WO1998047506A1 - Gastric-retained pharmaceutical composition - Google Patents

Gastric-retained pharmaceutical composition Download PDF

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Publication number
WO1998047506A1
WO1998047506A1 PCT/FR1998/000755 FR9800755W WO9847506A1 WO 1998047506 A1 WO1998047506 A1 WO 1998047506A1 FR 9800755 W FR9800755 W FR 9800755W WO 9847506 A1 WO9847506 A1 WO 9847506A1
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WO
WIPO (PCT)
Prior art keywords
carbon dioxide
composition according
benzamide
salts
dioxide generating
Prior art date
Application number
PCT/FR1998/000755
Other languages
French (fr)
Inventor
Jérôme BESSE
Original Assignee
Sanofi-Synthelabo
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi-Synthelabo filed Critical Sanofi-Synthelabo
Priority to KR1019997009438A priority Critical patent/KR20010006353A/en
Priority to CA002286081A priority patent/CA2286081A1/en
Priority to AU73416/98A priority patent/AU737634B2/en
Priority to IL13199598A priority patent/IL131995A0/en
Priority to NZ500288A priority patent/NZ500288A/en
Priority to PL98336273A priority patent/PL336273A1/en
Priority to EP98920623A priority patent/EP0983065A1/en
Priority to JP54514398A priority patent/JP2001523241A/en
Publication of WO1998047506A1 publication Critical patent/WO1998047506A1/en
Priority to NO995039A priority patent/NO995039L/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse

Definitions

  • the present invention relates to pharmaceutical compositions with gastric residence comprising an active principle of the family of benzamides.
  • Benzamides are chemical compounds whose structure includes the following motif:
  • benzamides are useful as an active ingredient in medicaments intended for the treatment, in particular, of disorders of the central nervous system.
  • Such benzamides may consist of amisulpride, tiapride, sulpiride, their salts, if any, their enantiomers and the salts of these enantiomers, as well as some of their derivatives.
  • benzamides can be administered orally.
  • bioavailability is understood here to mean the fraction of the active principle which is absorbed from its pharmaceutical form and which reaches the plasma.
  • Low or irregular bioavailability can be the result of several factors, among which we can cite: low solubility or very slow dissolution of the active principle or of the dosage form which contains it; instability of the active ingredient, either over the entire length of the gastrointestinal tract, or in only one of its parts; the enzymatic degradation in the mucosa or in the liver of the active ingredient; slow or incomplete absorption of the active ingredient due to slow passive diffusion through the intestine or, in the case of an active mechanism, saturation of the transport system. It is known that the bioavailability of certain active ingredients can be modified by means of a sustained-release formulation which releases the active ingredient over the entire length of the gastrointestinal tract.
  • the Applicant then considered improving the bioavailability of benzamides by formulating them in the form of a pharmaceutical composition with gastric residence promoting absorption in the small intestine, or even, more specifically, the upper parts of the small intestine.
  • the invention thus consists of a pharmaceutical composition with gastric residence, characterized in that it comprises:
  • (c) means allowing partial retention of the carbon dioxide generated by said carbon dioxide generating system.
  • the figure represents the plasma release profile, in humans, of tiapride hydrochloride, this profile being obtained with a pharmaceutical composition according to the invention.
  • the term "benzamide" within the meaning of the present invention, and unless otherwise indicated, covers the various enantiomers or diastereoisomers of these compounds, including their mixtures, in particular their racemic mixtures.
  • a pharmaceutical composition with gastric residence is intended to reside for more than one hour in the stomach with a view to a prolonged and / or controlled release of the active principle.
  • a pharmaceutical composition with gastric residence according to the invention has the advantage of being able to float on the surface of the liquids contained in the stomach, and this very quickly after having been absorbed. It has thus been found that a composition according to the invention can float for less than two minutes after being brought into contact with an aqueous liquid.
  • the invention is more particularly suitable for the active principles consisting of sulpiride, 1 amisulpride, their salts, their enantiomers and the salts of these enantiomers, as well as tiapride, its oxide and its salts.
  • Sulpiride is a neuroleptic useful in the treatment of acute and chronic psychoses (i) with a dehinibitating dosage: psychoses where predominantly withdrawal states, apragmatism, abuli or (ii) with dosage antiproductive: delusional or confusing psychoses, schizophrenia.
  • Tiapride in particular in the form of hydrochloride, is a neuroleptic useful in the treatment of agitation and aggressiveness of the demented subject, behavioral disorders when they are manifested by phenomena of hyperactivity, aggressiveness, d irritability, especially in alcohol and the elderly, motor behavior disorders such as, for example, tremors, spontaneous or iatrogenic neuromuscular dyskinesia, abnormal movements such as chorea, tics, hemiballism, sensory behavior disorders such as for example headaches, migraines, various pain, especially intense and rebellious pain.
  • the present invention is more particularly suitable for tiapride hydrochloride.
  • Amisulpride or 4-amino-N [(1-ethyl-2-pyrrolidinyl) methyl] -5- (ethylsulfonyl) -2-methoxybenzamide, its enantiomers and some of its derivatives are described in French Patent No. 78,01632, the teaching of which is fully incorporated in this description.
  • the invention is particularly suitable for amisulpride per se, ie 4 -amino-N- [(1-ethylpyrrolidin-2-yl) methyl] -5- (ethylsulfonyl) - 2-methoxybenzamide, its enantiomers levogyre
  • a preferred tartrate consists of the compound described in Example IV of patent FR 78 01632, that is to say the (D) -tartrate of (S) - (-) - amisulpride, in other words the [S- (R * , R *)] -2, 3-dihydroxybutanedioate du (S) - (-) -4-amino- N- [(1-ethylpyrrolidin-2-yl) methyl] -5- (ethylsulfonyl) -2- methoxybenzamide.
  • Amisulpride is a neuroleptic used in the treatment of psychosis, more particularly in the treatment of paranoid and productive schizophrenia, acute delusional psychosis, as well as in the treatment of deficit states of schizophrenia, residual psychotic changes and states of inhibition with slowdown. Amisulpride is also useful in the treatment of dysthymia.
  • benzamides can be used in the context of the present invention such as metoclopramide, veralipride, alizapride or clebopride.
  • the main function of the carbon dioxide generating system is to form carbon dioxide in the form of bubbles. These bubbles contribute to quickly bringing, then to maintaining the pharmaceutical composition of the invention on the surface of the liquids contained in the stomach.
  • a carbon dioxide generating system suitable in a pharmaceutical composition according to the invention generally comprises at least one carbon dioxide generating agent.
  • the carbon dioxide generating agent is usually a carbonate of an alkali or alkaline earth metal, such as calcium carbonate, or a bicarbonate of an alkali metal, preferably sodium bicarbonate.
  • Such a carbon dioxide generating system consisting only of a carbon dioxide generating agent, does not begin to form bubbles of carbon dioxide until after having been brought into contact with a medium at acidic pH, generally that of l 'stomach.
