HK1119077A - Combinations of eszopiclone and an antidepressant - Google Patents

Description

Combination of levozopiclone and an antidepressant

Technical Field

The present invention relates to compositions and methods for the treatment of menopause and mood, anxiety, and cognitive disorders.

Background

Menopause, caused by a decrease in estrogen production, typically occurs around the age of 50, but may also occur at an earlier or later age, and may result in the following conditions: such as edema, hot flashes (or flushes), night sweats, muscle and possibly joint pain, sleep disturbances, irritability, nervousness, mood swings, headaches, palpitations (increased heart rate), dry mucous membranes, dyspareunia and micturition disorders. Hot flashes or flushes are characterized by sudden warmth in the face and neck, often progressing to the chest. Seizures usually last several minutes and are evident as skin flushes. This attack is often accompanied by sweating, dizziness, nausea, palpitations and sweating. Such symptoms can interrupt sleep and interfere with quality of life.

Although the cause of hot flashes is not completely understood, it is believed that thermoregulatory disturbances exist in the hypothalamus as a result of decreased estrogen levels. Administration of female hormones such as estrogens is effective in alleviating these symptoms, but hormonal therapy is associated with undesirable side effects. Four out of five women have disturbing menopausal disorders for at least one year, and 25% have menopausal disorders for more than 5 years. More than half of women suffer from severe disorders. Men who have undergone androgen ablation (by bilateral orchiectomy or treatment with gonadotropin-releasing hormone agonists) for metastatic prostate cancer may also have hot flashes. Menopause and perimenopause may also be accompanied by mood disorders such as depression and anxiety.

Clinicians recognize the differences between central nervous system diseases and there are many classification schemes that classify mental disorders. A diagnostic Statistical Manual of Mental Disorders, Fourth Ed, TextRevision (hereinafter "DSM-IV-TR") published by the American psychological Association and incorporated herein by reference^TM") to provide a standard diagnostic system upon which one of skill in the art would be based. According to DSM-IV-TR^TMThe CNS disorder of classification axis I comprises: childhood diagnosed disorders (e.g., attention deficit disorder or "ADD" and attention deficit/hyperactivity disorder or "ADHD") and adult diagnosed disorders. Adult diagnosed CNS disorders include (1) schizophrenia and psychotic disorders; (2) cognitive disorders; (3) mood disorders; (4) anxiety-related disorders; (5) eating disorders; (6) a substance-related disorder; (7) personality disorder; and (8) sorting the "obstacles not yet included" in the table.

Mood disorders are a typical group of recurrent diseases of different kinds, including monophasic (depression) and biphasic (manic-depressive) disorders, characterized by generalized mood disorders, psychomotor dysfunctions and vegetative symptoms.

Among its full symptom expression, clinical depression manifests as major depressive disorder with residual manifestations of various degrees during and between episodes. The mood is typically depression, irritability and/or anxiety. The patient may look painful, have frown, angle of mouth downward, deep, have little eye contact, and pronounce words (or whisper). The morbid mood may be accompanied by indulgence in guilt, thoughts of self-depreciation, attentiveness reduction, hesitation, diminished interest in daily events, social withdrawal, helplessness, hopelessness, and repeated consideration of death and suicide. Sleep disorders are common. Sometimes, the depth of this pathological mood causes tears to dry up; patients complain of an inability to experience normal feelings including sadness, joy and pleasure, and feel the world as becoming uninteresting, angry and calm.

Melancholia (formerly endogenous depression) is characterized by marked psychomotor slowing (thought and activity) or excitement (e.g., restlessness, sprains and hands, urge to speak), weight loss, irrational guilt, and loss of ability to experience pleasure. Mood and activity changed during the day, with the lowest point occurring in the morning. Most melancholic patients complain of difficulty falling asleep, waking many times, and insomnia in the middle of the night or early morning. Libido often declines or disappears. Warp arrest may occur. Anorexia and weight loss can lead to debilitation and subsequent disturbance of the dielectric balance.

In atypical depression (atypical depression), the clinical manifestations are dominated by reversed vegetative features; these include anxiety-panic symptoms, night-time deterioration, incipient insomnia, sleepiness often extending to the day, and weight gain from hyperphagia. Unlike melancholic patients, those with atypical depression show mood pleasure for potential positive events, but often fall into paralytic depression due to mild difficulty. Atypical depressive-type and bipolar II disorder (bipolar II disorders) significantly overlap.

In dysthymic disorder (dynamic disorder), symptoms of depression typically begin insidiously in childhood or adolescence and continue this intermittent or low-grade process for many or decades; major depressive disorder (major depression) can be complicated by episodes (double depression). In pure dysthymia, the manifestations of depression occur at subthreshold levels and overlap significantly with those depressive moods: habitual depression, pessimism, lack of sense of consciousness, or inability to play; negative and lethargy; inward; suspicion, rigor or complaints; self-criticism, self-reprimation and self-depreciation; and is addicted to defects, failures, and negative events.

Thorough evaluation of many people with depression reveals a bipolar character, with up to one fifth of patients with depressive disorders also showing marked hypomania (hypomania) or mania. Most of the transition from monophasic to bipolar disorder occurs within 5 years of the manifestation of depression. Predictors of transition include onset of early depression (< 25 years), postpartum depression, recurrent episodes of depression, rapid mood pleasure via physical therapy (e.g., antidepressants, light therapy, sleep deprivation, electroshock therapy), and a family history of three consecutive generations of mood disorders.

Between episodes, bipolar affective patients exhibit depressed mood and sometimes energetic behavior; disruption of development and social functioning is more prevalent than in unipolar affective diseases. In bipolar affective disorders, the onset is short (3 to 6 months), the onset age is low, the onset is more abrupt and the cycle (onset of one episode to onset of the next) is shorter than in monophasic disorder. Periodicity is a significant feature in the rapid cycling form of bipolar disorder (commonly defined as > ═ 4 episodes/year).

In bipolar disorder type I, mature mania (full-fledged manic) alternates with major depressive episodes. Bipolar affective disease type I usually begins with depression and is characterized by at least one manic or excitatory phase during its course. The depressive phase may be a direct prelude or consequence of mania, or depression and mania may be separated by months or years.

In bipolar affective disorder type II, depressive episodes alternate with hypomania (relatively mild, non-psychotic periods typically < 1 week). During hypomania, mood is pleasurable, sleep needs are reduced and psychomotor activity is accelerated beyond the usual level for the patient. Often, this transition is caused by circadian factors (e.g., falling asleep with depression and waking up in the morning with hypomanic state). Lethargy and overeating are characteristic and recur seasonally (e.g. in autumn or winter); insomnia and loss of appetite occur during the depressive phase. For some people, hypomania is adaptive because it is accompanied by energetic, confident and extraordinary social abilities. Many patients who experience elevated mood pleasure, usually at the end of depression, do not report unless specifically asked.

Patients with major depressive episodes and a family history of bipolar affective disease (informally referred to as bipolar type III) often show a recessive hypomanic tendency; their temperament is called emotional prosperity (i.e., urgency, erection and pursuing famous interest).

In cyclic mood disorders (cyclothymic disorders), the less severe hypomanic and extremely depressed periods (mini-depression periods) follow an irregular course, each extending over several days. Circulatory mood disorders are often a precursor to bipolar affective disease type II. But it can also occur as an extreme emotion without the complication of severe mood disorders. In this case, a simple cycle of dull depression with low confidence and prolonged sleep alternates with vigorous or elevated enthusiasm and shortened sleep. In another form, low depression characteristics predominate; the biphasic tendency is mainly indicated by the ease of causing either elation or irritability by antidepressants. In the clinically rare form of chronic hypomania, the elative period predominates with a reduction in sleep habituation to < 6 hours. People in this form are often overly happy, confident, overly energetic, hesitant, reckless, overly intrusive, and idle; they are busy with restless impulses and accost.

