06 Kinetic Systems, Inc. Sleep-inducing pharmaceutical composition and method
US4505914A (en) * 1982-07-29 1985-03-19 Merckle Gmbh Pharmaceutical for the treatment of sleep disorders
US20020193378A1 (en) * 1991-01-17 2002-12-19 Sepracor Inc. Optically active 5H-pyrrolo[3,4-b]pyrazine derivative, its preparation and pharmaceutical compositions containing it
US5430029A (en) * 1991-05-13 1995-07-04 Iflo-Istituto Farmacologico Lombardo S.A.S. Di Giorgio E Ald. Laguzzi Pharmaceutical compositions active in the therapy of sleep disorders
US6436936B1 (en) * 1991-12-02 2002-08-20 Sepracor Inc. Methods and compositions for treating disorders, using optically pure (+) zopiclone
US5786357A (en) * 1991-12-02 1998-07-28 Sepracor Inc. Methods and compositions for treating sleep disorders, convulsive seizures and other disorders using optically pure (+) zopiclone
US5929065A (en) * 1995-07-13 1999-07-27 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Method for treating sleep disorders
US6211173B1 (en) * 1997-03-12 2001-04-03 Cenes Limited Use of 2,3,4,5-tetrahydro-1H-3-benzazepines for the manufacture of a pharmaceutical composition for the treatment of sleep disorders
US6348485B1 (en) * 1998-06-09 2002-02-19 Takeda Chemical Industries, Ltd. Method for treating or preventing sleep disorders
US20020019398A1 (en) * 1999-05-14 2002-02-14 Sepracor, Inc. Methods of making and using N-desmethylzopiclone
US20020143016A1 (en) * 1999-05-14 2002-10-03 Sepracor, Inc. Methods of treating muscle spasms using N-desmethylzopiclone
US20030119841A1 (en) * 1999-05-14 2003-06-26 Sepracor, Inc. Methods of making N-desmethylzopiclone
US20030166657A1 (en) * 1999-05-14 2003-09-04 Sepracor, Inc. Methods of making and using N-desmethylzopiclone
US6640105B1 (en) * 1999-07-02 2003-10-28 Lg Electronics, Inc. Method for controlling a radio access bearer in a communication system
US6781970B1 (en) * 1999-08-27 2004-08-24 Telefonaktiebolaget Lm Ericsson (Publ) Transport format combination indicator mapping for telecommunications
US6341125B1 (en) * 1999-11-19 2002-01-22 Lg Electronics Inc. Method for improving TFCI transportation performance
US6319927B1 (en) * 2000-10-13 2001-11-20 Schering Corporation Method of using levocetirizine and pharmaceutical compositions containing the same for inducing sleep
US6258814B1 (en) * 2000-10-13 2001-07-10 Schering Corporation Method of using cetirizine and pharmaceutical compositions containing the same for inducing sleep
US20040147521A1 (en) * 2002-10-24 2004-07-29 Jerussi Thomas P. Compositions comprising zopiclone derivatives and methods of making and using the same
US20040122104A1 (en) * 2002-10-25 2004-06-24 Collegium Pharmaceutical, Inc. Modified release compositions of milnacipran
US20040132826A1 (en) * 2002-10-25 2004-07-08 Collegium Pharmaceutical, Inc. Modified release compositions of milnacipran
US20050038042A1 (en) * 2002-11-15 2005-02-17 Jenet Codd Modified release composition comprising a short-acting hypnotic for treatment of sleep disorders
US20050031688A1 (en) * 2003-08-04 2005-02-10 Ayala William J. Positive wakeup pharmaceutical sleep system with compatible pre-bedtime administration

