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

Abstract

One aspect of the present invention relates to pharmaceutical compositions containing two or more active agents that when taken together can be used to treat, e.g., menopause, mood disorders, anxiety disorders, or cognitive disorders. The first component of the pharmaceutical composition is a sedative eszopiclone. The second component of the pharmaceutical composition is 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. The present invention also relates to a method of treating menopause, perimenopause, mood disorders, anxiety disorders, and cognitive disorders.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to compositions and methods for the treatment of menopause and mood, anxiety, and cognitive disorders.BACKGROUND OF THE INVENTION

[0002] Menopause, which is caused by a lowering of the production of female sex hormones that typically occurs at around age 50, but can occur at much earlier or later ages, can generate disorders such as edema, hot flushes (or flashes), attacks of sweating, muscle and possibly joint pain, sleep disturbances, dysphoria, nervousness, mood swings, headache, palpitations (enhanced frequency of heart rate), dry mucous membranes, pain during intercourse and urinary disturbances. Hot flashes or flushing are characterized by a sudden onset of warmth in the face and neck, often progressing to the chest. Episodes generally last several minutes and are evidenced by a visible flushing of the skin. Often such episodes are accompanied by sweating, dizziness, nausea, palpitations and diaphoresis. Such symptoms can...

Examples

example 1

Formulations

[0143]The following formulations are exemplary 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 combination tablet or capsule formulations:

TABLE 1Eszopiclone and trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine compositionsCombo Strengths(Eszopiclone / trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-Ingredientnapthalenamine, mg / unit)(Tablet and Capsule)3.0 / 25.03.0 / 50.03.0 / 100.0Eszopiclone3.003.003.00trans 4-(3,4-dichlorophenyl)-1,2,3,4-28.0056.00112.00tetrahydro-N-methyl-1-napthalenamine HCl1Microcrystalline Cellulose, NF (Avicel ®198.90198.90198.90PH102)Dibasic Calcium Phosphate Anhydrous90.0090.0090.00USPCroscarmellose Sodium, NF6.006.006.00Colloidal Silicon Dioxide, NF0.600.600.60Magnesium Stearate, NF1.501.501.50Total tablet wt. or capsule fill wt.328.00356.00412.00Empty Size 0 hard gelatin capsule wt.90.0090.0090.00Total w...

example 2

Clinical Study on Treatment of Menopause or Perimenopause with Eszopiclone

[0157]The study was aimed at observing efficacy of eszopiclone 3 mg compared to placebo in the treatment of insomnia secondary to perimenopause or menopause.

[0158]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 weeks of double blind treatment, and one week of single blind placebo wash-out. The primary method of analysis compared the post-randomization results between the two treatment groups.

[0159]Subjects were women with insomnia secondary to perimenopause or menopause. Subjects were perimenopausal or menopausal and had insomnia symptoms including ≧45 minutes sleep latency (SL) and total sleep time (TST) ≦6 hours. Perimenopausal / menopausal symptoms predated the onset of sleep disturbance symptoms. The patient population was predominately Caucasian (77.2%). The mean age was 49, with a ...

example 3

trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine Activity Assays

Experimental Conditions for Monoamine Uptake Assays

Serotonin Functional Uptake Assay

[0164]Characterization of serotonin uptake is performed using synaptosomes isolated in a 0.32 M sucrose buffer from a male Wistar rat cortex. The uptake of radiolabelled serotonin by synaptosomes (100 μg of proteins / point) is allowed by incubating them in a deep well for 15 minutes at 37° C. in presence of test compounds and [3H]5-hydroxytryptamin (0.1 μCi / point).

[0165]Synaptosomes and [3H]5-hydroxytryptamine are prepared in a Krebs buffer pH 7.4 containing 25 mM NaHCO3, 11 mM glucose and 50 μM ascorbic acid. This incubation buffer is oxygenated during 5 minutes before incubation. Basal control is incubated for 15 minutes at 4° C. in order to avoid any uptake. Following this incubation the uptake is stopped by filtration through an “unifilter 96-wells GFB” Packard plate washed with Krebs buffer containing 25 mM N...