Anxiety is more common than any other type of mental disorder. Panic attacks (facial attacks) are widespread, affecting populations > 1/3 each year. Most people recover without treatment; some people develop panic disorder (panic disorder). Panic disorders are not common, affecting < 1% of the population over a 6 month period. Panic disorder usually begins late adolescence or early adulthood and affects women two to three times as frequently as men. Phobic disorders (phobic disorders) include persistent, unrealistic and severe anxiety, unlike panic disorders, free-floating anxiety (free-floating anxiety), which is associated with external conditions or stimuli. People with phobias avoid this condition or irritation or suffer from great suffering. However, they remain aware and acknowledged of their excessive anxiety. In agoraphobia, if panic increases, anxiety or avoidance to a situation or place trapped in where there is no room to escape is likely to occur. Agoraphobia is more prevalent than panic disorder. It affects 3.8% of women and 1.8% of men during any 6 months. The peak age of onset is early 20 years of age; the first appearance after age 40 is not uncommon. In specific phobias, clinically significant anxiety is caused by exposure to a particular condition or object, often resulting in avoidance. Special phobias are the most common anxiety disorders, but are less troublesome than other anxiety disorders. It affects 7% of women and 4.3% of men during any 6 months.

One form of anxiety disorder is social phobia, which is a clinically meaningful anxiety caused by specific social or activity conditions, often leading to avoidance. Social phobia affects 1.7% of women and 1.3% of men during any 6 months. However, more recent epidemiological studies indicate a virtually higher lifetime prevalence of about 13%. Men are more likely than women to suffer from the most severe form of social anxiety, avoidant personality disorder.

Yet another anxiety disorder is Obsessive Compulsive Disorder (OCD) which is characterized by recurring, redundant, intrusive thoughts, imaginations or impulses that seem foolish, bizarre, messy or dreaded (delusions) and by pressing something that will alleviate the discomfort caused by the delusions (obsessions). Obsessive compulsive disorder occurs equally in men and women, affecting 1.6% of the population during any 6 months.

Post-traumatic Stress Disorder (Posttraumatic Stress Disorder) is another anxiety Disorder. It is a disorder in which repeated experiences of irresistible traumatic events, cause strong anxiety, helplessness, fear, and circumvent the stimuli associated with the trauma. The stress-producing event involves serious injury or death threat to the person or other person or the actual death of the other person; in this event, himself experiences strong anxiety, helplessness or fear. The lifetime prevalence is at least 1%, and in high risk populations, such as victims of war infantries or violent crimes, prevalence is reported to be between 3% and 58%.

Acute stress disorder (acute stress disorder) is similar to post-traumatic stress disorder in the following respects: the person is exposed to trauma, experiences repeated trauma, evades the stimulus that alerts him to the trauma and suffers from increased arousal. By definition, however, acute stress disorder occurs within 4 weeks of a traumatic event and persists for a minimum of 2 days but no more than 4 weeks. People with this disorder have three or more of the following schizophrenic symptoms: numbing, apathy, or lack of emotional responsiveness; reduced attention to the surroundings (e.g., at a loss); unreality for things; a sense of irreductivity of self; loss of memory for a significant portion of the wound. The prevalence of acute stress disorder is unknown, but is presumably proportional to the severity of the wound and the extent of exposure to the wound.

Generalized Anxiety Disorder (Generalized Anxiety Disorder) is excessive, almost daily Anxiety and Anxiety for a certain number of activities or events for up to ≧ 6 months. Generalized anxiety disorder is common, affecting 3 to 5% of the population over a 1 year period. Women are twice as likely to be affected as men. The disorder often begins in childhood or adolescence, but may begin at any age.

Anxiety may be secondary to physiological disorders such as neurological disorders (e.g., brain trauma, infection, inner ear disorders), cardiovascular disorders (e.g., heart disease, arrhythmia), endocrine disorders (e.g., adrenal or hyperthyroid), and respiratory disorders (e.g., asthma, chronic obstructive pulmonary disease). Anxiety can be caused by the use of drugs such as alcohol, stimulants, caffeine, cocaine, and many prescription drugs. Moreover, withdrawal is often associated with anxiety.

It is estimated that 4 to 5 million americans (about 2% of all ages and 15% of those > 65 years of age) suffer from some form and degree of cognitive impairment. Cognitive disorders (cognitive function-disturbances or deficits in the processes of acquiring, preserving and using knowledge) are most commonly caused by delirium (sometimes referred to as acute disorganized state) or dementia (dementia). It can occur with disorders of feelings of emotion (affect) such as depression.

Delirium (acute confused state) is a fluctuating disorder characterized by cognition, mood, attention, arousal and self-consciousness, and occurs transiently without prior intellectual impairment or a clinical state superimposed on chronic intellectual impairment. Some practitioners use the terms delirium and acute confusion state synonymously; others use delirium to refer to a subset of hyperactive confused patients. There are also some uses of delirium to refer to complete (full-brown) confusion, while the chaotic state is used to refer to a mild sense of orientation confusion.

Dementia is a chronic impairment of mental function and other cognitive skills that is severe enough to interfere with the ability to perform daily activities. Dementia can occur at any age and can affect young people as a result of injury or hypoxia. However, it is primarily an elderly disease affecting > 15% of elderly people > 65 years and up to 40% of those > 80 years. It accounts for more than half of the admitted people in nursing homes and is the most feared case for the elderly.

Alzheimer's Disease is a progressive, silent loss of cognitive function associated with excessive senile plaques (senile plaques) in the cerebral and subcortical gray matter, which also contains β -amyloid and neurofibrillary tangles composed of tau protein.

Dementia with Lewy bodies (dementia) may be the second most common dementia following alzheimer's disease. Lewy bodies are the hallmark damage of degenerating neurons in parkinson's disease and occur in dementia with or without features of parkinson's disease. In dementia with lewy bodies, lewy bodies may clearly dominate or be confused with typical pathological changes of alzheimer's disease. The symptoms, signs and processes of dementia with lewy bodies are similar to those of alzheimer's disease, except that hallucinations (primarily pseudoscopic vision) are more prevalent and the patient appears to have acute sensitivity to anti-psychotic drug-induced extrapyramidal reactions.

Cerebrovascular disease can destroy brain tissue sufficiently to impair function. Vascular dementia (vascular dementia), which includes damage due to a single infarct at a critical site or due to multiple small infarcts from small or medium vessel disease, is more common in men and usually begins after the age of 70. More often in people with hypertension and/or diabetes or people who abuse tobacco. Progressive vascular dementia is often slowed by controlling blood pressure, regulating blood glucose (90 to 150mg/dL) and quitting smoking. Some vascular lesions were found in the anatomy of dementia patients to a degree of up to 20%.

Binswanger's dementia (subcutaneous arteriosclerotic encephalopathy) is uncommon and involves multiple infarctions in the deep layer of the white matter of the hemisphere associated with severe hypertension and systemic vascular disease. Although clinically similar to vascular dementia, dementia with guest schwann may be characterized by more focal neurological syndromes and a more rapid exacerbation process associated with acute stroke. MRI and CT showed areas of leukoencephalopathy adjacent to the cortex in the brain hemioval.

More than 25% of patients with Parkinson's disease have dementia; some estimate is as high as 80% (see ch.179). In anatomy, parkinson's disease patients may have some neuropathological brain findings, and many biochemical changes are seen in alzheimer's disease patients. Less severe subcortical dementia is also associated with parkinson's disease.

Dementia associated with progressive supranuclear palsy (progressive supranuclear palsy) often occurs after other neurological syndromes, such as multiple falls, dystonia trunk rigidity, neck supination, supranuclear ophthalmoplegia, dysphagia, and dysarthria.

