JP2009013074A - Use of agomelatine in obtaining medicament intended for treatment for generalized anxiety disorder - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a medicament intended for the treatment of generalized anxiety disorder. <P>SOLUTION: Agomelatine, namely N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide is used for the treatment of generalized anxiety disorder. Agomelatine has an excellent receptor profile besides observed efficacy. The withdrawal syndrome observed as an adverse effect normally caused by an antipsycotic drug is not observed in agomelatine and agomelatine is used in the most suitable therapy. The medicine composition is obtained by using agomelatine, its hydrate, crystal form and an additional salt with a pharmacologically acceptable acid or a base. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

The present invention relates to generalized anxiety disorder, ie agomelatine, ie formula (I), for obtaining a medicament intended for the treatment of GAD:

And N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide, as well as its hydrates, crystalline forms and use of addition salts with pharmaceutically acceptable acids or bases.

Agomelatine, N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide, is on the one hand an agonist of the melatoninergic receptor and on the other hand 5-HT _2C.
It has the dual feature of being a receptor antagonist. Due to these properties, this is indicative of activity in the central nervous system, more specifically major depression, seasonal affective disorder, sleep disorders, cardiovascular diseases, digestive disorders, insomnia and fatigue due to jet lag, appetite disorders and Has activity in the treatment of obesity.

Agomelatine, its preparation and its use in therapy is described in European Patent Specification EP 0
447,285 and EP 1,564,202.

Applicant has now added agomelatine, ie, N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide, as well as its hydrates, crystalline forms and pharmaceutically acceptable acids or bases. It has been found that salt has beneficial properties that allow its use in the treatment of generalized anxiety disorder.

Generalized anxiety disorder characterized by significant and unfounded anxiety meets well-defined criteria and constitutes a complete disease entity (300.02-DSM IV Mental Troubles Diagnostic and Statistic Handbook handbook), 4th edition, American Psychiatric Association (Ame
rican Psychiatric Association)). This chronic illness leads to many associated troubles, and in particular cognitive dysfunction, and more specifically to the same disorder of thinking and mental representation; inference, judgment and (for that reason) changes in behavior, which is also awkward It leads to difficulties in the underlying psychomotor, weakening of the ability to react, and in some cases its neutralization (Wittchen HU et al., A
rch Gen Psychiatry, 1994, 51 (5), 355-364).

Specificity for this symptom is recognized by other Western health agencies that have published guidelines for the development of drugs that specifically claim this indication (European Pharmaceutical Commission)
(Committee for Proprietary Medicinal Products) (CPMP) / EWP / 4284/02 / London-2005
January 20, 2010-Guidelines for clinical trials for the treatment of drugs for generalized anxiety disorder).

Recent epidemiological studies show that the prevalence of the disease represents 5-6% of the world population and up to 10% for women over 40 years of age. Therefore, the impact of this condition is significant from both health and economic perspectives.

Currently, there is no completely satisfactory approved treatment for generalized anxiety disorder. Benzodiazepines have long been first-line drugs and are still used in some countries.

More recently, venlafaxine, paroxetine
Or administration of molecules such as escitalopram is recommended. Nonetheless, these various treatments list a number of side effects, most often reported of sedation, drug dependence, alcohol interactions, and negligence on cardiovascular and / or sexual aspects. It is an effect that cannot be done. In addition, in many cases, cessation of treatment results in a withdrawal syndrome that is unbearable to the patient.

Thus, as emphasized in the CPMP guidelines, synthesis of new treatments for this disease is inevitable.

Agomelatine, a new chemical with innovative pharmacological effects, has shown high efficacy in major depression in a comparative clinical trial against placebo.

Applicants have now found that agomelatine can be used in generalized anxiety disorder due to its pharmacological action.

Clinical trials conducted on placebo in patients with generalized anxiety disorder have significantly shown that agomelatine is a truly suitable treatment for this disorder.