FIELD OF THE INVENTION

[0001] The present invention relates to compositions and methods for the treatment of menopause and mood, anxiety, and cognitive disorders.BACKGROUND OF THE INVENTION

[0002] Menopause, which is caused by a lowering of the production of female sex hormones that typically occurs at around age 50, but can occur at much earlier or later ages, can generate disorders such as edema, hot flushes (or flashes), attacks of sweating, muscle and possibly joint pain, sleep disturbances, dysphoria, nervousness, mood swings, headache, palpitations (enhanced frequency of heart rate), dry mucous membranes, pain during intercourse and urinary disturbances. Hot flashes or flushing are characterized by a sudden onset of warmth in the face and neck, often progressing to the chest. Episodes generally last several minutes and are evidenced by a visible flushing of the skin. Often such episodes are accompanied by sweating, dizziness, nausea, palpitations and diaphoresis. Such symptoms can...

Examples

example 1

Formulations

[0143]The following formulations are exemplary 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 combination tablet or capsule formulations:

TABLE 1Eszopiclone and trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine compositionsCombo Strengths(Eszopiclone / trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-Ingredientnapthalenamine, mg / unit)(Tablet and Capsule)3.0 / 25.03.0 / 50.03.0 / 100.0Eszopiclone3.003.003.00trans 4-(3,4-dichlorophenyl)-1,2,3,4-28.0056.00112.00tetrahydro-N-methyl-1-napthalenamine HCl1Microcrystalline Cellulose, NF (Avicel ®198.90198.90198.90PH102)Dibasic Calcium Phosphate Anhydrous90.0090.0090.00USPCroscarmellose Sodium, NF6.006.006.00Colloidal Silicon Dioxide, NF0.600.600.60Magnesium Stearate, NF1.501.501.50Total tablet wt. or capsule fill wt.328.00356.00412.00Empty Size 0 hard gelatin capsule wt.90.0090.0090.00Total w...

example 2

Clinical Study on Treatment of Menopause or Perimenopause with Eszopiclone

[0157]The study was aimed at observing efficacy of eszopiclone 3 mg compared to placebo in the treatment of insomnia secondary to perimenopause or menopause.

[0158]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 weeks of double blind treatment, and one week of single blind placebo wash-out. The primary method of analysis compared the post-randomization results between the two treatment groups.

[0159]Subjects were women with insomnia secondary to perimenopause or menopause. Subjects were perimenopausal or menopausal and had insomnia symptoms including ≧45 minutes sleep latency (SL) and total sleep time (TST) ≦6 hours. Perimenopausal / menopausal symptoms predated the onset of sleep disturbance symptoms. The patient population was predominately Caucasian (77.2%). The mean age was 49, with a ...

example 3

trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine Activity Assays

Experimental Conditions for Monoamine Uptake Assays

Serotonin Functional Uptake Assay

[0164]Characterization of serotonin uptake is performed using synaptosomes isolated in a 0.32 M sucrose buffer from a male Wistar rat cortex. The uptake of radiolabelled serotonin by synaptosomes (100 μg of proteins / point) is allowed by incubating them in a deep well for 15 minutes at 37° C. in presence of test compounds and [3H]5-hydroxytryptamin (0.1 μCi / point).

[0165]Synaptosomes and [3H]5-hydroxytryptamine are prepared in a Krebs buffer pH 7.4 containing 25 mM NaHCO3, 11 mM glucose and 50 μM ascorbic acid. This incubation buffer is oxygenated during 5 minutes before incubation. Basal control is incubated for 15 minutes at 4° C. in order to avoid any uptake. Following this incubation the uptake is stopped by filtration through an “unifilter 96-wells GFB” Packard plate washed with Krebs buffer containing 25 mM N...

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