Huntington's disease patients may also present with symptoms of dementia, but diagnosis is often clarified by family history, age of onset at a younger age, and motor abnormalities characteristic of the disease. In case of doubt, genetic analysis can be used for diagnosis.

Pick's disease is a less common form of dementia, affecting the anterior and temporal regions of the cortex. Patients had significant apathy and dysmnesia; they may exhibit increasing concentration, poor personal hygiene and reduced attention span. Although clinical manifestations and CT outcomes may be very unique in pick's disease, definitive diagnosis is only possible at the time of dissection. Kruyver-buyi syndrome (kluyver-Bucy syndrome) can occur early in the course of pick's disease, with dysesthesia, excessive sexual behavior, hyperorality (hungry and sucking the lips), and visual agnosia.

Frontal dementia syndromes (front lobe deficiency syndromes) can be caused by: internal pathology, primary or metastatic tumor, previous surgical procedures, brain radiation, or severe brain trauma. Repeated brain trauma in dementia pugilistica, which occurs in professional boxers, appears to be genetically related to the 4 allele of apolipoprotein E.

Normal-pressure hydrocephalus is characterized by triad features of progressive dementia, incontinence and an unstable slow and wide-step gait. The onset is usually insidious and most occurs in late middle age or elderly. The disease is more common in men and is sometimes associated with previous meningitis, subarachnoid hemorrhage, head injury, or neurological intervention. In most cases, there is a lack of evidence of prior injury. Normal pressure hydrocephalus can be caused by scarring of the arachnoid villi on the convex side of the brain, which results in slowed CSF (cerebrospinal fluid) absorption, ventricular dilation, and frontal lobe movement abnormalities. Laboratory diagnosis is based on high-normal CSF pressure (150 to 200mmHg) and evidence of ventricular dilatation and CT of narrowed sulci at the apex of the brain without widening of the subarachnoid space. The results of treatment with CSF shunt were inconsistent. The dementia is sometimes reversible; some experts recommend therapeutic lumbar puncture to remove about 30mL of CSF. Improvement in gait and cognition for hours or days indicates diversion configuration values.

Subdural hematomas (subdural hematomas) can cause changes in mental status, producing coma, delirium or dementia symptoms. Cognitive changes may begin at any time after blood begins to accumulate and may progress rapidly or slowly, depending on the size or location of the hematoma. This chronic condition may be similar to vascular dementia, with focal neurological signs and cognitive changes. Removal of hematoma can restore function or prevent further loss of mental function. However, some experts believe that after a hematoma has exerted pressure on the brain for a long period of time (perhaps more than a year), its removal has had little effect on cognitive function improvement.

The best known infectious agent of dementia is Creutzfeldt-Jakob disease (Creutzfeldt-Jakob disease), in which memory deficits, changes in electroencephalogram, muscle spasms and sometimes ataxia are significant. Infectious agents are destructive proteins called prions, which are genetically acquired by tissue transplantation, cannibalism and apparently by consumption of preparations of infected cattle (suffering from mad cow disease). Most of the cases are sporadic. It produces characteristic spongiform encephalopathies, quite unlike changes in Alzheimer's disease. This process is faster than that of Alzheimer's disease, and usually lasts for 6 to 12 months.

Gerstmann-Straussler-Scheinker (Gerstmann-Scheinker disease-another dementia with causes related to the prion-patients typically develop ataxia followed by cognitive decline. This syndrome affects young people and has a longer duration than creutzfeldt-jakob disease.

Paralytic dementia (general dementia), a form of neurosyphilis, has been a common cause of dementia in western societies. It is still prevalent in developing countries. In addition to mental decline, tremors and pupil changes can occur. CSF was tested using a Fluorescent Treponema Antibody (FTA) assay. Positive FTA test for syphilis can be confirmed.

AIDS dementia can develop in the late stages of HIV infection. Dementia can be caused by HIV, by JC virus causing progressive multifocal leukoencephalopathy, or by a variety of other conditionally pathogenic infectious agents including fungi, bacteria, viruses, or anatomically distinguishable protozoa. Early manifestations include slowed thinking and expression, difficulty concentrating and apathy, retention of self-awareness and few depressive manifestations. The motion is slowed down; ataxia and debilitation may be evident. Reflexes, including extensor plantar responses, become abnormal. Treatment with zidovudine (zidovudine) often results in improvements that are sometimes nearly dramatic. Thus, there is a need to develop effective and minimally adverse treatments for the conditions listed above.

Disclosure of Invention

The present invention relates generally to pharmaceutical compositions comprising levozopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and an antidepressant including, but not limited to: 5-hydroxytryptamine reuptake inhibitors, norepinephrine reuptake inhibitors, dopamine reuptake inhibitors, CRS antagonists and 5-HT_2AA receptor modulator. The pharmaceutical composition of the present invention is effective in the treatment of menopause, perimenopause, mood disorders, anxiety disorders, and cognitive disorders.

Furthermore, the present invention relates to a method for enhancing antidepressant therapy in a patient, the method comprising administering to the patient a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof. The invention also relates to a method for inducing a dose sparing effect in a patient undergoing antidepressant therapy, the method comprising administering to the patient a therapeutically effective amount of levozopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.

Furthermore, the present invention relates to a method for reducing the recurrence of depression in a patient receiving antidepressant therapy, the method comprising administering to the patient a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.

The combined administration of levzopiclone, a sedative agent and an antidepressant is beneficial for the treatment of such conditions as menopause, perimenopause, mood disorders, anxiety disorders and cognitive disorders.

Detailed Description

The present invention generally relates to pharmaceutical compositions comprising two or more active agents which when used together are beneficial for the treatment of menopause, perimenopause, mood disorders, anxiety disorders, or cognitive disorders. In certain embodiments, the present invention relates to pharmaceutical compositions comprising levozopiclone and an antidepressant. In certain embodiments, the present invention relates to pharmaceutical compositions comprising levozopiclone and a 5-hydroxytryptamine reuptake inhibitor (SRI). In certain embodiments, the present invention relates to pharmaceutical compositions comprising levozopiclone and a Norepinephrine Reuptake Inhibitor (NRI). In certain embodiments, the present invention relates to compositions comprising levzopiclone and 5-HT_2APharmaceutical compositions of modulators. In certain embodiments, the present invention relates to pharmaceutical compositions comprising levozopiclone and a Dopamine Reuptake Inhibitor (DRI). In certain embodiments, the present invention relates to pharmaceutical compositions comprising a reuptake inhibitor of both levozopiclone and 5-hydroxytryptamine and norepinephrine and a sedative agent. In certain embodiments, the present invention relates to pharmaceutical compositions comprising levozopiclone and three monoamines, a reuptake inhibitor of 5-hydroxytryptamine, norepinephrine, and dopamine, and a sedative agent. In one embodiment, the eszopiclone of the above embodiments exists as a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof. In another embodiment, the active agent other than eszopiclone is present in the pharmaceutical composition of the invention as a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.

Another aspect of the invention relates to a method of treating a patient suffering from menopause, perimenopause, mood disorders, anxiety disorders, or cognitive disorders, comprising the step of administering to said patient a therapeutically effective amount of a pharmaceutical composition comprising two or more active agents that, when taken together, improve the quality of sleep or sleep disorders in said patient.

Yet another aspect of the invention relates to a method of treating a patient suffering from menopause, perimenopause, mood disorders, anxiety disorders, or cognitive disorders, comprising the step of administering to said patient a therapeutically effective amount of a pharmaceutical composition comprising two or more active agents, which when taken together, improves the treatment of the patient.