Cited By (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050234093A1 (en) * 2003-06-25 2005-10-20 H. Lundbeck A/S Treatment of depression and other affective disorders
US20090203731A1 (en) * 2003-06-25 2009-08-13 H. Lundbeck A/S Treatment of depression and other affective disorders
US8097625B2 (en) 2003-12-11 2012-01-17 Sunovion Pharmaceuticals Inc. Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
US20070299055A1 (en) * 2003-12-11 2007-12-27 Sepracor Inc. Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
US8877755B2 (en) 2004-02-18 2014-11-04 Sunovion Pharmaceuticals Inc. Dopamine-agonist combination therapy for improving sleep quality
US20100004251A1 (en) * 2004-02-18 2010-01-07 Sepracor Inc. Dopamine-Agonist Combination Therapy For Improving Sleep Quality
US8247417B2 (en) 2004-04-05 2012-08-21 Sunovion Pharmaceuticals Inc. Methods of treatment of chronic pain using eszopiclone
US20100280038A1 (en) * 2004-04-05 2010-11-04 Sepracor Inc. Methods of treatment of chronic pain using eszopiclone
US8071599B2 (en) 2004-04-05 2011-12-06 Sunovion Pharmaceuticals, Inc. Methods of treatment of chronic pain using eszopiclone
US8012958B2 (en) * 2005-04-07 2011-09-06 Hythlam, Inc. Methods for treating anxiety related disorders
US20080280885A1 (en) * 2005-04-07 2008-11-13 Hythiam, Inc. Methods for Treating Anxiety Related Disorders
US7884136B2 (en) 2005-06-27 2011-02-08 Biovail Laboratories International S.R.L. Modified-release formulations of a bupropion salt
US20080038348A1 (en) * 2005-06-27 2008-02-14 Bioavail Laboratories International S.R.L. Modified release formulations of a bupropion salt
US7241805B2 (en) 2005-06-27 2007-07-10 Biovail Laboratories, Inc. Modified release formulations of a bupropion salt
US20070027213A1 (en) * 2005-06-27 2007-02-01 Biovail Laboratories International S.R.L. Modified release formulations of a bupropion salt
US8932628B2 (en) 2005-06-27 2015-01-13 Valeant International Bermuda Modified release formulations of a bupropion salt
US9504640B2 (en) 2005-06-27 2016-11-29 Valeant Pharmaceuticals Luxembourg S.Á.R.L. Modified release formulations of a bupropion salt
US8329950B2 (en) 2005-07-06 2012-12-11 Sunovion Pharmaceuticals Inc. Process for preparation of trans 4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-1Napthalenamine
US20080293726A1 (en) * 2005-07-06 2008-11-27 Sepracor Inc. Combinations of Eszopiclone and Trans 4-(3,4-Dichlorophenyl)-1,2,3,4-Tetrahydro-N-Methyl-1-Napthalenamine or Trans 4-(3,4-Dichlorophenyl)-1,2,3,4-Tetrahydro-1-Napthalenamine, and Methods of Treatment of Menopause and Mood, Anxiety, and Cognitive Disorders
US20090111817A1 (en) * 2005-07-06 2009-04-30 Sepracor Inc. Combinations of Eszopiclone and an Antidepressant
US20090111818A1 (en) * 2005-07-06 2009-04-30 Sepracor Inc. Combinations of Eszopiclone and O-Desmethylvenlafaxine, and Methods of Treatment of Menopause and Mood, Anxiety, and Cognitive Disorders
WO2007006003A3 (en) * 2005-07-06 2009-04-30 Sepracor Inc Combinations of eszopiclone and trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-n-methyl-1-napthalenamine or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, and methods of treatment of menopause and mood, anxiety, and cognitive disorders
US20100291204A1 (en) * 2005-08-19 2010-11-18 Sanofi-Aventis Combination of a long-acting hypnotic agent and a short-acting hypnotic agent and therapeutic use thereof
US20080181943A1 (en) * 2005-08-19 2008-07-31 Sanofi-Aventis Combination of a long-acting hypnotic agent and a short-acting hypnotic agent and therapeutic use thereof
AU2006281334B2 (en) * 2005-08-19 2012-10-18 Sanofi-Aventis Combination of a long-acting hypnotic agent and a short-acting hypnotic agent and therapeutic use of same
US20070250375A1 (en) * 2006-02-24 2007-10-25 Mcclellan William Dynamic Capture Rate Performance Metric