  • a system that generates carbon dioxide. carbon independent of pH.
  • a system can comprise a carbon dioxide generating agent such as those mentioned above, as well as at least one acid compound chosen from the group consisting of monocarboxylic acids such as lactic acid, polycarboxylic acids and the partial salts of polycarboxylic acids. Mention may more particularly be made, as acid compounds, of tartaric, maleic, malonic, malic, fumaric, succinic, adipic, citric acids and their partial salts, such as monosodium citrate.
  • the acid compound content is generally chosen so that the number of moles in said acid compound relative to the number of moles in said carbon dioxide generating agent is between 0.7 and 1.4 times the stoichiometry.
  • the active principle or any other component used in the formulation of the composition according to the invention has a basic character, it may be necessary to increase the content of acidic compound accordingly.
  • the means allowing the partial retention of the carbon dioxide generated by the carbon dioxide generating system must allow the diffusion of the carbon dioxide in a controlled manner. It must prevent the too rapid diffusion of carbon dioxide which would lead to too short a flotation in time of the pharmaceutical composition according to the present invention. Conversely, it must allow sufficient diffusion of carbon dioxide to ensure a determined flotation time of said composition in the stomach, as well as sufficient diffusion of water or an aqueous compound within the composition according to the invention.
  • This means can consist of a porous mineral matrix, in particular matrices based on silicates or calcium fluoride, or, preferably, in a polymer.
  • said polymer consists of at least one hydrophilic polymer.
  • the hydrophilic polymers suitable for a pharmaceutical composition according to the invention are those which can form a hydrocolloid gel in contact with an aqueous liquid, in particular the aqueous liquids contained in the stomach.
  • hydrophilic polymers mention may be made of (i) natural polysaccharides such as alginates, xanthan gum, guar gum or locust bean gum, (ii) hemisynthetic polysaccharides, in particular cellulose derivatives such as methylcellulose, Ethylcellulose, methylhydroxyethylcellulose, carboxymethylcellulose and its salts such as sodium carboxymethylcellulose or carboxymethylcellulose calcium, and preferably hydroxypropylcellulose, hydroxypropylmethylcellulose and mixtures of hydroxypropylcellulose and hydroxypropylmethylcellulose or hydroxypropylmethylcellulose synthetic hydrophilic polymers such as polymers derived from acrylic and methacrylic acids and their salts, such polyacrylates include those sold under the Carbopol ® brand, amino acid polymers such as polylysine and (iv) certain proteins or derivatives thereof such as gelatins. Cellulose derivatives are particularly preferred.
  • contents of the various constituent components of a pharmaceutical composition according to the invention are generally chosen so that the relative density in the stomach of this composition is less than 1.00.
  • a pharmaceutical composition according to the invention comprises from 5 to 70%, preferably from 10 to 60% by weight of active principle, from 10 to 75%, preferably from 15 to 50% by weight in at least one hydrophilic polymer and from 5 to 50%, preferably 10 to 40% by weight of carbon dioxide generating agent, the percentages being expressed relative to the total weight of said composition.
  • a pharmaceutical composition with gastric residence according to the invention can be in the form of capsules, granules or, preferably, tablets. These last are floating tablets, that is, they can float on stomach fluids.
  • Such a pharmaceutical composition can be prepared by simple mixing of its components, followed by pharmaceutical shaping carried out in a conventional manner.
  • the mixture comprising all or part of the constituent components of the composition according to the invention, may be granulated or agglomerated.
  • the mixture of constituent components of the composition according to the invention can be compressed.
  • Lubricants such as polyethylene glycols with a molecular weight between 1,500 and 10,000, magnesium stearate or sodium stearyl fumarate, as well as conventional excipients such as flow agents or compression agents, can be added to the tablet mixture.
  • a pharmaceutical composition according to the invention comprising a given benzamide, can be used for the treatment of diseases already treated with the same benzamide in its conventional form.
  • the pharmaceutical composition according to the invention can be used in the treatment of one of the pathologies mentioned above, respectively, for each of these benzamides.
  • Example 1 floating tablets containing tiapride hydrochloride
  • tiapride hydrochloride 37.0% hydroxypropyl methylcellulose 1 3 0.0% polyethylene glycol 6000 3.0% anhydrous sodium citrate 16.8% sodium bicarbonate 13.2%
  • the homogeneous mixture thus formed was compressed on an alternative tableting machine, to obtain round, flat tablets, with a diameter of 15 mm and comprising 300 mg of tiapride hydrochloride.
  • the tablets were placed in rotating baskets at 75 rpm, submerged in 1000 ml of 0.01 M hydrochloric acid at a temperature of 37 ⁇ 0.5 ° C.
  • tiapride was determined for each sample by UV spectrophotometry, in comparison with the absorbance of a standard solution containing 300 ⁇ g / ml of tiapride hydrochloride, in 0.01M hydrochloric acid.
  • tiapride hydrochloride 44.17% hydroxypropyl methylcellulose 1 28.68% magnesium stearate 0.50% sodium stearyl fumarate 2.87% anhydrous monosodium citrate 13.26% anhydrous monosodium carbonate 10.42% silica Aerosil 200 2 0.10%
  • the homogeneous mixture thus formed was compressed on an alternative tableting machine, to obtain round, convex tablets, with a diameter of 10 mm and comprising 200 mg of tiapride expressed as tiapride base.
  • the tablets were placed in cylindrical baskets, length 35 mm and diameter 19 mm, perforated in diameter 5 mm. They are immersed in 1000 mL of 0.01M hydrochloric acid at a temperature of 37 ⁇ 0.5 ° C. The dissolution medium was stirred by rotating vanes at 100 rpm. The medium was taken every 15 minutes in a closed circuit by a peristaltic pump, and the tiapride dosage determined by UV spectrophotometry in comparison with the absorption of a standard solution containing 200 ⁇ g / mL of tiapride base, in acid. 0.01M hydrochloric.
  • the tablets to be tested were introduced into 6 tubes.
  • the tiapride hydrochloride tablets of Example 2 started to float at 2 min, and continued to float for at least 120 min.
  • Example 2 The tablets of Example 2 were administered to 12 volunteers. Plasma samples were taken every 30 min. from 0 to 3 h, every 2 h from 4 to 12 h, then at 16, 20, 24, 36 and 48 h after administration. The results are shown in Figure, which shows the average plasma levels of tiapride base for the tablets of Example 2.
  • the mixture was then granulated with 10% water, and the granule dried in vacuo. After calibration, the granule was mixed with 13.7% sodium bicarbonate, then lubricated with 1% magnesium stearate and 0.2% Aerosil silica 200 (marketed by Degussa).
  • the homogeneous mixture thus formed was compressed on an alternative tableting machine to obtain round convex tablets with a diameter of 10 mm and comprising 200 mg of amisulpride.