In certain embodiments, the pharmaceutical composition comprises levzopiclone and a 5-hydroxytryptamine reuptake inhibitor. In certain embodiments, the pharmaceutical composition comprises levozopiclone and a norepinephrine reuptake inhibitor. In certain embodiments, the pharmaceutical composition comprises levzopiclone and 5-HT_2AA modulator. In certain embodiments, the pharmaceutical composition comprises levozopiclone and a dopamine reuptake inhibitor. In certain embodiments, the pharmaceutical composition comprises levozopiclone and a reuptake inhibitor of both 5-hydroxytryptamine and norepinephrine. In certain embodiments, the pharmaceutical composition comprises levzopiclone and three monoamines, a reuptake inhibitor of 5-hydroxytryptamine, norepinephrine, and dopamine, and a sedative. In one embodiment, the eszopiclone of the compositions listed above exists as a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.

In another embodiment, the invention relates to a method for enhancing antidepressant therapy in a patient, the method comprising administering to the patient a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.

The invention also relates to a method for inducing a dose sparing effect in a patient undergoing antidepressant therapy, the method comprising administering to the patient a therapeutically effective amount of levozopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.

Furthermore, the present invention relates to a method for reducing the recurrence of depression in a patient receiving antidepressant therapy, the method comprising administering to the patient a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof.

Levozopiclone

Levozopiclone is a cyclic pyrrolidone with the following chemical name: (+)6- (5-chloropyridin-2-yl) -5- (4-methylpiperazin-1-yl) carbonyloxy-7-oxo-6, 7-dihydro-5H-pyrrolo [3-4-b ] pyrazine or (+)6- (5-chloro-2-pyridyl) -6, 7-dihydro-7-oxo-5H-pyrrolo [3, 4-b ] pyrazin-5-yl 4-methylpiperazine-1-carboxylate. The chemical structure of levozopiclone is shown below:

levozopiclone, the S- (+) -optical isomer of the compound zopiclone, is described in us patents 6,319,926 and 6,444,673. Racemic zopiclone is described in Goa and Heel, [ Drugs, 32: 48-65(1986), and U.S. Pat. Nos. 3,862,149 and 4,220,646. S- (+) -zopiclone, hereinafter referred to by its USAN-approved generic name as levozopiclone, includes optically pure and substantially optically pure (e.g., 90%, 95% or 99% optically pure) S- (+) -zopiclone isomers.

Zopiclone, the first chemically distinct class of hypnotic and anxiolytic compounds, provides psychotherapeutic characteristics with efficacy and side effects approximating those of benzodiazepinesAnd (4) class. Some of these compounds, cyclic pyrrolidones, and benzodiazepinesThe generic phase ratio appears to cause less residual sedation and less slowing of reaction time, and it provides more than benzodiazepinesImproved therapeutic index of the class. Recently, the USFDA has approved Levozopiclone (LUNESTA)^TM) Can be used for treating insomnia.

Levozopiclone is active effectively in the treatment of sleep disorders such as insomnia. Levozopiclone also has potent activity in the treatment of sleep disorders while avoiding the usual adverse effects including, but not limited to, drowsiness, tiredness acting in the morning the next day, inattention and headache. Us patent 5,786,357 relates to a method of using levozopiclone also for the treatment of spastic disorders such as epilepsy.

In the acute or chronic management of the disease, the size of the prophylactic or therapeutic dose of levozopiclone will vary with the severity of the condition to be treated and the route of administration. The dosage, and possibly the frequency of dosage, will also vary according to age, weight and response of the individual patient. In general, the total daily dosage range, for the conditions described herein, is from about 0.25mg to about 10 mg. Preferably, the daily dosage should range between about 0.5mg to about 5 mg. Most preferably, the daily dosage should range from about 0.5mg to about 3.0 mg. In one embodiment, the daily dose is 0.5mg, 1.0mg, 1.5mg, 2.0mg, 2.5mg or 3.0 mg. In the treatment of patients, the therapy may be started at lower doses, which may range from about 0.5mg to about 2mg and increase depending on the patient's overall response. It is further recommended that children and patients over 65 years of age, as well as those with impaired renal or hepatic function, initially receive low doses to gradually change based on a combined response and plasma concentration (titrate). It may be necessary in some cases to use dosages outside these ranges.

Where oral compositions are used, suitable dosages are used in the range of about 0.25mg to about 10.0mg, with lower dosages generally being used for more general insomnia and higher dosages being presented in divided doses for management of psychiatric disorders. Preferably, the dosage range is between about 0.5mg to about 5mg, as a once daily dose or as divided doses as necessary; most preferably, the dosage is in the range of about 0.5mg to about 3mg, or as a once daily dose or as divided doses as necessary. The dosage can be gradually increased from low to within the dosage range until a suitable satisfactory control of the symptoms is obtained.

Antidepressants

A considerable number of antidepressants are known in the art. Most known antidepressants are the monoamine 5-hydroxytryptamine and/or norepinephrine reuptake inhibitors. Some antidepressants are dopamine reuptake inhibitors. It should be noted that some antidepressants are selective reuptake inhibitors of specific monoamines, while others inhibit two or three monoamines. Thus, Clomipramine (Clomipramine) -like drugs have an effect on both 5-hydroxytryptamine and norepinephrine levels.

A number of antidepressants are 5-hydroxytryptamine reuptake inhibitors (SRI). Examples of SRI agents are: citalopram (Citalopram), Duloxetine (Duloxetine) ((R))) Escitalopram (Escitalopram), Fluoxetine (Fluoxetine), Fluvoxamine (Fluvoxamine), Milnacipran (Milnacipran), Paroxetine (parooxetine), Sertraline (Sertraline), clomipramine, Femoxetine (Femoxetine), indapane (indapine) ((estrapline))) Alapropyl ester (Alaproclate), chloramine (Cericiamine), efoxetine (Ifosetine), 5-HT_2AModulators, MDL 100907, SR 46349B, YM 992, Fananserin (Fananserin), oxazolidine compound a (described in WO 98/38189), phenylindole compound a (described in us 6,486,153), piperidinyl compound B (described in us 2004/0106600), spiroazacyclics compound C (described in us 2003/0166928), and azacyclics compound D (described in us 6,756,393). Considered for the purposes of the inventionAdditional 5-hydroxytryptamine reuptake inhibitors include buspirone, clovoxamine, cyanothiopine, N-dimethyl-a- [2- (naphthyloxy) ethyl]Benzylamine (for the purposes of the present invention, this compound may be the racemate having the common name dapoxetine (dapoxetine), the R-enantiomer or the S-enantiomer), imipramine (imipramine), ritoxetine (litoxetine), lofepramine (lofepramine), nefazodone (nefazodone), norzimelidine (trazodone), venlafaxine (venlafaxine), visoline (vivaline) and zimelidine (zimeldine).

Many antidepressants are Norepinephrine Reuptake Inhibitors (NRIs). Examples of NRI agents are: desipramine (Desipramine), Maprotiline (Maprotiline), Lofepramine (Lofepramine), Reboxetine (Reboxetine), Oxaprotiline (Oxaprotiline), fezolamide (Fezolamine), Tomoxetine (Tomoxetine) and (S, S) -hydroxybupropion ((S, S) -hydroxybutapro pion). The present invention also contemplates the use of noradrenaline reuptake inhibitors in general, including nortriptyline (nortriptyline), maprotiline (maprotiline), protriptyline (protriptyline), trimipramine (trimipramine), venlafaxine (venlafaxine), amitriptyline (amitriptyline), amoxapine (amoxapine), doxepin (doxepin), clomipramine, and lamotrigine (lamotrigine).

Some of the antidepressants of the invention are Dopamine Reuptake Inhibitors (DRI). Examples of DRI agents are: aminimidine (Amineptine), bupropion, GBR-12935, venlafaxine (V-LAV)) And 2 β -propionyl-3 β - (4-tolyl) -tropane (PTT).