WO2007117581A3 (en) * 2006-04-06 2008-02-28 Collegium Pharmaceutical Inc Stabilized transdermal bupropion preparations
US20080044462A1 (en) * 2006-04-06 2008-02-21 Collegium Pharmaceutical, Inc. Delaware Stabilized transdermal bupropion preparations
WO2007117581A2 (en) * 2006-04-06 2007-10-18 Collegium Pharmaceutical, Inc. Stabilized transdermal bupropion preparations
US20080051429A1 (en) * 2006-04-19 2008-02-28 Van Kammen Daniel Use of 4-amino-piperidines for treating sleep disorders
WO2008112968A1 (en) * 2007-03-14 2008-09-18 Caliper Life Sciences, Inc. Sydnonimines - specific dopamine reuptake inhibitors and their use in treating dopamine related disorders
US8691853B2 (en) 2007-03-14 2014-04-08 Caliper Life Sciences, Inc. Method of using dopamine reuptake inhibitors and their analogs for treating autoimmune conditions and delaying or preventing autoimmune related pathologic progressions
US20080319030A1 (en) * 2007-03-14 2008-12-25 Hao Chen Sydnonimines - specific dopamine reuptake inhibitors and their use in treating dopamine related disorders
US8415385B2 (en) 2007-03-14 2013-04-09 Hao Chen Sydnonimines-specific dopamine reuptake inhibitors and their use in treating dopamine related disorders
US9149466B2 (en) 2007-03-14 2015-10-06 Caliper Life Sciences, Inc. Method of using dopamine reuptake inhibitors and their analogs for treating autoimmune conditions and delaying or preventing autoimmune related pathologic progressions
US9604945B2 (en) 2007-03-14 2017-03-28 Caliper Life Sciences, Inc. Sydnonimines-specific dopamine reuptake inhibitors and their use in treating dopamine related disorders
US20090215839A1 (en) * 2007-03-14 2009-08-27 Hao Chen Sydnonimines-specific dopamine reuptake inhibitors and their use in treating dopamine related disorders
US8198278B2 (en) 2007-12-19 2012-06-12 Sunovion Pharmaceuticals Inc. Besylate salts of 6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine
US20100009995A1 (en) * 2007-12-19 2010-01-14 Sepracor Inc. Maleate Salts of 6-(5-Chloro-2-Pyridyl)-5-[(4-Methyl-1-Piperazinyl)Carbonyloxy]-7-oxo-6,7-dihydro-5H-Pyrrolo[3,4-b]Pyrazine
US8212036B2 (en) 2007-12-19 2012-07-03 Sunovion Pharmaceuticals Inc. Maleate salts of 6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine
US20090209545A1 (en) * 2007-12-19 2009-08-20 Sepracor Inc. Besylate Salts of 6-(5-Chloro-2-Pyridyl)-5-[(4-Methyl-1-Piperazinyl)Carbonyloxy]-7-oxo-6,7-dihydro-5H-Pyrrolo[3,4-b]Pyrazine
US8269005B2 (en) 2007-12-19 2012-09-18 Sunovion Pharmaceuticals Inc. L-malate salts of 6-(5-chloro-2-Pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-Oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine
US8268832B2 (en) 2007-12-19 2012-09-18 Sunovion Pharmaceuticals Inc. Maleate salts of 6-(5-chloro-2-Pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine
US20090215784A1 (en) * 2007-12-19 2009-08-27 Sepracor Inc. Maleate Salts of 6-(5-Chloro-2-Pyridyl)-5-[(4-Methyl-1-Piperazinyl)Carbonyloxy]-7-oxo-6,7-dihydro-5H-Pyrrolo[3,4-b]Pyrazine
US8198277B2 (en) 2007-12-19 2012-06-12 Sunovion Pharmaceuticals Inc. L-malate salts of 6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine
US8889686B2 (en) 2007-12-19 2014-11-18 Sunovion Pharmaceuticals Inc. Method of decreasing the bitterness of a pharmaceutical dosage form containing zopiclone
US20110053945A1 (en) * 2007-12-19 2011-03-03 Sepracor Inc. Salts of 6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihy-dro-5h-pyrrolo[3,4-b]pyrazine
US8497267B2 (en) 2007-12-19 2013-07-30 Sunovion Pharmaceuticals Inc. Method for treating a sleep disorder with a dosage form of besylate salts of zopiclone or eszopiclone
US8497268B2 (en) 2007-12-19 2013-07-30 Sunovion Pharmaceuticals Inc. Method for providing blood levels of eszopiclone with maleate salts
US8889685B2 (en) 2007-12-19 2014-11-18 Sunovion Pharmaceuticals Inc. Method for treating a sleep disorder with eszopiclone maleate