  • Example 2 The dissolution method of Example 2 was used to determine the dissolution profile of the tablets thus prepared.
  • the standard used was 200 ⁇ g / ml of amisulpride base. The following results were obtained:
  • Amisulpride floating tablets were prepared according to the method described in Example 3. The tablets obtained included (% by mass) and were dosed at 50 mg in (D) -tartrate of (S) - ⁇ -) - amisulpride .
  • Example 2 The dissolution method of Example 2 was used, to determine the dissolution profile of the tablets thus prepared.
  • the standard used was 50 ⁇ g / mL of amisulpride base. The following results were obtained.
  • Floating tablets of amisulpride were prepared according to the process described in Example 1.
  • the tablets obtained included (% by mass):
  • Example 1 The dissolution method of Example 1 was used, by modifying the sample collection times, to determine the dissolution profile of the tablets thus prepared. The following results were obtained:

Abstract

The invention concerns a gastric-retained pharmaceutical composition, characterised in that it comprises: (a) an active principle consisting in a benzamide or a benzamide salt; (b) a system for generating carbon dioxide; and (c) means for partially retaining the carbon dioxide generated by the carbon dioxide generating means.

Description

Composition pharmaceutique à résidence gastrique Pharmaceutical composition with gastric residence
La présente invention a pour objet des compositions pharmaceutiques à résidence gastrique comprenant un principe actif de la famille des benzamides.The present invention relates to pharmaceutical compositions with gastric residence comprising an active principle of the family of benzamides.
Les benzamides sont des composés chimiques dont la structure comprend le motif suivant :Benzamides are chemical compounds whose structure includes the following motif:
Figure imgf000003_0001
Figure imgf000003_0001
Certains benzamides sont utiles comme principe actif de médicaments destinés au traitement, notamment, des troubles du système nerveux central. De tels benzamides peuvent consister en 1 ' amisulpride, le tiapride, le sulpiride, leurs sels, le cas échéant, leurs énantiomères et les sels de ces énantiomères, ainsi que certains de leurs dérivés.Certain benzamides are useful as an active ingredient in medicaments intended for the treatment, in particular, of disorders of the central nervous system. Such benzamides may consist of amisulpride, tiapride, sulpiride, their salts, if any, their enantiomers and the salts of these enantiomers, as well as some of their derivatives.
Ces benzamides peuvent être administrés par voie orale.These benzamides can be administered orally.
Toutefois la demanderesse a pu constater que l'administration par voie orale de ces benzamides pouvait conduire à une biodisponibilité faible et/ou irrégulière. On entend ici par le terme "biodisponibilité", la fraction du principe actif qui est absorbé depuis sa forme pharmaceutique et qui parvient dans le plasma.However, the Applicant has found that the oral administration of these benzamides could lead to low and / or irregular bioavailability. The term "bioavailability" is understood here to mean the fraction of the active principle which is absorbed from its pharmaceutical form and which reaches the plasma.
Une biodisponibilité faible ou irrégulière peut être le résultat de plusieurs facteurs parmi lesquels on peut citer : une faible solubilité ou une dissolution très lente du principe actif ou de la forme galénique qui le contient; l'instabilité du principe actif, soit sur toute la longueur du tractus gastro-intestinal , soit dans une de ses parties seulement; la dégradation enzy atique dans la muqueuse ou au niveau hépatique du principe actif ; l'absorption lente ou incomplète du principe actif en raison d'une diffusion passive lente à travers l'intestin ou, dans le cas d'un mécanisme actif, d'une saturation du système de transport. Il est connu que la biodisponibilité de certains principes actifs peut être modifiée au moyen d'une formulation à libération prolongée qui libère le principe actif sur toute la longueur du tractus gastro-intestinal.Low or irregular bioavailability can be the result of several factors, among which we can cite: low solubility or very slow dissolution of the active principle or of the dosage form which contains it; instability of the active ingredient, either over the entire length of the gastrointestinal tract, or in only one of its parts; the enzymatic degradation in the mucosa or in the liver of the active ingredient; slow or incomplete absorption of the active ingredient due to slow passive diffusion through the intestine or, in the case of an active mechanism, saturation of the transport system. It is known that the bioavailability of certain active ingredients can be modified by means of a sustained-release formulation which releases the active ingredient over the entire length of the gastrointestinal tract.
La demanderesse a toutefois pu établir qu'une telle formulation ne convenait pas aux composés de la famille des benzamides. En effet, la demanderesse a pu déterminer que les benzamides sont généralement mal absorbés au niveau colonique chez l'homme, mais, qu'en revanche, ils sont mieux absorbés dans l'intestin grêle. Pour certains de ces benzamides, l'absorption se fait quasi -exclusivement dans les parties hautes de l'intestin grêle, à savoir le jéjunum, le duodénum ou 1 ' ileum proximal .The Applicant has however been able to establish that such a formulation is not suitable for compounds of the family of benzamides. Indeed, the Applicant has been able to determine that benzamides are generally poorly absorbed at the colonic level in humans, but, on the other hand, they are better absorbed in the small intestine. For some of these benzamides, absorption takes place almost exclusively in the upper parts of the small intestine, namely the jejunum, the duodenum or the proximal ileum.
Poursuivant ses recherches, la demanderesse a alors envisagé d'améliorer la biodisponibilité des benzamides en les formulant sous la forme d'une composition pharmaceutique à résidence gastrique favorisant une absorption au niveau de l'intestin grêle, voire, plus spécifiquement, les parties hautes de l'intestin grêle.Continuing her research, the Applicant then considered improving the bioavailability of benzamides by formulating them in the form of a pharmaceutical composition with gastric residence promoting absorption in the small intestine, or even, more specifically, the upper parts of the small intestine.
L'invention consiste ainsi en une composition pharmaceutique à résidence gastrique, caractérisée en ce qu'elle comprend :The invention thus consists of a pharmaceutical composition with gastric residence, characterized in that it comprises:
(a) un principe actif consistant en un benzamide ou un sel de benzamide ,(a) an active principle consisting of a benzamide or a benzamide salt,
(b) un système générateur de dioxyde de carbone, et(b) a carbon dioxide generating system, and
(c) un moyen permettant la rétention partielle du dioxyde de carbone généré par ledit système générateur de dioxyde de carbone .(c) means allowing partial retention of the carbon dioxide generated by said carbon dioxide generating system.
La figure représente le profil de libération plasmatique, chez l'homme, du chlorhydrate de tiapride, ce profil étant obtenu avec une composition pharmaceutique selon l'invention.The figure represents the plasma release profile, in humans, of tiapride hydrochloride, this profile being obtained with a pharmaceutical composition according to the invention.