The present invention also includes atypical antidepressants. Atypical antidepressants do not have the traditional tricyclic structure, but do have the ability to elevate synaptic monoamines in most cases by blocking their reuptake. Bupropion, mianserin (mianserin), mirtazapine (mirtazapine), nefazadone (nefazadone) and trazodone are examples of atypical antidepressantsFor example. Some atypical antidepressants may be classified as 5-hydroxytryptamine, norepinephrine or dopamine reuptake inhibitors. Bupropion inhibits the dopamine transporter and to some extent the norepinephrine transporter. Naphthozalone and trazodone show relative selectivity for the 5-hydroxytryptamine transporter. Mirtazapine is shown to block the α 2-adrenergic autoreceptors at the nerve endings, thereby increasing norepinephrine release. Mirtazapine and mianserin also block the post-synaptic 5-hydroxytryptamine receptor, 5-HT_2A、5-HT_2CAnd 5-HT₃A receptor.

In general, the dose of antidepressant or a pharmaceutically acceptable salt thereof suitable for administration to humans is in the range of 0.01 to 50 mg/day per kg body weight of the recipient, preferably in the range of 0.1 to 3 mg/day per kg body weight. All active ingredient weights are calculated as drug/as such, unless otherwise indicated. In certain embodiments, the desired dose is administered in two, three, four, five or more sub-doses at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, e.g. containing from about 5 to 50 mg.

Combination therapy

One aspect of the invention relates to combination therapy. This type of therapy is advantageous because the combined administration of the active ingredients achieves a much better therapeutic effect than the administration of a single therapeutic agent. In one embodiment, the combined administration of two or more therapeutic agents achieves a synergistic effect, i.e., a therapeutic effect that is much better than the sum of the therapeutic effects of the individual components of the combination. In another embodiment, the combination of two or more therapeutic agents achieves an enhanced effect.

The active ingredients comprising the combination therapy may be administered together in separate dosage forms or by separate administration of each active agent. In certain embodiments, the first and second therapeutic agents are administered in separate dosage forms. The preparation can be formulated into single tablet, pill, capsule or injection solution.

Alternatively, the first therapeutic agent and the second therapeutic agent may be administered as separate compositions, e.g., as separate tablets or solutions. The first agent may be administered simultaneously with the second agent or the first agent may be administered separately from the second agent. The length of time between administration of the first and second therapeutic agents can be adjusted to achieve the desired therapeutic effect. In certain examples, the second therapeutic agent can be administered only a few minutes (e.g., 1, 2, 5, 10, 30, or 60min) after the administration of the first therapeutic agent. Alternatively, the second therapeutic agent may be administered several hours (e.g., 2, 4,6, 10, 12, 24, or 36hr) after the administration of the first therapeutic agent. In certain embodiments, it is advantageous to administer more than one dose of the second therapeutic agent between administrations of the first therapeutic agent. For example, the second therapeutic agent may be administered 2 hours after the administration of the first therapeutic agent, and then administered again after 10 hours. Alternatively, it may be advantageous to administer more than one dose of the first therapeutic agent between administrations of the second therapeutic agent. Importantly, it is preferred that the therapeutic effect of each active ingredient overlap for at least a portion of the duration of each therapeutic agent, such that the overall therapeutic effect of the combination therapy is due in part to the combined or synergistic effect of the combination therapy.

The dosage of the active agent will generally depend on a number of factors including: the pharmacodynamic characteristics of each agent of the combination, the mode and route of administration of the active agents, the health of the patient being treated, the extent of treatment desired, the nature and kind of concurrent therapy (if any), the frequency of treatment, and the nature of the effect desired. In general, the dosage range of the active agent will often be in the range of about 0.001 to about 250mg/kg body weight per day. For example, for an average adult human having a body weight of about 70kg, a dosage in the range of about 0.1 to about 25mg/kg body weight is typically preferred. However, depending on the age and weight of the subject to be treated, the intended route of administration, the particular agent being administered, etc., some variation within this usual dosage range may be required. Because two or more different active agents are co-administered in combination therapy, the potency of each agent and the interaction achieved by its co-administration must be considered. Importantly, the dosage ranges and determination of optimal dosages for a particular mammal are also within the ability of one of ordinary skill in the art having the benefit of this disclosure.

In certain embodiments, it is advantageous for the pharmaceutical combination to have a relatively large amount of the first component compared to the second component. In certain examples, the ratio of the first active agent to the second active agent is 30: 1, 20: 1, 15: 1, 10: 1, 9: 1, 8: 1, 7: 1, 6: 1, or 5: 1. In certain embodiments, it is preferred to have a more even distribution of the agent. In certain examples, the ratio of the first active agent to the second active agent is 4: 1, 3: 1, 2: 1, 1: 2, 1: 3, or 1: 4. In certain embodiments, it is advantageous for the pharmaceutical combination to have a relatively large amount of the second component compared to the first component. In certain examples, 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. Importantly, compositions comprising any of the above combinations of the first and second therapeutic agents can be administered in separate doses, 1, 2, 3, 4, 5, 6 or more times per day, or in a form that provides an effective release rate to achieve the desired effect. In a preferred embodiment, the dosage form comprises both the first and second active agents. In a more preferred embodiment, the dosage form need only be administered once daily and the dosage form contains both the first and second active agents.

For example, a formulation intended for oral administration to humans may contain 0.1mg to 5g of a first therapeutic agent and 0.1mg to 5g of a second therapeutic agent, both compounded with a suitable and convenient amount of carrier material having a variation of about 5 to about 95% of the total composition. The unit dose typically contains from about 0.5mg to about 1500mg of the first therapeutic agent and from 0.5mg to about 1500mg of the second therapeutic agent. In a preferred embodiment, the dose comprises 0.5mg, 1mg, 2mg, 3mg, 4mg, 5mg, 10mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, 1000mg, etc., up to 1500mg of the first therapeutic agent. In preferred embodiments, the dose comprises 0.5mg, 1mg, 2mg, 3mg, 4mg, 5mg, 10mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or 1,000mg, etc., up to 1,500mg of the second therapeutic agent. The optimal ratio of the first and second therapeutic agents can be determined by standard assays known in the art.

Toxicity and therapeutic efficacy of the compositions of the invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining LD₅₀(dose lethal to 50% of all subjects) and ED₅₀(a dose therapeutically effective for 50% of all subjects). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD₅₀/ED₅₀. Compounds that exhibit large therapeutic indices are preferred. The data obtained from these cell culture assays and animal experiments can be used to determine the dosage range for use in humans. The dosage of the compound is preferably such that it includes a very small or non-toxic ED₅₀Within a range around the concentration of (c). The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the methods of the invention, a therapeutically effective dose can be initially estimated from cell culture assays. The dosage can be determined in animal models to achieve inclusion of IC₅₀(i.e., the concentration of test compound measured in cell culture that achieves half-maximal inhibition of RT product from infected cells compared to untreated controls) in the plasma. This information can be used to more accurately determine useful doses for humans. Levels in plasma can be measured by, for example, High Performance Liquid Chromatography (HPLC).

Synergy and enhancement

The term "synergistic" refers to a combination that is more effective than the additive effects of any two or more single agents. The synergistic effect makes it possible to effectively treat the disease using one of the individual therapies in lower amounts (doses). Lower doses resulted in lower toxicity without reduced efficacy. In addition, the synergistic effect may bring about an enhanced effect, such as enhanced antidepressant activity. Finally, synergy may lead to improved avoidance or reduction of disease compared to any monotherapy.

Combination therapy may make possible: a lower dose of either the first therapeutic agent or the second therapeutic agent (referred to herein as "significant one-way synergy"), or a lower dose of both therapeutic agents (referred to herein as "two-way synergy"), than would normally be required if either agent was used alone.