Furthermore, besides the efficacy observed in the treatment of generalized anxiety disorder, agomelatine also has a good receptive profile for patients: in particular, agomelatine lacks the side effects normally associated with psychotropic drugs. Of these effects, withdrawal syndrome, which is observed with classic psychotropic drugs to stop treatment, is not observed with agomelatine, making it an optimal treatment for this disease.

Thus, the present invention provides a combination of agomelatine, as well as its hydrates, crystalline forms, and pharmaceutically acceptable acid or base addition salts to obtain a pharmaceutical composition intended for the treatment of generalized anxiety disorder. Regarding use.

In particular, the present invention relates to the use of agomelatine obtained as Form II crystal form as described in patent specification EP 1,564,202 for obtaining a pharmaceutical composition intended for the treatment of generalized anxiety disorder.

This pharmaceutical composition is suitable for administration by oral, parenteral, transdermal, nasal, rectal or sublingual route, and in particular for injectable preparations, tablets, sublingual tablets, glossettes, Presented in dosage forms such as gelatin capsules, capsules, troches, suppositories, creams, ointments, and skin gels.

In addition to agomelatine and optionally a mood stabilizer used in conjunction therewith, the pharmaceutical composition of the present invention is selected from diluents, lubricants, binders, disintegrants, absorbents, colorants, sweeteners and the like. Contains one or more excipients or carriers.

As non-limiting examples, mention may be made of:
・ Diluent: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerol,
・ As a lubricant: silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol,
As binders: aluminum and magnesium silicates, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone,
As disintegrant: agar, alginic acid and its sodium salt, effervescent mixture.

Useful doses will vary depending on the patient's gender, age and weight, route of administration, nature of the disorder and any combination therapy and range from 1 mg to 50 mg agomelatin per 24 hours.

The daily dose of agomelatin is preferably 25 mg per day and could be increased to 50 mg per day.

Pharmaceutical composition:
Formulation for the preparation of 1000 tablets each containing 25 mg of active ingredient:
25 g of N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide
Lactose monohydrate 62g
Magnesium stearate 1.3g
Povidone 9g
Anhydrous colloidal silica 0.3g
Sodium cellulose glycolate 30g
Stearic acid 2.6g

Clinical trial:
A clinical trial for placebo was conducted in 121 patients. These 121 patients were randomly divided into two equivalent groups and administered either 25 mg agomelatin or placebo daily.

After 2 weeks of treatment and in cases of poor response, the dose is 50 mg per day in a double-blind study in which the patient is administered agomelatin with the IVRS system (Interactive Voice Response System). Increased to. Treatment was performed for 12 weeks.

Efficacy was measured using the Hamilton Anxiety Scale (Hamilton M., J. Ne
urol. Neurosurg. Psychiat., 1959, 23, 56-62) or Sheehan's Inability Rating Scale (Sheeh
an Disability Scale) (International Clinical Psychopharmacology, 1996, 11, 89-9
Evaluation was conducted using an evaluation tool recommended by the health institution, such as 5). The acceptability profile was also evaluated.

The result obtained is the total score on the Hamilton scale, the first criterion for evaluation, and the difference between the group treated with Agomelatine and the group under placebo is -3.28 (p = 0.040) This represents a clinically and statistically significant difference.

The study also showed a good acceptability profile for the patient and no withdrawal syndrome appeared when treatment was stopped.

Claims (4)

Agomelatine, ie, N- [2], for obtaining a medicament for the treatment of generalized anxiety disorder
Use of-(7-methoxy-1-naphthyl) ethyl] acetamide as well as its hydrates, crystalline forms and addition salts with pharmaceutically acceptable acids or bases.   Use according to claim 1, characterized in that agomelatine is obtained as a type II crystal form. Agomelatin, or one of its hydrates, crystalline forms and pharmaceutically acceptable acid or base addition salts, alone, for use in the manufacture of a medicament for the treatment of generalized anxiety disorder,
Or a pharmaceutical composition comprising in combination with one or more pharmaceutically acceptable excipients. 4. A pharmaceutical composition according to claim 3, characterized in that agomelatine is obtained as a type II crystal form.