Lorsque le principe actif est un composé comprenant un ou plusieurs centres d'asymétrie, le terme "benzamide" au sens de la présente invention, et sauf indication contraire, couvre les différents énantiomères ou diastéréoisomères de ces composés, y compris leurs mélanges, en particulier leurs mélanges racémiques .When the active principle is a compound comprising one or more centers of asymmetry, the term "benzamide" within the meaning of the present invention, and unless otherwise indicated, covers the various enantiomers or diastereoisomers of these compounds, including their mixtures, in particular their racemic mixtures.
Une composition pharmaceutique à résidence gastrique est destinée à résider plus d'une heure dans l'estomac en vue d'une libération prolongée et/ou contrôlée du principe actif.A pharmaceutical composition with gastric residence is intended to reside for more than one hour in the stomach with a view to a prolonged and / or controlled release of the active principle.
Une composition pharmaceutique a résidence gastrique selon l'invention a pour avantage de pouvoir flotter a la surface des liquides contenus dans l'estomac, et ce, très rapidement après avoir été absorbée. Il a ainsi pu être constaté qu'une composition selon l'invention pouvait flotter moins de deux minutes après avoir été mis en contact avec un liquide aqueux.A pharmaceutical composition with gastric residence according to the invention has the advantage of being able to float on the surface of the liquids contained in the stomach, and this very quickly after having been absorbed. It has thus been found that a composition according to the invention can float for less than two minutes after being brought into contact with an aqueous liquid.
Il est très important que la flottaison intervienne le plus rapidement possible après absorption afin d'éviter à la composition pharmaceutique d'être chassée de l'estomac. En effet, on considère généralement que si la composition pharmaceutique à résidence gastrique ne flotte pas dans les trois minutes suivant l'absorption chez un sujet à jeun, la probabilité qu'elle soit évacuée hors de l'estomac devient inacceptable.It is very important that the flotation occurs as quickly as possible after absorption in order to prevent the pharmaceutical composition from being driven from the stomach. Indeed, it is generally considered that if the pharmaceutical composition with gastric residence does not float within three minutes of absorption in a fasted subject, the probability that it is evacuated from the stomach becomes unacceptable.
L'invention convient plus particulièrement aux principes actifs consistant en le sulpiride, 1 ' amisulpride, leurs sels, leurs énantiomères et les sels de ces énantiomères, ainsi qu'au tiapride, son oxyde et ses sels.The invention is more particularly suitable for the active principles consisting of sulpiride, 1 amisulpride, their salts, their enantiomers and the salts of these enantiomers, as well as tiapride, its oxide and its salts.
Le sulpiride ou 5- (aminosulfonyl) -N- [ (l-éthyl-2- pyrrolidinyl) méthyl] -2-méthoxybenzamide et son procédé de préparation, sont décrits dans le brevet spécial de médicament français N° 4879M , dont l'enseignement est intégralement incorporé dans la présente description.Sulpiride or 5- (aminosulfonyl) -N- [(1-ethyl-2-pyrrolidinyl) methyl] -2-methoxybenzamide and its preparation process, are described in the French special patent for medicament No. 4879M, the teaching of which is fully incorporated into this description.
Le sulpiride est un neuroleptique utile dans le traitement des psychoses aiguës et chroniques (i) à posologie déshinibitrice : psychoses où prédominent états de repli, apragmatisme, aboulie ou (ii) à posologie antiproductive : psychoses délirantes ou confusionnelles, schizophrénie .Sulpiride is a neuroleptic useful in the treatment of acute and chronic psychoses (i) with a dehinibitating dosage: psychoses where predominantly withdrawal states, apragmatism, abuli or (ii) with dosage antiproductive: delusional or confusing psychoses, schizophrenia.
Le tiapride ou N- [2- (diéthylamino) éthyl] -2-méthoxy-5- (méthylsulfonyl) benzamide, ses sels, son oxyde et leurs procédés de préparation, sont décrits dans le brevet français N° 75 09808, dont l'enseignement est intégralement incorporé dans la présente description. Le tiapride, en particulier sous forme de chlorhydrate, est un neuroleptique utile dans le traitement de l'agitation et l'agressivité du sujet dément, des troubles du comportement lorsqu'ils se manifestent par des phénomènes d' hyperactivité, d'agressivité, d'irritabilité notamment chez l'éthylique et le vieillard, des troubles du comportement moteur tels que par exemple les tremblements, les dyskinésie neuromusculaires spontanées ou iatrogènes, les mouvements anormaux tels que la chorée, les tics, 1 ' hémiballisme, les troubles du comportement sensitif tels que par exemple les céphalées, les migraines, les algies diverses, notamment les algies intenses et rebelles. La présente invention convient plus particulièrement au chlorhydrate de tiapride.Tiapride or N- [2- (diethylamino) ethyl] -2-methoxy-5- (methylsulfonyl) benzamide, its salts, its oxide and their preparation processes, are described in French patent No. 75 09808, including teaching is fully incorporated into this description. Tiapride, in particular in the form of hydrochloride, is a neuroleptic useful in the treatment of agitation and aggressiveness of the demented subject, behavioral disorders when they are manifested by phenomena of hyperactivity, aggressiveness, d irritability, especially in alcohol and the elderly, motor behavior disorders such as, for example, tremors, spontaneous or iatrogenic neuromuscular dyskinesia, abnormal movements such as chorea, tics, hemiballism, sensory behavior disorders such as for example headaches, migraines, various pain, especially intense and rebellious pain. The present invention is more particularly suitable for tiapride hydrochloride.
L'amisulpride ou 4-amino-N [ (l-éthyl-2-pyrrolidinyl) méthyl] -5- (éthylsulfonyl) -2-méthoxybenzamide, ses énantiomères et certains de ses dérivés sont décrits dans le brevet français N° 78 01632, dont l'enseignement est intégralement incorporé dans la présente description. L'invention convient tout particulièrement pour l'amisulpride per se, c'est à dire le 4 -amino-N- [ (l-éthylpyrrolidin-2-yl) méthyl] -5- (éthylsulfonyl) - 2-méthoxybenzamide, ses énantiomères levogyreAmisulpride or 4-amino-N [(1-ethyl-2-pyrrolidinyl) methyl] -5- (ethylsulfonyl) -2-methoxybenzamide, its enantiomers and some of its derivatives are described in French Patent No. 78,01632, the teaching of which is fully incorporated in this description. The invention is particularly suitable for amisulpride per se, ie 4 -amino-N- [(1-ethylpyrrolidin-2-yl) methyl] -5- (ethylsulfonyl) - 2-methoxybenzamide, its enantiomers levogyre
( (S) - ( - ) - amisulpride) et dextrogyre ( (R) - ( +) - amisulpride) , des mélanges de ces énantiomères, les tartrates de l'amisulpride per se et de ses énantiomères, ainsi que des mélanges de ces tartrates. Un tartrate préféré consiste en le composé décrit dans l'exemple IV du brevet FR 78 01632, c'est à dire le (D) -tartrate du (S) - ( - ) - amisulpride, autrement dit le [S- (R*,R*) ] -2, 3-dihydroxybutanedioate du (S) - ( -) -4-amino- N- [ (l-éthylpyrrolidin-2-yl) méthyl] -5- (éthylsulfonyl) -2- méthoxybenzamide .((S) - (-) - amisulpride) and dextrorotatory ((R) - (+) - amisulpride), mixtures of these enantiomers, the tartrates of amisulpride per se and its enantiomers, as well as mixtures of these tartrates. A preferred tartrate consists of the compound described in Example IV of patent FR 78 01632, that is to say the (D) -tartrate of (S) - (-) - amisulpride, in other words the [S- (R * , R *)] -2, 3-dihydroxybutanedioate du (S) - (-) -4-amino- N- [(1-ethylpyrrolidin-2-yl) methyl] -5- (ethylsulfonyl) -2- methoxybenzamide.