In certain embodiments, the synergy between the second therapeutic agent and the first therapeutic agent is manifested by: if a dose of the second therapeutic agent is not administered, the dose of the first therapeutic agent will be sub-therapeutic. Alternatively, the synergy between the second therapeutic agent and the first therapeutic agent is manifested by: if the first therapeutic agent dose is not administered, the dose of the second therapeutic agent will be sub-therapeutic.

The term "potentiation" or "enhancement" refers to a combination in which one of the compounds administered to a patient enhances or potentiates the therapeutic effect of the other compound or compounds. In some examples, the enhancement may bring about an improvement in the efficacy, tolerability, or safety of a certain therapy, or any combination thereof.

In certain embodiments, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a first therapeutic agent, and a dose of a second therapeutic agent effective to enhance the therapeutic effect of the first therapeutic agent. In other embodiments, the invention relates to methods of enhancing the therapeutic effect of a first therapeutic agent on a patient by administering a second therapeutic agent to the patient. In other embodiments, the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a second therapeutic agent, and a dose of a first therapeutic agent effective to enhance the therapeutic effect of the second therapeutic agent. In other embodiments, the invention relates to methods of enhancing the therapeutic effect of a second therapeutic agent on a patient by administering the first therapeutic agent to the patient.

In certain preferred embodiments, the invention is, in part, a synergistic combination of a first therapeutic agent in an amount sufficient to confer a therapeutic effect in conjunction with a second therapeutic agent. For example, in certain embodiments, a therapeutic effect of at least about 2 (or at least about 4,6, 8, or 10) times the therapeutic effect of the dose of the first therapeutic agent alone is obtained. In certain embodiments, the synergistic combination provides a therapeutic effect that is up to about 20, 30, or 40 times the therapeutic effect of the dose of the first therapeutic agent used alone. In this embodiment, the synergistic combination exhibits what is referred to herein as "significant unidirectional synergy," meaning that the dosage of the second therapeutic agent synergistically potentiates the effect of the first therapeutic agent, but the dosage of the first therapeutic agent does not exhibit significant potentiation of the effect of the second therapeutic agent.

In certain embodiments, the combination of active agents exhibits bilateral synergy, 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. Thus, other embodiments of the present invention are directed to combinations of a second therapeutic agent and a first therapeutic agent, wherein the therapeutic effect of the combination resulting from the reduced dose of the drugs is enhanced by the reduction in the dose of each drug due to the synergistic effect between the drugs. In actual dosages, bilateral synergy is not always very significant due to the potency ratio of the first therapeutic agent to the second therapeutic agent. For example, when one therapeutic agent exhibits a much greater therapeutic efficacy relative to another, bilateral synergy may be difficult to detect.

The synergy of the combination therapy can be assessed by biological activity assays. For example, the therapeutic agents are mixed in molar ratios designed to give therapeutic effects of about the same potency based on EC90 values. Three different molar ratios were then used for each combination to allow variability in the estimation of relative potency. These molar ratios were maintained throughout the dilution series. The corresponding monotherapy was also evaluated in parallel to the combination therapy using a standard primary analytical model. Comparison of the therapeutic effect of the combination treatment with that of the monotherapy gives a measure of synergy. Further details of combinatorial assay design may be found in B EKorba (1996) Antiviral Res.29: 49. Analysis of synergy, additive or antagonistic effects can be achieved by using Calcusyn^TMThe program analyzes the aforementioned data (Biosoft, Inc.). This procedure evaluates drug interactions by using the widely recognized Chou and Telalay method in combination with statistical evaluation using the Monte Carlostatic Package. In several different modes, including half-effect and dose-effect plots, isobolograms (isobolograms), and combination index with standard deviation [ CI]The figure shows the data.For later analysis, CI greater than 1.0 indicates antagonism and CI less than 1.0 indicates synergy.

The compositions of the present invention present an opportunity to obtain a reduction of disease from moderate to severe cases. Reduced doses of each therapeutic agent may be used due to the synergistic and/or additive effects provided by the inventive combination of the first and second therapeutic agents. By using smaller amounts of the other or both drugs, the side effects associated with each can be reduced in number and extent. Furthermore, the combination of the invention avoids the side effects to which some patients are particularly sensitive.

Formulation and definition

The pharmaceutical compositions of the present invention may be administered by any suitable route of administration which provides the patient with a therapeutically effective dose of the active ingredient. Typically, the pharmaceutical compositions described herein will be formulated for oral administration or inhalation. Suitable dosage forms include tablets, troches, cachets, caplets, capsules including hard and soft gelatin capsules, and the like. However, tablets remain a preferred dosage form because they provide convenience not only to the patient (e.g., precise dosage, compactness, portability, mild mouth feel and ease of administration), but also to the manufacturer (e.g., simple and economical to manufacture, stable and convenient to package, transport and dispense).

The pharmaceutical composition may further comprise a "pharmaceutically acceptable inert carrier," which expression is intended to include one or more inert excipients including starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents and the like. If desired, tablet dosages of the disclosed compositions can be coated using standard aqueous or non-aqueous techniques. In one embodiment, a hydroxypropyl methylcellulose (HPMC) coating is used. The "pharmaceutically acceptable carrier" also comprises a controlled release means. The compositions of the present invention may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweeteners, colorants, flavorants, drying agents, plasticizers, dyes, and the like. However, any such optional ingredients must be compatible with the combination of active ingredients to ensure stability of the formulation.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic and organic acids and bases. When the compounds of the invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts (acids addition salt) for the compounds of the present invention include the following: acetic acid, benzenesulfonic acid (besylate), benzoic acid, camphorsulfonic acid, citric acid, vinylsulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. When the compounds contain acidic side chains, suitable pharmaceutically acceptable base addition salts (base addition salts) of the compounds used in the present invention include the following: metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts prepared from lysine, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-meglumine) and procaine. In one embodiment, the levozopiclone is formulated as a succinate salt. In another embodiment, the levozopiclone is formulated as a fumarate.

Levozopiclone, and many antidepressants including, but not limited to, 5-hydroxytryptamine reuptake inhibitors, norepinephrine reuptake inhibitors, and 5-HT_2AModulators are chiral compounds that may exist as a racemic mixture, a mixture of unequal enantiomers, or as a single enantiomer. Importantly, the expression of a compound that can be a racemic mixture, a mixture of unequal enantiomers, or a single enantiomer is intended to encompass all three forms described above unless otherwise indicated. The term "enantiomeric excess" is well known in the art and is defined by the formula:

the term "enantiomeric excess" is related to the earlier term "optical purity", both of which are measures of the same phenomenon. The value of e.e. should be a number from 0 to 100, 0 being racemic and 100 being a pure single enantiomer. The compound, once referred to as 98% optically pure in the past, is now more accurately described as 96% e.e.; in other words, 90% e.e. reflects the presence of 95% of one enantiomer and 5% of the other enantiomer in the material in question. When a particular enantiomer (e.g., levozopiclone) is enumerated in the examples for use in the compositions or methods of the invention, this indicates that the composition comprises a significantly greater proportion of the particular enantiomer than the non-particular enantiomer. In a preferred embodiment, a composition comprising a particular enantiomer comprises that particular enantiomer at least 90% of the e.e. More preferably, a composition comprising a particular enantiomer comprises that particular enantiomer at least 95% of the e.e. Even more preferably, such compositions comprising a particular enantiomer comprise that particular enantiomer at least 98% of the e.e. Most preferably such compositions comprising a particular enantiomer comprise that particular enantiomer at least 99% of the e.e.

For example, a composition comprising eszopiclone comprises the S-enantiomer of zopiclone at least 90% of the e.e. More preferably, the composition comprising eszopiclone comprises the S-enantiomer of zopiclone at least 95% of the e.e. Even more preferred compositions comprising eszopiclone comprise the S-enantiomer of zopiclone at least 98% of the e.e. More preferably, the composition comprising eszopiclone comprises the S-enantiomer of zopiclone in at least 99% of the e.e.