US8541416B2 (en) 2007-12-19 2013-09-24 Sunovion Pharmaceuticals Inc. Method for treating a sleep disorder with a dosage form of a zopiclone or eszopiclone L-malate salt
US20100009994A1 (en) * 2007-12-19 2010-01-14 Sepracor Inc. L-Malate Salts of 6-(5-Chloro-2-Pyridyl)-5-[(4-Methyl-1-Piperazinyl)Carbonyloxy]-7-Oxo-6,7-Dihydro-5H-Pyrrolo[3,4-b]Pyrazine
US8809332B2 (en) 2007-12-19 2014-08-19 Sunovion Pharmaceuticals Inc. Method for treating anxiety with a dosage form of besylate salts of zopiclone or eszopiclone
EP2123626A1 (en) * 2008-05-21 2009-11-25 Laboratorios del Dr. Esteve S.A. Co-crystals of duloxetine and co-crystal formers for the treatment of pain
WO2010116385A3 (en) * 2009-04-08 2011-01-20 Rubicon Research Private Limited Pharmaceutical compositions for alleviating unpleasant taste
US8979730B2 (en) * 2009-06-04 2015-03-17 Koninklijke Philips N.V. Method and system for providing behavioural therapy for insomnia
US20120238800A1 (en) * 2009-06-04 2012-09-20 Koninklijke Philips Electronics N.V. Method and system for providing behavioural therapy for insomnia
USRE48841E1 (en) 2009-10-23 2021-12-07 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-c]pyrroles as orexin receptor modulators
US11667644B2 (en) 2009-10-23 2023-06-06 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-c]pyrroles as orexin receptor modulators
US11059828B2 (en) 2009-10-23 2021-07-13 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-C]pyrroles as orexin receptor modulators
US9119843B2 (en) 2009-12-04 2015-09-01 Caliper Life Sciences, Inc. Method of using dopamine reuptake inhibitors and their analogs for treating diabetes symptoms and delaying or preventing diabetes-associated pathologic conditions
WO2011076420A3 (en) * 2009-12-23 2011-12-08 Laboratorios Del Dr. Esteve, S.A. Co-crystals of venlafaxine and celecoxib
EP2340818A1 (en) * 2009-12-23 2011-07-06 Laboratorios Del. Dr. Esteve, S.A. Co-crystals of venlafaxine and celecoxib
US20110224196A1 (en) * 2010-01-07 2011-09-15 Vivus, Inc. Treatment of obstructive sleep apnea syndrome with a combination of a carbonic anhydrase inhibitor and an additional active agent
WO2013134080A2 (en) * 2012-03-05 2013-09-12 Knobler Robert L Improved method and compound for treatment of menopausal symptoms
WO2013134080A3 (en) * 2012-03-05 2013-12-27 Knobler Robert L Improved method and compound for treatment of menopausal symptoms
US10758508B2 (en) 2012-09-26 2020-09-01 Seth Feuerstein Combination methods and compositions including sleep therapeutics for treating mood
EP2900331A4 (en) * 2012-09-26 2016-09-28 Seth D Feuerstein METHODS AND COMBINATION COMPOSITIONS COMPRISING SLEEP THERAPY FOR TREATING MOOD
US11564900B2 (en) 2012-09-26 2023-01-31 Seth Feuerstein Combination methods and compositions including sleep therapeutics for treating mood
WO2014052394A1 (en) * 2012-09-26 2014-04-03 Feuerstein Seth D Combination methods and compositions including sleep therapeutics for treating mood
WO2017156266A1 (en) * 2016-03-10 2017-09-14 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists
US10828302B2 (en) 2016-03-10 2020-11-10 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists
US11241432B2 (en) 2016-03-10 2022-02-08 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists
CN112930179A (zh) * 2018-10-31 2021-06-08 爱普宁公司(特拉华) 治疗睡眠呼吸暂停的方法和组合物
WO2022073058A1 (en) * 2020-10-08 2022-04-14 Omniscient Neurotechnology Pty Limited Natural language processing of electronic records
US20220114342A1 (en) * 2020-10-08 2022-04-14 Omniscient Neurotechnology Pty Limited Natural language processing of electronic records
US11080484B1 (en) * 2020-10-08 2021-08-03 Omniscient Neurotechnology Pty Limited Natural language processing of electronic records
US12029714B2 (en) 2023-01-10 2024-07-09 Seth Feuerstein Combination methods and compositions including sleep therapeutics for treating mood