L'amisulpride est un neuroleptique utilisé dans le traitement des psychoses, plus particulièrement dans le traitement des schizophrénies paranoïdes et productives, des psychoses délirantes aiguës, ainsi que dans le traitement des états déficitaires des schizophrénies, des évolutions psychotiques résiduelles et des états d'inhibition avec ralentissement. L'amisulpride est également utile dans le traitement de la dysthymie .Amisulpride is a neuroleptic used in the treatment of psychosis, more particularly in the treatment of paranoid and productive schizophrenia, acute delusional psychosis, as well as in the treatment of deficit states of schizophrenia, residual psychotic changes and states of inhibition with slowdown. Amisulpride is also useful in the treatment of dysthymia.
Outre les benzamides cités ci-dessus, d'autres benzamides peuvent être mis en oeuvre dans le cadre de la présente invention tels que le métoclopramide, le véralipride, l'alizapride ou le clébopride.In addition to the benzamides mentioned above, other benzamides can be used in the context of the present invention such as metoclopramide, veralipride, alizapride or clebopride.
Le système générateur de dioxyde de carbone a pour principale fonction de former du dioxyde de carbone sous forme de bulles. Ces bulles contribuent à amener rapidement, puis à maintenir la composition pharmaceutique de l'invention à la surface des liquides contenus dans l'estomac.The main function of the carbon dioxide generating system is to form carbon dioxide in the form of bubbles. These bubbles contribute to quickly bringing, then to maintaining the pharmaceutical composition of the invention on the surface of the liquids contained in the stomach.
Un système générateur de dioxyde de carbone convenant dans une composition pharmaceutique selon l'invention, comprend généralement au moins un agent générateur de dioxyde de carbone. L'agent générateur de dioxyde de carbone est habituellement un carbonate d'un métal alcalin ou alcalino- terreux, tel le carbonate de calcium, ou un bicarbonate d'un métal alcalin, de préférence le bicarbonate de sodium.A carbon dioxide generating system suitable in a pharmaceutical composition according to the invention generally comprises at least one carbon dioxide generating agent. The carbon dioxide generating agent is usually a carbonate of an alkali or alkaline earth metal, such as calcium carbonate, or a bicarbonate of an alkali metal, preferably sodium bicarbonate.
Un tel système générateur de dioxyde de carbone, constitué seulement d'un agent générateur de dioxyde de carbone, ne commence à former des bulles de dioxyde de carbone qu'après avoir été mis en contact avec un milieu à pH acide, généralement celui de l'estomac.Such a carbon dioxide generating system, consisting only of a carbon dioxide generating agent, does not begin to form bubbles of carbon dioxide until after having been brought into contact with a medium at acidic pH, generally that of l 'stomach.
Afin d'accélérer la formation des bulles de dioxyde de carbone, et donc améliorer la flottaison de la composition pharmaceutique à résidence gastrique de l'invention, on préfère mettre en oeuvre un système générateur de dioxyde de carbone indépendant du pH. Un tel système peut comprendre un agent générateur de dioxyde de carbone tel que ceux mentionnés plus haut, ainsi qu'au moins un composé acide choisi dans le groupe constitué par les acides monocarboxyliques comme l'acide lactique, les acides polycarboxyliques et les sels partiels d'acides polycarboxyliques . A titre de composés acides on peut plus particulièrement citer les acides tartrique, maléïque, malonique, malique, fumarique, succinique, adipique, citrique et leurs sels partiels, tels le citrate monosodique.In order to accelerate the formation of carbon dioxide bubbles, and therefore to improve the flotation of the pharmaceutical composition with gastric residence of the invention, it is preferable to use a system that generates carbon dioxide. carbon independent of pH. Such a system can comprise a carbon dioxide generating agent such as those mentioned above, as well as at least one acid compound chosen from the group consisting of monocarboxylic acids such as lactic acid, polycarboxylic acids and the partial salts of polycarboxylic acids. Mention may more particularly be made, as acid compounds, of tartaric, maleic, malonic, malic, fumaric, succinic, adipic, citric acids and their partial salts, such as monosodium citrate.
Dans un tel système générateur de dioxyde de carbone, la teneur en composé acide est généralement choisie de sorte que le nombre de moles en ledit composé acide par rapport au nombre de moles en ledit agent générateur de dioxyde de carbone soit compris entre 0,7 et 1,4 fois la stoechiométrie. Toutefois, si le principe actif ou tout autre composant entrant dans la formulation de la composition selon l'invention présente un caractère basique, Il peut être requis d'augmenter en conséquence la teneur en composé acide.In such a carbon dioxide generating system, the acid compound content is generally chosen so that the number of moles in said acid compound relative to the number of moles in said carbon dioxide generating agent is between 0.7 and 1.4 times the stoichiometry. However, if the active principle or any other component used in the formulation of the composition according to the invention has a basic character, it may be necessary to increase the content of acidic compound accordingly.
Le moyen permettant la rétention partielle du dioxyde de carbone généré par le système générateur de dioxyde de carbone doit autoriser la diffusion du dioxyde de carbone de manière contrôllée. Il doit empêcher la diffusion trop rapide du dioxyde de carbone qui conduirait a une flottaison trop courte dans le temps de la composition pharmaceutique selon la présente invention. A l'inverse, il doit permettre une diffusion suffisante du dioxyde de carbone pour assurer un temps de flottaison déterminé de ladite composition dans l'estomac, ainsi que la diffusion suffisante d'eau ou d'un composé aqueux au sein de la composition selon l'invention.The means allowing the partial retention of the carbon dioxide generated by the carbon dioxide generating system must allow the diffusion of the carbon dioxide in a controlled manner. It must prevent the too rapid diffusion of carbon dioxide which would lead to too short a flotation in time of the pharmaceutical composition according to the present invention. Conversely, it must allow sufficient diffusion of carbon dioxide to ensure a determined flotation time of said composition in the stomach, as well as sufficient diffusion of water or an aqueous compound within the composition according to the invention.