The term "5-hydroxytryptamine reuptake inhibitor" refers to a compound that at least partially inhibits 5-hydroxytryptamine reuptake. In a preferred embodiment, the 5-hydroxytryptamine reuptake inhibitor is a selective 5-hydroxytryptamine reuptake inhibitor.

The term "selective 5-hydroxytryptamine reuptake inhibitor" refers to a compound that preferentially inhibits 5-hydroxytryptamine reuptake compared to its ability to modulate the activity of other receptors.

The term "norepinephrine reuptake inhibitor" refers to a compound that at least partially inhibits norepinephrine reuptake. In a preferred embodiment, the norepinephrine reuptake inhibitor is a selective norepinephrine reuptake inhibitor.

The term "selective norepinephrine reuptake inhibitor" refers to a compound that preferentially inhibits norepinephrine reuptake compared to its ability to modulate the activity of other receptors.

The term "dopamine reuptake inhibitor" refers to a compound that at least partially inhibits dopamine reuptake.

The term "5-HT_2AModulator "refers to modulation of 5-HT_2AA receptor active compound. The term "5-HT_2AModulators "include 5-HT_2AAntagonists and 5-HT_2AInverse agonists and 5-HT_2AA partial agonist.

The term "antagonist" refers to a compound that binds to the receptor binding site, but does not activate the receptor; a compound that binds to a receptor and blocks the receptor binding site; or binding to an allosteric site on a receptor (a non-competitive antagonist) results in a compound that prevents activation of the receptor by its ligand. The resulting receptor inhibition varies in extent and persistence.

The term "patient" refers to a mammal in need of special treatment. In preferred embodiments, the patient is a primate, canine, feline, or equine. In another embodiment, the patient is a human.

The terms "co-administration" and "co-administration" both refer to the simultaneous administration (of two or more therapeutic agents at the same time) and the administration at a different time (the administration of one or more therapeutic agents at a different time than the administration of another therapeutic agent or agents), so long as the therapeutic agents are present in the patient at some point in time.

The term "solvate" refers to a form of a particular compound that is pharmaceutically acceptable containing one or more solvent molecules, which still retains the biological potency of the compound. Examples of solvates include combinations of the compounds of the invention with solvents such as: water (to form a hydrate), isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or acetone. Also included are solvate mixture formulations, such as a combination of a compound of the invention and two or more solvents.

The term "antidepressant" refers to a compound used to treat depression, including without limitation: tricyclic antidepressants, such as clomipramine, amoxapine, nortriptyline, moprotilene, trimipramine, imipramine or protriptyline; (ii) a monoamine oxidase inhibitor; 5-hydroxytryptamine reuptake inhibitors, including selective 5-hydroxytryptamine reuptake inhibitors, such as citalopram, escitalopram, duloxetine, fluoxetine, sertraline, norsertraline (norsertraline), paroxetine, mirtazapine, fluvoxamine, milnacipran, clomipramine, femoxetine, indapadine, alaproclate, cilazachlor, or ifoxetine; norepinephrine reuptake inhibitors, including selective norepinephrine reuptake inhibitors such as desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamide, tomoxetine, or (S, S) -hydroxybupropion; dopamine reuptake inhibitors such as climbazole, bupropion, and venlafaxine; and atypical antidepressants such as venlafaxine, nefazodone or trazodone; a therapeutically active isomer or a metabolite of any of the foregoing; and a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any of the foregoing.

The term "disorder" as used herein includes menopause, perimenopause, mood disorders, anxiety disorders, and cognitive disorders.

The term "menopause" as used herein includes various menopausal and perimenopausal symptoms such as hot flashes, waking up due to hot flashes, nocturnal waking up and mood disorders associated with menopause or perimenopause such as depression and anxiety.

The term "mood disorder" as used herein includes major depressive disorder, minor depressive disorder (mil depression), psychotropic symptom major depressive disorder (severe depression with depressive disorder), psychotic symptom major depressive disorder, melancholia (former endogenous depression), atypical depression, dysthymic disorder, manic depression (manic depression), bipolar disorder I, bipolar disorder II, bipolar disorder III, cyclothymic disorder, and chronic hypomania.

The term "mood disorder" as used herein includes premenstrual syndrome (PMS), premenstrual dysthymic disorder (PMDD), prenatal depression and postpartum depression.

The term "anxiety disorder" as used herein refers to panic attacks, panic disorders, phobic disorders (such as agoraphobia, specific phobias, social phobias, avoidant personality disorders), Obsessive Compulsive Disorders (OCD), post-traumatic stress disorders, acute stress disorders, and generalized anxiety disorders.

The term "cognitive disorder" as used herein refers to delirium (acute disorganized state), dementia, alzheimer's disease, dementia with lewy bodies, vascular dementia, bewaring dementia (subcutaneous arteriosclerotic encephalopathy), parkinson's disease, progressive supranuclear palsy, huntington's chorea (chorea), pick's disease, kruywaukee-buy syndrome, frontal lobe syndrome, normal pressure hydrocephalus, subdural hematoma, creutzfeldt-jakob disease, gerstmann-straussler-scheinker disease, paralytic dementia and AIDS dementia. The term "cognitive disorder" as used herein also includes a decrease in cognitive function and memory loss.

The term "treatment" when used in connection with a disorder means amelioration, prevention, or alleviation of symptoms and/or the effects associated with such disorders, and includes prophylactic administration of a composition of the invention, or a pharmaceutically acceptable salt thereof, to substantially reduce the likelihood or severity of the condition.

The present invention will now be described in its entirety and will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

Examples

Example 1 formulation

The following formulations are exemplary of formulations for the combination tablet or capsule of levzopiclone and antidepressant:

TABLE 1 Lzopiclone and fluoxetine compositions

TABLE 2 Levozopiclone and sertraline compositions

TABLE 3 Levozopiclone and Ediprenyl compositions

TABLE 4 composition of eszopiclone and duloxetine

TABLE 5 combination of levozopiclone and paroxetine

TABLE 6 combination of Eszopiclone and S-fluoxetine

The formulations shown above can be prepared by performing the following steps:

1. the levozopiclone API (active pharmaceutical ingredient) was selected through a 80 mesh sieve.

2. The antidepressant API (active pharmaceutical ingredient) was screened through a 40 mesh screen.

3. The remaining ingredients were screened through a #20 or #30 mesh screen.

4. The levozopiclone API was blended with a portion of MCC (microcrystalline cellulose).

5. The antidepressant API was blended with the blend from step 4.

6. The mixture from step 5 was blended with the MCC remaining in the three steps.

7. The API from step 6: the MCC mixture was blended with dicalcium phosphate salts.

8. The crosslinked hydroxymethylcellulose is mixed with silica and then blended with the mixture from step 7.

9. The mixture from step 8 was blended with magnesium stearate.

10. For tablets, compression is carried out on a suitable tablet press.

11. For capsules, hard gelatin capsules of size 0 are filled on a suitable capsule filling machine.

12. For the tablets, the tablet cores from step 10 were coated in Opadry II on a suitable conventional tablet coating machine.

EXAMPLE 2 clinical study of Levozopiclone for the treatment of menopause or perimenopause

The study was aimed at observing the effect of levzopiclone 3mg compared to placebo in the treatment of insomnia secondary to perimenopause or menopause. The study was a multicenter, randomized, double-blind, placebo-controlled, parallel group study. The study had a one-week single-blind placebo run-in period, followed by four-week double-blind treatment, and one-week single-blind placebo washout. The primary method of analysis compares the post-randomization results between the two treatment groups.

