HK1100205A - New association between agomelatine and a thymoregulatory agent and pharmaceutical compositions containing it - Google Patents

Description

Novel combination of agomelatine and a psychotropic agent and pharmaceutical compositions containing same

The technical field is as follows:

the invention relates to a novel association of agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide of formula (I) or hydrates, crystalline forms thereof and addition salts of pharmaceutically acceptable acids or bases with psychotropic agents,

for obtaining a pharmaceutical composition for the treatment of mood disorders, more particularly major depression, circulatory mood disorders and dysthymia.

Background art:

agomelatine, or N- [2- (7-methoxy-1-naphthyl) ethyl]Acetamide with melatoninergic system receptor agonists and 5-HT_2CDual features of receptor antagonists. These characteristics make it active in the central nervous system, more particularly in the treatment of major depression, seasonal affective disorder, sleep disorders, cardiovascular disease, diseases of the digestive system, insomnia and fatigue due to jet lag, appetite disorders and obesity.

Agomelatine, its preparation and use in therapy have been described in european patent specification EP 0447285.

The invention content is as follows:

the applicant has now found that the combination of agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide or its hydrates, crystalline forms and addition salts of a pharmaceutically acceptable acid or base with psychotropic agents has valuable properties which allow its use in the treatment of mood disorders, more particularly major depression, circulatory mood disorders and dysthymia.

Central nervous system disorders, such as mood disorders, affect a large number of people of all ages. They are so named because of the persistent positive or negative effects that are drawn, and are strong enough to produce maladaptive behavior.

Major depression is an acute and severe mood disorder characterized by sadness, pessimism, thoughts of suicide, unexpected slowness of movement, and various physical ailments. Extreme obstacles can cause all functional or social activities to cease. The depressed patients had their own involvement in the family.

Cyclic mood disorders are characterized by recurrent positive (mood swelling) and negative (mood depression) mood changes, which are less mood changes and less dysfunctional than bipolar disorder; however, there are diagnostic difficulties and several factors have led to the belief that circulatory mood disorders are a precursor to bipolar disorder. The combination of antidepressants with psychomodulators allows to control mental changes and prevent them from developing into typical bipolar disorders.

Finally, dysthymia is a chronic and violent mood disorder characterized by long-term dysphoria with mood and functional impairment. As for professional extreme fatigue syndrome (professionally severe syndrome), other symptoms of dysthymia may include the following emotions: lack of adaptability, hopelessness, irritability or excessive anger, guilt, lack of interest or general enjoyment, social avoidance, chronic fatigue, reduced activity or productivity, and inattention. Dysthymia is a insidious mental disorder. In contrast to the symptoms of loss of function associated with diseases such as major depression, patients suffering from dysthymia often suffer from appropriate social and occupational dysfunctions. For example, patients with poor mood are often seen to work diligently and maintain a normal appearance despite their general interpersonal interaction function often being impaired.

Although there are many effective molecules in this field, which may be mentioned more particularly as psychostimulants (psychoanaleptics) and psychomodulators, none of them is entirely satisfactory in treating those different pathological conditions, and some of them have significant side effects. Therefore, new alternative therapies are being developed and are becoming necessary.

The applicant has now surprisingly found that the combination of agomelatine with a psychotropic agent has properties which are entirely suitable for the treatment of mood disorders, more particularly major depression, circulatory mood disorders and dysthymia. Psychomodulators (usually mentioned for their antimanic properties which allow them to act on the mental distension of the manic state) are currently used for the treatment of bipolar disorders. The applicant has now found that those psychomodulators exhibit properties that enhance the action of agomelatine in both depressive mood disorders and manic disorders. The unpredictable effects allow the use of the combination of the invention to be considered in the treatment of mood disorders, more particularly major depression, circulatory mood disorders and dysthymia.

Among the psychotropic agents of the present invention, lithium, carbamazepine, valproate and lamotrigine may be mentioned more particularly and without any limiting significance, more preferably valproate.

The present invention therefore relates to the use of agomelatine or its hydrates, crystalline forms and addition salts of a pharmaceutically acceptable acid or base in combination with a psychotropic compound for obtaining a pharmaceutical composition for the treatment of mood disorders, more particularly major depression, circulatory mood disorders and dysthymia.

The invention also relates to a pharmaceutical composition comprising agomelatine or a hydrate, crystalline form and addition salts of a pharmaceutically acceptable acid or base thereof in combination with a psychotropic compound, and one or more pharmaceutically acceptable excipients.

Among the pharmaceutical compositions of the invention, mention may be made more particularly of those suitable for oral, parenteral or nasal administration, such as tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels and the like.

In addition to agomelatine and the psychotropic compound, the pharmaceutical composition of the invention comprises one or more excipients or carriers selected from diluents, lubricants, binders, disintegrants, absorbents, colorants, sweeteners, and the like.

By way of example and without any limiting sense, mention may be made of:

diluent: lactose, glucose, sucrose, mannitol, sorbitol, cellulose, glycerol,

lubricant: silicon dioxide, talcum powder, stearic acid and its magnesium salt and calcium salt, polyethylene glycol,

binder: magnesium aluminum silicate, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone,

disintegrant: agar, alginic acid and sodium salt thereof, effervescent mixture.

The useful dose varies according to the sex, age and weight of the patient, the route of administration, the nature of the disorder and any combination of treatments, and is between 1mg and 50mg agomelatine per 24 hours, more preferably 25mg per day. The dose of the psychotropic agent will be lower than the dose used when it is administered alone.

The specific implementation mode is as follows:

the specific implementation mode is as follows:

the pharmaceutical composition comprises:

a formulation for making 1000 tablets, each tablet containing 25mg of active ingredient:

..25 g. of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide

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Clinical research

The clinical studies conducted used the international glossary, mainly DSM-IV, and approved measurement tools such as Hamilton Depression Scale (Hamilton Scale of Depression), Young's mania Scale and Global clinical impression Scale, which are recommended by effective guidelines. Comparing the agomelatine-valproate combination with the placebo psychotropic agent under optimal methodological conditions, we conclude that: the combination is better.

Claims (5)

1. Combination of agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide or its hydrates, crystalline forms and addition salts of pharmaceutically acceptable acids or bases with psychotropic agents.

2. Combination according to claim 1, wherein the psychotropic agent is valproate.

3. Pharmaceutical composition comprising as active ingredient agomelatine or the hydrates, crystalline forms and addition salts of pharmaceutically acceptable acids or bases according to claim 1 or 2, in combination with a psychotropic agent, alone or in combination with one or more pharmaceutically acceptable excipients.

4. A pharmaceutical composition according to claim 3 for the manufacture of a medicament for the treatment of mood disorders.

5. Use of a combination according to claim 1 or 2 for obtaining a pharmaceutical composition for the treatment of mood disorders.