Ce moyen peut consister en une matrice poreuse minérale, notamment des matrices à base de silicates ou de fluorure de calcium, ou, de préférence, en un polymère. Selon un aspect particulièrement avantageux de l'invention, ledit polymère consiste en au moins un polymère hydrophile. Les polymères hydrophiles convenant pour une composition pharmaceutique selon l'invention sont ceux pouvant former un gel hydrocolloïdal au contact d'un liquide aqueux, en particulier les liquides aqueux contenus dans l'estomac. A titre de tels polymères hydrophiles on peut citer (i) les polysaccharides naturels comme les alginates, la gomme xanthane, la gomme guar ou la gomme de caroube, (ii) les polysaccharides hémisynthétiques, en particulier les dérivés de la cellulose comme la méthylcellulose, 1 ' éthylcellulose, la méthylhydroxyéthylcellulose, la carboxyméthylcellulose et ses sels tels la carboxyméthylcellulose sodique ou la carboxyméthylcellulose calcique, et, préférentiellement , l'hydroxypropylcellulose, 1 ' hydroxypropylméthylcellulose et les mélanges d' hydroxypropylcellulose et d' hydroxypropylméthylcellulose ou (iii) les polymères vinyliques, les polymères hydrophiles synthétiques comme les polymères dérivés des acides acrylique et méthacrylique et leurs sels, tels les polyacrylates, notamment ceux commercialisés sous la marque Carbopol®, les polymères d'acides aminés comme les polylysines et (iv) certaines protéines ou leurs dérivés comme les gélatines. Les dérivés de la cellulose sont particulièrement préférés.This means can consist of a porous mineral matrix, in particular matrices based on silicates or calcium fluoride, or, preferably, in a polymer. According to a particularly advantageous aspect of the invention, said polymer consists of at least one hydrophilic polymer. The hydrophilic polymers suitable for a pharmaceutical composition according to the invention are those which can form a hydrocolloid gel in contact with an aqueous liquid, in particular the aqueous liquids contained in the stomach. As such hydrophilic polymers, mention may be made of (i) natural polysaccharides such as alginates, xanthan gum, guar gum or locust bean gum, (ii) hemisynthetic polysaccharides, in particular cellulose derivatives such as methylcellulose, Ethylcellulose, methylhydroxyethylcellulose, carboxymethylcellulose and its salts such as sodium carboxymethylcellulose or carboxymethylcellulose calcium, and preferably hydroxypropylcellulose, hydroxypropylmethylcellulose and mixtures of hydroxypropylcellulose and hydroxypropylmethylcellulose or hydroxypropylmethylcellulose synthetic hydrophilic polymers such as polymers derived from acrylic and methacrylic acids and their salts, such polyacrylates include those sold under the Carbopol ® brand, amino acid polymers such as polylysine and (iv) certain proteins or derivatives thereof such as gelatins. Cellulose derivatives are particularly preferred.
Les teneurs en les différents composés constitutifs d'une composition pharmaceutique selon l'invention sont généralement choisies de sorte que la densité relative dans l'estomac de cette composition soit inférieure à 1,00.The contents of the various constituent components of a pharmaceutical composition according to the invention are generally chosen so that the relative density in the stomach of this composition is less than 1.00.
Habituellement, une composition pharmaceutique selon l'invention comprend de 5 à 70 %, de préférence de 10 à 60 % en poids de principe actif, de 10 à 75 %, de préférence de 15 à 50% en poids en au moins un polymère hydrophile et de 5 à 50 %, de préférence 10 à 40% en poids d'agent générateur de dioxyde de carbone, les pourcentages étant exprimés par rapport au poids total de ladite composition.Usually, a pharmaceutical composition according to the invention comprises from 5 to 70%, preferably from 10 to 60% by weight of active principle, from 10 to 75%, preferably from 15 to 50% by weight in at least one hydrophilic polymer and from 5 to 50%, preferably 10 to 40% by weight of carbon dioxide generating agent, the percentages being expressed relative to the total weight of said composition.
Une composition pharmaceutique à résidence gastrique selon l'invention peut se présenter sous la forme de gélules, de granulés ou, de préférence, de comprimés. Ces derniers sont des comprimés flottants, c'est à dire qu'ils peuvent flotter sur les liquides de l'estomac.A pharmaceutical composition with gastric residence according to the invention can be in the form of capsules, granules or, preferably, tablets. These last are floating tablets, that is, they can float on stomach fluids.
Une telle composition pharmaceutique peut être préparée par simple mélange de ses composants, suivi d'une mise en forme pharmaceutique réalisée de manière conventionnelle. Préalablement à la mise en forme pharmaceutique, en particulier en vue de l'obtention d'un comprimé flottant, le mélange comprenant tout ou partie des composants constitutifs de la composition selon l'invention, peut être granulé ou aggloméré.Such a pharmaceutical composition can be prepared by simple mixing of its components, followed by pharmaceutical shaping carried out in a conventional manner. Prior to pharmaceutical shaping, in particular with a view to obtaining a floating tablet, the mixture comprising all or part of the constituent components of the composition according to the invention, may be granulated or agglomerated.
En vue de la préparation d'un comprimé flottant selon l'invention on peut comprimé le mélange des composants constitutifs de la composition selon l'invention. On peut ajouter au mélange à comprimer des agents lubrifiants comme les polyéthylèneglycols de poids moléculaire compris entre 1.500 et 10.000, le stéarate de magnésium ou le stéaryl fumarate de sodium, ainsi que des excipients classiques tels des agents d'écoulement ou des agents de compression.With a view to the preparation of a floating tablet according to the invention, the mixture of constituent components of the composition according to the invention can be compressed. Lubricants such as polyethylene glycols with a molecular weight between 1,500 and 10,000, magnesium stearate or sodium stearyl fumarate, as well as conventional excipients such as flow agents or compression agents, can be added to the tablet mixture.
Une composition pharmaceutique selon l'invention, comprenant un benzamide donné, peut être utilisée pour le traitement de maladies déjà traitées par le même benzamide sous sa forme classique. Ainsi, si le benzamide consiste en l'amisulpride, le sulpiride, l'un de leurs énantiomères, le tiapride, ou un de leurs sels, la composition pharmaceutique selon l'invention peut être utilisée dans le traitement de l'une des pathologies mentionnées plus haut, respectivement, pour chacun de ces benzamides.A pharmaceutical composition according to the invention, comprising a given benzamide, can be used for the treatment of diseases already treated with the same benzamide in its conventional form. Thus, if the benzamide consists of amisulpride, sulpiride, one of their enantiomers, tiapride, or one of their salts, the pharmaceutical composition according to the invention can be used in the treatment of one of the pathologies mentioned above, respectively, for each of these benzamides.
Les exemples qui suivent ont pour objet d'illustrer la présente invention.The following examples are intended to illustrate the present invention.
