HK1152661A - Use of agomelatine in obtaining medicaments intended for the treatment of bipolar disorders - Google Patents

Description

Use of agomelatine for obtaining a medicament for the treatment of bipolar disorders

The application is a divisional application of Chinese patent application No. 200610076498.5 with an application date of 2006-4-20 and a priority date of 2005-4-20.

Technical Field

The invention relates to the use of agomelatine (agomelatine) or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide of formula (I) and its hydrates, crystalline forms and addition salts with pharmaceutically acceptable acids or bases, alone or in combination, for obtaining medicaments,

the medicament is for the treatment of bipolar disorders, in particular bipolar I and II disorders, more in particular bipolar I disorder.

Background

Agomelatine, or N- [2- (7-methoxy-1-naphthyl) ethyl]Acetamide, possessing the dual properties of being an agonist of receptors of the melatoninergic system on the one hand and of being 5-HT on the other hand_2CAn antagonist of the receptor. These properties 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 its use in therapy have been disclosed in european patent specifications EP 0447285 and EP 1564202.

Disclosure of Invention

The applicant has now found that agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide, and its hydrates, crystalline forms and addition salts with pharmaceutically acceptable acids or bases, alone or in combination, have valuable properties which make them useful in the treatment of bipolar disorders, in particular bipolar I and II disorders, more particularly bipolar I disorder.

Bipolar disorder is a psychotic disorder with a severe impact on the life of the patient, both socially and domestically and occupationally. It is characterized by recurrent episodes of depression, mania, hypomania or mixed episodes that are separated by periods in which the patient is unaffected by major psychological dysfunction. In other words, bipolar disorder patients are characterized by a susceptibility to repeated marked fluctuations in mood. The nature of seizures and their development over time allow several clinical forms to be distinguished: bipolar I disorder is most typical and is characterized by one or more manic or mixed episodes, often accompanied by major depressive episodes; for bipolar II disorder, it includes a combination of at least one major depressive episode and a hypomanic episode (a mild form of mania). Bipolar disorder patients are at high risk of suicide, with 25% to 50% of patients having at least one suicide attempt.

There is currently no satisfactory, accepted treatment for bipolar disorder. First line treatments are usually mood stabilisers or mood regulators (thymomodulators), but these treatments are usually not able to alleviate depressive symptoms (j.clin.psychiatry, 2004, 65(4), 569-. Although concomitant antidepressants are commonly used, this is a highly controversial act, as antidepressants can trigger or exacerbate manic and mixed states, and must be discontinued when a manic episode develops. Antidepressants are particularly believed to cause or accelerate periods of emotional fullness and to promote the appearance of manic or hypomanic processes two to three times, and finally, their long-term use appears to increase the number of depressive and manic episodes.

The applicant has now surprisingly found that agomelatine alone or in combination can be used for the treatment of bipolar disorders, in particular bipolar I and II disorders, more in particular bipolar I disorder.

The expected effect of agomelatine in the treatment of bipolar disorder, more particularly bipolar I disorder, is the same as that reported in the literature for antidepressants such as paroxetine, due to the fact that it is active in depression.

Surprisingly, agomelatine behaves differently than conventional antidepressants, which has been observed in clinical studies conducted in patients with bipolar I disorder. These results make it possible to consider their use, even for long periods of time, in bipolar disorders, in particular bipolar I and II disorders, more in particular bipolar I disorder.

The present invention therefore relates to the use of agomelatine and its hydrates, crystalline forms and addition salts with pharmaceutically acceptable acids or bases, alone or in combination, for obtaining a pharmaceutical composition for the treatment of bipolar disorders, in particular bipolar I and II disorders, more particularly bipolar I disorder.

The present invention also relates to the combination of agomelatine with mood stabilising or affective conditioning agents, for obtaining a pharmaceutical composition useful for the treatment of bipolar disorders, in particular bipolar I and II disorders, more in particular bipolar I disorder. The mood stabilizer or mood modulator of the present invention relates to lithium and antiepileptic drugs such as carbamazepine, valproic acid and lamotrigine, among others. More particularly, the mood stabilising or mood regulating agent of the combination of the invention is lithium or valproic acid. When agomelatine is combined with a mood stabilizer, it can be administered before, simultaneously with or after the mood stabilizer, provided that the time interval between the two administrations is such that the desired synergy is obtained in the central nervous system. If both components of the combination of the invention are administered simultaneously, it is preferred to administer a pharmaceutical composition comprising agomelatine and a mood stabilizer, together with one or more pharmaceutically acceptable excipients.

The pharmaceutical compositions are in a form suitable for administration by the oral, parenteral, transdermal, nasal, rectal or buccal routes, particularly in the form of injections, tablets, sublingual tablets, glossettes, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels and the like.

In addition to agomelatine and, optionally, in combination with it, a mood stabilizer, the pharmaceutical compositions of the invention also comprise one or more excipients or carriers selected from diluents, lubricants, binders, disintegrants, absorbents, colorants, sweeteners, and the like.

By way of non-limiting example, mention may be made of:

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

lubricant: silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol;

binder: aluminum and magnesium silicates, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone;

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

The useful dose varies according to the sex, age and weight of the patient, the route of administration, the nature of the disease and any concomitant therapy, and the useful dose of agomelatine is from 1mg to 50mg per 24 hours.

The daily dose of agomelatine is preferably 25 mg/day.

Detailed Description

Pharmaceutical composition：

Prescription of 1000 tablets containing 25mg of active ingredient per tablet:

n- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide 25g

Lactose monohydrate 62g

Magnesium stearate 1.3g

Povidone 9g

0.3g of anhydrous colloidal silica

30g of cellulose sodium glycolate

Stearic acid 2.6g

Clinical research：

The study was performed in 21 patients with bipolar I disorder, treated with lithium (n-14) or valproic acid (n-7) for at least 6 months. Treatment with agomelatine (25 mg/day) for 6 weeks. Of these patients, 19 continued treatment after 6 weeks of acute treatment, and 11 of these continued treatment patients were treated for 1 year. The results obtained show that: 81% of patients responded positively to treatment, and about 50% responded positively at the end of only one week of treatment. Only 3 manic or hypomanic episodes were observed after 6 weeks of treatment at levels quite comparable to patients treated with mood stabilising agents, which clearly indicates that the positive effect of agomelatine in bipolar I disorder patients is not accompanied by an increased incidence of manic and/or hypomanic episodes, even after prolonged treatment.

Claims (3)

1. A combination comprising N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide, or an addition salt thereof with a pharmaceutically acceptable acid or base, and a mood modulator, wherein the mood modulator is valproic acid.

2. A pharmaceutical composition comprising the combination product of claim 1 alone or in combination with one or more pharmaceutically acceptable excipients.

3. Use of a combination according to claim 1 for the obtainment of a pharmaceutical composition for the treatment of bipolar I disorder.