The test subject was a female with insomnia secondary to perimenopause or menopause. The subject is perimenopausal or menopausal and has insomnia symptoms comprising a Sleep Latency (SL) of 45 minutes or more and a Total Sleep Time (TST) of 6 hours or less. Perimenopausal/menopausal symptoms precede the onset of sleep disorder symptoms. Patients were predominantly Caucasian (Caucasian) (77.2%). The average age is 49 years, and the age range is 40-60 years.

A total of 410 subjects were randomly selected. Of these, 201 were taking 3mg of levozopiclone (ESZ) for 4 weeks at night (bedtime) and 209 were taking matched Placebo (PBO). The discontinuation rate was moderate, 11.9% in the ESZ group and 12.9% in the PBO group.

In the first week, the ESZ group had significantly less night awakenings due to hot flashes than the PBO group (0.3 and 0.5 LS mean per night for ESZ and PBO, respectively; p ═ 0.0016). This effect was not significant for other weeks, but was more or less significant for the DB mean (p ═ 0.059). When analyzing changes from baseline, ESZ significantly reduced the number of nighttime awakenings due to hot flashes compared to PB O in the first week (p < 0.0001). The difference was not significant for week two, but was more or less significant for weeks 3 and 4 (p 0.094 and 0.055, respectively) and for the DB mean (p 0.0045). See table 7.

TABLE 7-number of nighttime awakenings due to Hot flashes (number of people to be treated)

[1] Week 1 is the first week of double-blind treatment, week 2 is the second week of double-blind treatment, etc. The DB average includes all of the predetermined evaluations taken after visit 3 up to and including visit 5. Baseline is the average of all pre-DB observations.

[2] In contrast, a two-way test was performed using an ANOVA mode using a MIXED procedure with treatment and site as a fixed effect.

[3] Comparative two-way tests were performed using ANOVA mode, using the MIXED procedure with treatment and site as fixed effect, baseline as co-variable.

A full medical evaluation was performed at the end of the double-blind treatment period at week 4. This time, ESZ patients had significantly better scores than PBO (LS averages 2.7 and 3.3 for ESZ and PBO, respectively; p < 0.0001). See table 8.

TABLE 8-menopausal and perimenopausal Studies, overall assessment of internal medicine (number of people to be treated)

[1] In contrast, a two-way test was performed using an ANOVA mode using a MIXED procedure with treatment and site as a fixed effect.

[2] Comparative two-way tests were performed using ANOVA mode, using the MIXED procedure with treatment and site as fixed effect, baseline as co-variable.

Note that: response to evaluation problem: all subjects had perimenopausal or menopausal symptoms since the last evaluation:

0 is not evaluated, 1 is a large improvement, 2 is a large improvement, 3 is a small improvement, 4 is unchanged, 5 is a small deterioration, 6 is a large deterioration, and 7 is a large deterioration.

The results of this study will vary slightly because data from one site consisting of 11 out of 410 subjects was excluded due to negative results in the site check. The conclusions of the study are expected to be unchanged after excluding these 11 subjects.

The contents of each reference cited herein, including the contents cited in the main reference, are hereby incorporated by reference in their entirety.

While the invention has been described in this connection, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications and equivalents as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.

Claims (26)

1. A pharmaceutical composition comprising eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and an antidepressant.

2. The pharmaceutical composition of claim 1, wherein the antidepressant is a 5-hydroxytryptamine reuptake inhibitor.

3. The pharmaceutical composition according to claim 2, wherein the 5-hydroxytryptamine reuptake inhibitor is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clomipramine, femoxetine, indapaine, alapropyl ester, cilansam, or efoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one thereof.

4. The pharmaceutical composition of claim 1, wherein the antidepressant is a norepinephrine reuptake inhibitor.

5. The pharmaceutical composition of claim 4, wherein the norepinephrine reuptake inhibitor is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamide, tomoxetine, or (S, S) -hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one thereof.

6. The pharmaceutical composition of claim 1, wherein the antidepressant is a dopamine reuptake inhibitor.

5. The pharmaceutical composition of claim 6, wherein the dopamine reuptake inhibitor is climbazole, bupropion, GBR-12935, venlafaxine, or 2 β -propionyl-3 β - (4-tolyl) -tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one thereof.

7. The pharmaceutical composition of claim 1, wherein the antidepressant is 5-HT_2AA modulator.

8. The pharmaceutical composition according to claim 7, wherein the 5-HT_2AThe modulator is 5-HT_2AAn antagonist.

9. The pharmaceutical composition according to claim 7, wherein the 5-HT_2AThe modulator is 5-HT_2AAn inverse agonist.

10. The pharmaceutical composition according to claim 7, wherein the 5-HT_2AThe modulator is MDL 100907, SR 46349B, YM 992, fannanserin, oxazolidine compound a, phenylindole compound a, piperidinyl compound B, spiroazacyclo compound C, or azacyclo compound D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any of them.

11. A method of treating a menopausal or perimenopausal patient, comprising the steps 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 an antidepressant.

12. A method of treating a patient with a mood disorder comprising the steps 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 an antidepressant.

13. A method of treating a patient with an anxiety disorder comprising the steps 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 an antidepressant.

14. A method of treating a patient with a cognitive disorder, comprising co-administering to a patient in need thereof a therapeutically effective amount of levozopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of an antidepressant.

15. The method according to any one of claims 11 to 14, wherein the antidepressant is a 5-hydroxytryptamine reuptake inhibitor.

16. The method according to any one of claims 11 to 14, the antidepressant is a 5-hydroxytryptamine reuptake inhibitor selected from the group consisting of: citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, clomipramine, femoxastine, indaparine, alaproclate, cilansam, or ifoxetine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any of them.

17. The method of any one of claims 11 to 14, wherein the antidepressant is a norepinephrine reuptake inhibitor.

18. The method according to any one of claims 11 to 14, wherein the antidepressant is a norepinephrine reuptake inhibitor selected from the group consisting of: desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamide, tomoxetine, or (S, S) -hydroxybupropion, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any of them.

19. The method according to any one of claims 11 to 14, wherein the antidepressant is a dopamine reuptake inhibitor.

20. The method according to any one of claims 11 to 14, wherein the antidepressant is a dopamine reuptake inhibitor selected from the group consisting of: imazetidine, bupropion, GBR-12935, venlafaxine, or 2 β -propionyl-3 β - (4-tolyl) -tropane, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any one thereof.

21. The method according to any one of claims 11 to 14, wherein the antidepressant is 5-HT_2AA modulator.

22. The method according to any one of claims 11 to 14, wherein the antidepressant is 5-HT selected from the group consisting of_2AA regulator: MDL 100907, SR 46349B, YM 992, fannanserin, oxazolidine compound a, phenylindole compound a, piperidinyl compound B, spiroazacyclo compound C, or azacyclo compound D, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal of any of them.

23. The method of claim 12, wherein the mood disorder is selected from the group consisting of: major depressive disorder, minor depressive disorder, non-psychotic major depressive disorder, melancholia, atypical depression, dysthymic disorder, manic depressive disorder, bipolar affective disorder type I, bipolar affective disorder type II, bipolar affective disorder type III, cyclothymic disorder, chronic mild mania, premenstrual syndrome, premenstrual dysthymic disorder, prenatal depression, and postpartum depression.

24. The method of claim 13, wherein the anxiety disorder is selected from the group consisting of: panic attack, panic disorder, phobic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, and generalized anxiety disorder.

25. The method of claim 14, wherein the cognitive disorder is selected from the group consisting of: delirium, dementia, Alzheimer's disease, dementia with Lewy bodies, vascular dementia, Binswanger dementia, Parkinson's disease, progressive supranuclear palsy, Huntington's chorea, pick's disease, Kluyverburg syndrome, frontal lobe syndrome, normal pressure hydrocephalus, subdural hematoma, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, paralytic dementia, AIDS dementia, decreased cognitive function, and memory loss.