Exemple 1 : comprimés flottants contenant du chlorhydrate de tiaprideExample 1: floating tablets containing tiapride hydrochloride
Dans un mélangeur lemniscate (Turbula®) on a mélangé les composés suivants (% en masse) : chlorhydrate de tiapride 37 , 0 % hydroxypropylméthylcellulose1 3 0 , 0 % polyéthylène glycol 6000 3 , 0% citrate monosodique anhydre 16 , 8 % bicarbonate de sodium 13 , 2 %In a lemniscate mixer (Turbula ® ), the following compounds were mixed (% by mass): tiapride hydrochloride 37.0% hydroxypropyl methylcellulose 1 3 0.0% polyethylene glycol 6000 3.0% anhydrous sodium citrate 16.8% sodium bicarbonate 13.2%
1 hydroxypropylméthylcellulose 90 SH4000SR commercialisée par la société Shin-Etsu 1 hydroxypropyl methylcellulose 90 SH4000SR sold by the company Shin-Etsu
Le mélange homogène ainsi formé a été comprimé sur une machine à comprimer alternative, pour obtenir des comprimés ronds, plats, de diamètre de 15 mm et comprenant 300 mg de chlorhydrate de tiapride.The homogeneous mixture thus formed was compressed on an alternative tableting machine, to obtain round, flat tablets, with a diameter of 15 mm and comprising 300 mg of tiapride hydrochloride.
La dissolution des comprimés a été testée selon la méthode suivante, en utilisant l'appareil de dissolution à palette décrit dans la Pharmacopée européenne :The dissolution of the tablets was tested according to the following method, using the pallet dissolution apparatus described in the European Pharmacopoeia:
les comprimés ont été disposés dans des paniers tournants à 75 rpm, submergés dans 1000 ml d'acide chlorhydrique 0,01 M à une température de 37 ± 0,5°C. Un échantillon du milieu, d'un volume de 3 ml , a été prélevé toutes les heures jusqu'à quatre heures, puis toutes les deux heures jusqu'à 12 heures.the tablets were placed in rotating baskets at 75 rpm, submerged in 1000 ml of 0.01 M hydrochloric acid at a temperature of 37 ± 0.5 ° C. A sample of the medium, with a volume of 3 ml, was taken every hour until four hours, then every two hours until 12 hours.
Le dosage en tiapride a été déterminé pour chaque échantillon par spectrophotométrie U.V. , en comparaison de 1 ' absorbance d'une solution étalon contenant 300 μg/ml de chlorhydrate de tiapride, dans l'acide chlorhydrique 0,01M.The dosage of tiapride was determined for each sample by UV spectrophotometry, in comparison with the absorbance of a standard solution containing 300 μg / ml of tiapride hydrochloride, in 0.01M hydrochloric acid.
Le profil de dissolution ci-dessous a ainsi pu être déterminé:The dissolution profile below could thus be determined:
Figure imgf000011_0001
Exemple 2 : comprimés flottants contenant du chlorhydrate de tiapride
Figure imgf000011_0001
EXAMPLE 2 Floating Tablets Containing Tiapride Hydrochloride
Dans un mélangeur lemniscate (Turbula*) , on a mélangé les composés suivants (% en masse) : chlorhydrate de tiapride 44,17 % hydroxypropylméthylcellulose1 28,68 % stéarate de magnésium 0,50 % stéarylfumarate de sodium 2,87 % citrate monosodique anhydre 13,26 % carbonate monosodique anhydre 10,42 % silice Aérosil 2002 0,10 %In a lemniscate mixer (Turbula * ), the following compounds were mixed (% by mass): tiapride hydrochloride 44.17% hydroxypropyl methylcellulose 1 28.68% magnesium stearate 0.50% sodium stearyl fumarate 2.87% anhydrous monosodium citrate 13.26% anhydrous monosodium carbonate 10.42% silica Aerosil 200 2 0.10%
λ hydroxypropylméthylcellulose 90 SH4000SR commercialisée par la société Shm-Etsu λ hydroxypropyl methylcellulose 90 SH4000SR sold by the company Shm-Etsu
2 commercialisé par la société Degussa 2 marketed by Degussa
Le mélange homogène ainsi formé a été comprimé sur une machine à comprimer alternative, pour obtenir des comprimés ronds, convexes, de diamètre 10 mm et comprenant 200 mg de tiapride exprimé en tiapride base.The homogeneous mixture thus formed was compressed on an alternative tableting machine, to obtain round, convex tablets, with a diameter of 10 mm and comprising 200 mg of tiapride expressed as tiapride base.
La dissolution des comprimés a été testée, en utilisant l'appareil de dissolution à palettes, décrit dans la pharmacopée européenne selon la méthode suivante :The dissolution of the tablets was tested, using the paddle dissolution apparatus, described in the European Pharmacopoeia according to the following method:
Les comprimés ont été disposés dans des paniers de forme cylindrique, longueur 35 mm et diamètre 19 mm, perforés en diamètre 5 mm. Ils sont immergés dans 1000 mL d'acide chlorhydrique 0,01M à une température de 37 ± 0,5°C. Le milieu de dissolution était agité par des palettes tournants à 100 tpm. Le milieu a été prélevé toutes les 15 minutes en circuit fermé par une pompe péristaltique, et le dosage en tiapride déterminé par spectrophotometrie UV en comparaison de l'absorption d'une solution étalon contenant 200 μg/mL de tiapride base, dans l'acide chlorhydrique 0.01M.The tablets were placed in cylindrical baskets, length 35 mm and diameter 19 mm, perforated in diameter 5 mm. They are immersed in 1000 mL of 0.01M hydrochloric acid at a temperature of 37 ± 0.5 ° C. The dissolution medium was stirred by rotating vanes at 100 rpm. The medium was taken every 15 minutes in a closed circuit by a peristaltic pump, and the tiapride dosage determined by UV spectrophotometry in comparison with the absorption of a standard solution containing 200 μg / mL of tiapride base, in acid. 0.01M hydrochloric.
Le profil de dissolution ci-dessous a ainsi pu être déterminé.The dissolution profile below could thus be determined.
heure 1 12 3 4 6 • 8 10 12 14hour 1 1 2 3 4 6 • 8 10 12 14
% dissous 24 33 42 49 63 76 86 93 98% dissolved 24 33 42 49 63 76 86 93 98
Pour mesurer la flottaison des comprimés, on utilise l'appareil à désagrégation des comprimés décrit à la Pharmacopée Européenne aux conditions expérimentales suivantes :To measure the buoyancy of the tablets, we use the tablet disintegration device described in the European Pharmacopoeia under the following experimental conditions:
- volume d'eau à 37°C ± 1°C, 800 ml- volume of water at 37 ° C ± 1 ° C, 800 ml
- mécanisme d'agitation arrêté en position basse- stirring mechanism stopped in the low position
- extrémités des tubes ouvertes- open tube ends
Les comprimés à tester ont été introduits dans 6 tubes. Les comprimés de chlorhydrate de tiapride de l'exemple 2 ont commencé à flotter à 2 min, et ils ont continué à flotter pendant au moins 120 min.The tablets to be tested were introduced into 6 tubes. The tiapride hydrochloride tablets of Example 2 started to float at 2 min, and continued to float for at least 120 min.
