Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-03-16
2000-05-30
Reamer, James H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 313140
Patent
active
060691654
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR97/01633 filed Sep. 17, 1997.
The subject of the present invention is new pharmaceutical compositions, typically suitable for oral administration, comprising 4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-(ethylsulphonyl)-2-methoxyben zamide (or amisulpride), its isomers and some of their derivatives, these compositions exhibiting an improved bioavailability.
Amisulpride, its isomers and some of their derivatives are described in French Patent 78 01632, the teaching of which is integrally incorporated in the present description. Amisulpride is a neuroleptic used in the treatment of psychoses, more particularly in the treatment of paranoid and productive schizophrenias or acute delirious psychoses and in the treatment of schizophrenia deficiency states, residual psychotic changes and inhibitory states with slowing. Amisulpride is also useful in the treatment of dysthymia.
Amisulpride can be administered by the oral route, generally in the form of tablets each containing a dose of 50 or 200 mg (see Vidal, Solian heading, page 1463 and 1464, published by Vidal, 1996). The daily doses of amisulpride thus administered are often very high and can exceed 1 g/day. In this case, the patients treated with amisulpride must absorb several of these tablets daily. Some of these patients, because of their condition itself, can encounter difficulties in regularly absorbing, without forgetting, a high number of tablets and in thus correctly following their treatment.
The Applicant Company has thus sought to develop a new amisulpride form, intended mainly for administration by oral route, which only requires a limited daily number of intakes (or number of doses/day), indeed a single daily intake.
Tablets comprising a higher dose of amisulpride, for example doses greater than 600 mg, were first of all envisaged. However, such tablets often proved to be too large to be easily swallowed by the patients.
Moreover, and without being committed to the theory, the Applicant Company was able to observe that the limited bioavailability (of the order of 35 to 45%) of amisulpride administered by the oral route could be attributed to partial and uneven passage of this compound at the gastrointestinal level and that consequently, its passage at the cerebral level could sometimes be insufficient.
It was then envisaged to prolong and/or to intensify the gastrointestinal absorption of amisulpride in order to improve the bioavailability thereof, for the purpose, in particular, of decreasing the number of daily intakes of amisulpride while maintaining, indeed while improving, the therapeutic effectiveness of this compound.
The main subject of the invention is consequently a new amisulpride form exhibiting an improved bioavailability, in particular when administered by the oral route.
More specifically, the invention comprises a new pharmaceutical composition, typically suitable for oral administration, comprising a lipophilic phase and, as active principle, at least one compound selected from an optically active isomer or a racemate of amisulpride and an optically active isomer or a racemate of a pharmacologically acceptable acid, a quaternary ammonium salt or an oxide of amisulpride.
FIG. 1 represents the plasma concentrations of amisulpride, measured in the rat after absorption of various formulations comprising the same amisulpride dose.
FIG. 2 represents the plasma concentrations of amisulpride, measured in the rat after absorption of formulations comprising variable amisulpride doses .
Generally, the said active principle is dissolved, partially or completely, in the lipophilic phase.
A composition according to the invention is very particularly suitable for the administration of amisulpride per se, that is to say 4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-(ethylsulphonyl)-2-methoxyben zamide, its laevorotatory ((S)-(-)-amisulpride) and dextrorotatary ((R)-(+)-amisulpride) isomers, mixtures of these isomers. It is also particularly suitable for the administration of tartrates of amisulpride per se and o
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J. Reynolds et al., "Martindale The Extra Pharmacopoeia", Royal Pharmaceutical Society, XP002032111, 1996.
Andrieu Veronique
Cuine Alain
Montel Jean
Reamer James H.
Synthelabo
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