Also Published As

Publication number Publication date
DK1691811T3 (da) 2014-10-20
PT1691811E (pt) 2014-10-30
AU2011201056A1 (en) 2011-03-31
JP2007513956A (ja) 2007-05-31
AU2004305563A1 (en) 2005-07-07
US20120122874A1 (en) 2012-05-17
EP1691811A1 (en) 2006-08-23
JP2011162557A (ja) 2011-08-25
AU2004305563B2 (en) 2010-12-16
AU2004305563C1 (en) 2011-07-07
HK1095279A1 (en) 2007-05-04
CA2548917C (en) 2014-09-23
ES2515092T3 (es) 2014-10-29
WO2005060968A1 (en) 2005-07-07
EP1691811B1 (en) 2014-07-23
CA2548917A1 (en) 2005-07-07
JP5646126B2 (ja) 2014-12-24
EP2343073A2 (en) 2011-07-13
EP2343073A3 (en) 2011-10-12
US20070299055A1 (en) 2007-12-27
PL1691811T3 (pl) 2014-12-31
US8097625B2 (en) 2012-01-17
US20140343069A1 (en) 2014-11-20

Similar Documents

Publication Publication Date Title
US8097625B2 (en) Combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
US8877755B2 (en) Dopamine-agonist combination therapy for improving sleep quality
US20050164987A1 (en) Melatonin combination therapy for improving sleep quality
US20050215521A1 (en) Modafinil combination therapy for improving sleep quality
US20020151543A1 (en) Compositions and methods employing R (-) fluoxetine and other active ingredients
TW200803901A (en) Methods of treating anxiety disorders
MX2008007589A (es) Un metodo para tratar eyaculacion prematura en seres humanos.
JP2024050575A (ja) Ｌ－４－クロロキヌレニンの治療的使用
WO2000024399A1 (en) Compositions and methods employing r(-) fluoxetine and other active ingredients
WO1999061014A2 (en) Compositions and methods employing r(-) fluoxetine and other active ingredients
EP2236157A1 (en) Pipamperone and a second agent in treating mood and anxiety disorders
WO2018075481A1 (en) Compounds, compositions and methods for treating or preventing depression and other diseases
WO2023023038A1 (en) Treatment compositions and methods
JP2007511577A (ja) （２ｓ，３ｓ）−２−（３−クロロフェニル）−３，５，５−トリメチル−２−モルホリノールの使用

Legal Events

Date Code Title Description
AS Assignment

Owner name: SEPRACOR INC., MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LALJI, KARIM;BARBERICH, TIMOTHY J.;CARON, JUDY;AND OTHERS;REEL/FRAME:016173/0731;SIGNING DATES FROM 20050315 TO 20050317

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION