SA07280634B1 - Use of Agomelatine in Obtaining Medicaments Intended for the Treatment of - Google Patents

Abstract

Abstract The present invention relates to the use of agomelatine, or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide in a drug for the treatment of periventricular leukomalacia.

Description

oy = _ Use of agomelatine in obtaining medicaments intended for the treatment of periventricular leukomalacia Full Description BACKGROUND The present invention relates to the use of agomelatine “or: I) dally N-[2-(7-methoxy-1 -naphthyl)ethyl]acetamide NHCOMe MeO 00 km© and its hydrates also and crystalline forms and its addition salts with an acid Or an acceptable base Liana in obtaining drugs for the treatment of cali periventricular leukomalacia . agomelatine + or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide has two advantages” df is a melatoninergic receptor agonist on the one hand; And against the future: 5-111 on the other hand. 0 These properties provide it with efficacy in the central nervous system; More specifically, in the treatment of major depression, seasonal affective disorder, sleep disorders, cardiovascular pathologies, and pathologies of the digestive system. Insomnia and fatigue caused by different ‎yvaiy

0 time zones, cinsomnia and fatigue due to jet-lag, appetite disorders and obesity. agomelatine has been described; preparation and use in therapeutics in the two European patent applications 0 YAS ££Y Roa Lak 1 © The applicant discovered that N-[2-(7-methoxy-1 -naphthyl)ethyl]acetamide and its hydrates Loa hydrates, crystalline forms, and its addition salts with a pharmaceutically acceptable acid or base that has remarkable properties that allow its use in the treatment of periventricular leukomalacia. General description of the invention 0 Periventricular leukomalacia is the most common cause of cerebral paralysis in the premature child. This early neonatal disorder is due to one or more injuries to the substance ring periventriculaire 6; Where infection occurs in premature or premature birth after 71 to 4 7 weeks of pregnancy; And after the end of pregnancy in exceptional cases. VO results from cali periventricular leukomalacia most of the motor prematurity prematurity. However; Other neurological after-effects or complications may be observed, although rare, indicating extension of the lesions beyond the periventricular white matter: cranial perimeter abnormalities of the development of the cranial perimeter, which mainly refers to abnormalities of the proliferation 0 and/or regression of dendrites; And mental deficiency, which is secondary, yviy

= associated cortical reach, intellectual, secondary deficit (special developmental deficit affecting 1 in 2 or 3 children at enrollment disorders); disturbances at school in the seventh year; secondary sensory defects; albeit exceptional; For backwardness damages add to ald and high child mortality ¢ auditory or visual radiations

That is the suffering of parents who find themselves facing a problem that has neurological consequences or the death of their young due to the inability of the medical team that is completely at a loss when periventricular leukomalacia appears to a large extent in newborns who suffer nothing but prematurity, in fact. We do not currently have any treatment strategy to prevent or reduce the spread

Jie these injuries. Fle on that; It leads to an increase in the number of repeated pregnancies and a severe decrease

0 in the life chances of a premature child after birth leads to a significant increase in the incidence of periventricular leukomalacia, which is the main challenge faced by neonatologists. The disorder is due to several factors: Early pregnancy factors and perinatal and prenatal factors may be associated with the formation of injuries during the development of the brain.

Among these factors, episodes of hypoxia, hypoxia-ischaemia, and lack of oxygen can be mentioned

0 imbalances endocriniens and genetic factors and disorders related to the growth promoters; and infections maternal infection resulting in increased production of cytokines; Exposure to pro-inflammatory agents ¢ etc. These risk factors have generic Aga markers; In turn, pala increases the release of excitatory amino acids

yviy reactive oxygenated Ale ll) and increase the production of oxidative organisms Exciting amino acid release .species It has a protective effect on nerves and enhances the mechanisms of treating agomelatine The applicant has now proven that Jie agomelatine is a solution to secondary injuries of the white matter surrounding the ventricle . Accordingly; the . periventricular leukomalacia is new for the treatment of periventricular leukomalacia ° that it is highly tolerable and does not interfere with agomelatine in addition; Al-Khuss. dag any drugs to become a suitable medicine for this case. crystalline forms, hydrates and its hydrates «agomelatine» The invention relates to the use of cella] according to an acceptable base or acid base as well and its addition salts with pharmaceutical crystalline forms 0 acid in obtaining pharmaceutical formulations for the treatment of softening White blood cells surrounding the ventricle. periventricular leukomalacia obtained in the form ll agomelatine The invention relates specifically to the use of crystalline [1] described in EP 1974707 in obtaining pharmaceutical compositions for the treatment of periventricular leukomalacia.5; or oral injections, the pharmaceutical formulations will be given in appropriate forms to be administered through the mouth, tongue, rectal, or rectum; transcutaneous Mall or nasally, or via parenteral tablets, injectable tablets, especially in the form of injectable preparations, capsules, glossettes, sublingual tablets and sublingual tablets 0 yviy

- 01 gelatin capsules; capsules; lozenges, suppositories, and creams; Ointments 75, Dermal gels, etc. in addition to; agomelatine includes; And pharmaceutical compositions according to the invention contain excipients or one or more carriers determined from Aside diluents; lubricants ¢, bond 5, disintegration agents ¢, absorbents, colourants ¢, sweeteners, etc. The following can be stated by non-restrictive example: { As diluents, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, : diluents «glycerol, Ve b. As lubricants silica, talc, stearic acid and its magnesium and calcium salts: lubricants for polyethylene glycol c) as binders: aluminum and magnesium silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone, V0 d) as materials Dissociation of alginic acid ¢ agar: disintegrants, sodium salt and its effervescent mixtures. The effective dose varies according to the patient's age and weight; route of administration; nature of the disorder and any associated medications and ranges from 1 to 0.5 mg of agomelatine every hour. yvay

- It is not recommended that the daily dose of agomelatine be YY mg with the possibility of increasing it to 50 mg daily. Pharmaceutical Composition: Formula for preparing 0 0 tablet; Each tablet contains YO mg of active ingredient: YO N-[2-(7-methoxy-1-naphthyl)ethyl] acetamide 17 g Lactose monohydrate © 17 g Y Magnesium stearate Povidone 4 g Non-aqueous colloidal silica 1g Anhydrous colloidal silica 01mg Cellulose sodium glycolate 00g Stearic acid 1g. Pharmacological study The neuroprotective effects of 06a©00a2._ were observed in an infant rat aged 2 days, in which brain white matter lesions were produced by intracerebral injection of 016. After administration of 01 micrograms of also ibotenate, injections were made intraperitoneally. peritoneum with a total size of μg; veo to 0 0 mg/kg agomelatine; 01 mg/kg of fluoxetine was used as a standard cantidepressant, or the solvent was used alone. in a second experiment; The intraperitoneal injection was done two to eight hours after the intracerebral injection of ibotenate. yviy

A - - results: after | ibotenate ¢ Uae “The infant La had cortical lesions as well as lesions of the periventricular white matter. The co-administration of agomelatine was reflected in a dose-dependent decrease in white matter lesions of up to 54 7 Alia with the administration of © mg/kg. No significant effect was observed on white matter lesions in the case of co-administration of fluoxetine or the solvent alone (Phosphate Buffered Saline). Neuroprotection observed with agomelatine decreased when it was given in a period ranging from zero to hours after the injection of ibotenate ¢ and then regained neuroprotection when administered within hours after the injection of ibotenate . { Yes from mm hea - 0 + : J a0 3 3 HPL 5 £05 3 3 a 4 l 3 1 + 113 3 1 1 5l 0 and b and agomelatine © mg/kg a Animals treated with 10010818 developed lesions that increased in size in the first 24 sela period after injection and were eventually stabilized. yviy

CL

one or eight hours later); OF (in agomelatine) was observed in co-treated animals with the same infections in the first 24 hours; then a very significant decline was observed during the next 4 days. yviy

Claims (1)

= . \ — protection elements 1-1 Using agomelatine “or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide” or one of those? Its hydrates, crystalline forms, and its addition salts with an acid or base are pharmaceutically acceptable in obtaining a drug for the treatment of periventricular leukomalacia. 1 ?- Lady use of claim 1 which is characterized by obtaining agomelatine in Y crystal form Al 1 “- Pharmaceutical compositions comprising agomelatine; Or one of its hydrates ¢ and crystalline images? crystalline forms, as well as its addition salts with a pharmaceutically acceptable acid or base, either alone or with pharmaceutically acceptable excipients for use in the manufacture of; Medication for the treatment of periventricular leukomalacia. 14- A pharmaceutical composition according to the claim? It is characterized by obtaining agomelatine in the crystal form [1. agomelatine -©; Or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide ¢ or one of its hydrates? hydrates ¢ and crystalline forms, as well as its addition salts with acid "or base", are pharmaceutically acceptable for use in the treatment of periventricular leukomalacia ¢. 1 "- crystal image [1] For agomelatine to be used in the treatment of ali periventricular leukomalacia. yvay