Etude pharmacocinétique des comprimés de l'exemple 2Pharmacokinetic study of the tablets of Example 2
Les comprimés de l'exemple 2 ont été administrés à 12 volontaires. Des échantillons plasmatiques ont été prélevés toutes les 30 min. de 0 à 3 h, toutes les 2 h de 4 à 12 h, puis à 16, 20, 24, 36 et 48 h après administration. Les résultats sont présentés dans la Figure, qui montre les niveaux plasmatiques moyens de tiapride base pour les comprimés de l'exemple 2.The tablets of Example 2 were administered to 12 volunteers. Plasma samples were taken every 30 min. from 0 to 3 h, every 2 h from 4 to 12 h, then at 16, 20, 24, 36 and 48 h after administration. The results are shown in Figure, which shows the average plasma levels of tiapride base for the tablets of Example 2.
Exemple 3 : comprimés flottants contenant de l'amisulprideEXAMPLE 3 Floating Tablets Containing Amisulpride
Dans un mélangeur type granulateur/mélangeur, on a mélangé les composés suivants :In a granulator / mixer type mixer, the following compounds were mixed:
amisulpride 39.4 % hydroxypropylméthylcellulose1 29.8 % acide succinique 15.9 %amisulpride 39.4% hydroxypropylmethylcellulose 1 29.8% succinic acid 15.9%
1 hydroxypropylméthylcellulose 90 SH4000SR commercialisé par la société Shin-Etsu 1 hydroxypropylmethylcellulose 90 SH4000SR sold by the company Shin-Etsu
Le mélange a été ensuite granulé avec 10% d'eau, et le granulé séché sous vide. Après calibration, le granulé a été mélangé avec le bicarbonate de sodium 13.7%, puis lubrifié avec 1% de stéarate de magnésium et 0,2% de silice Aerosil 200 (commercialisé par la société Degussa) .The mixture was then granulated with 10% water, and the granule dried in vacuo. After calibration, the granule was mixed with 13.7% sodium bicarbonate, then lubricated with 1% magnesium stearate and 0.2% Aerosil silica 200 (marketed by Degussa).
Le mélange homogène ainsi formé a été comprimé sur une machine à comprimer alternative pour obtenir des comprimés ronds convexes de diamètre 10 mm et comprenant 200 mg amisulpride.The homogeneous mixture thus formed was compressed on an alternative tableting machine to obtain round convex tablets with a diameter of 10 mm and comprising 200 mg of amisulpride.
On a utilisé la méthode de dissolution de l'exemple 2, pour déterminer le profil de dissolution des comprimés ainsi préparés. L'étalon utilisé était à 200 μg/ml d' amisulpride base. On a obtenu les résultats suivants :The dissolution method of Example 2 was used to determine the dissolution profile of the tablets thus prepared. The standard used was 200 μg / ml of amisulpride base. The following results were obtained:
heure 1 .2 3 4 : 6 8 10 12 14hour 1 .2 3 4: 6 8 10 12 14
% dissous 22 34 43 51 • 65 76 . 84 91 96% dissolved 22 34 43 51 • 65 76. 84 91 96
Leur flottabilité a été testée par la méthode de l'exemple 2. Ils ont commencé à flotter après 2 mm, et ils ont continué à flotter pendant au moins 120 mm.Their buoyancy was tested by the method of Example 2. They started to float after 2 mm, and they continued to float for at least 120 mm.
Exemple 4 : Comprimés flottants contenant du (D) -tartrate du (S) - ( - ) - amisulprideEXAMPLE 4 Floating Tablets Containing (D) -Startrate of (S) - (-) - Amisulpride
On a préparé des comprimés flottants d' amisulpride selon le procédé décrit dans l'exemple 3. Les comprimés obtenus comprenaient (% en masse) et étaient dosés à 50 mg en (D) -tartrate du (S) - { - ) - amisulpride.Amisulpride floating tablets were prepared according to the method described in Example 3. The tablets obtained included (% by mass) and were dosed at 50 mg in (D) -tartrate of (S) - {-) - amisulpride .
(D) -tartrate du (S) - ( - ) - amisulpride 15.0 % lactose 150 mesh 30.0 % hydroxypropylméthylcellulose1 32.6 % stéarate de magnésium 1.0 % acide tartrique 10.0 % bicarbonate de sodium 11.2 % silice Aérosil 2002 0.2 %(D) -tartrate of (S) - (-) - amisulpride 15.0% lactose 150 mesh 30.0% hydroxypropylmethylcellulose 1 32.6% magnesium stearate 1.0% tartaric acid 10.0% sodium bicarbonate 11.2% silica Aerosil 200 2 0.2%
1 hydroxypropylméthylcellulose 90 SH4000SR commercialisé par la société Shin-Etsu 1 hydroxypropylmethylcellulose 90 SH4000SR sold by the company Shin-Etsu
2 commercialisé par la société Degussa 2 marketed by Degussa
On a utilisé la méthode de dissolution de l'exemple 2, pour déterminer le profil de dissolution des comprimés ainsi préparés. L'étalon utilisé était à 50 μg/mL d'amisulpride base. On a obtenu les résultats suivants.The dissolution method of Example 2 was used, to determine the dissolution profile of the tablets thus prepared. The standard used was 50 μg / mL of amisulpride base. The following results were obtained.
Figure imgf000015_0001
Figure imgf000015_0001
Leur flottabilité a été testée par la méthode d'exemple 1. Ils ont commencé à flotter après 2 min, et ils ont continué à flotter pendant au moins 120 min.Their buoyancy was tested by the method of example 1. They started to float after 2 min, and they continued to float for at least 120 min.
Exemple 5 : comprimés flottants à libération contrôlée contenant de l'amisulprideEXAMPLE 5 Floating Release Tablets Containing Amisulpride
On a préparé des comprimés flottants d'amisulpride selon le procédé décrit dans 1 ' exemple 1. Les comprimés obtenus comprenaient (% en masse) :Floating tablets of amisulpride were prepared according to the process described in Example 1. The tablets obtained included (% by mass):
amisulpride 41,9% hydroxypropylméthylcellulose1 20,0% stéaryl fumarate de sodium 2,0% stéarate de magnésium 1,0% citrate monosodique anhydre 20,0% bicarbonate de sodium 15,0% silice Aerosil 2002 0, 1%amisulpride 41.9% hydroxypropyl methylcellulose 1 20.0% sodium stearyl fumarate 2.0% magnesium stearate 1.0% anhydrous sodium citrate 20.0% sodium bicarbonate 15.0% silica Aerosil 200 2 0.1%
1 hydroxypropylméthylcellulose 90 SH4000SR commercialisée par la société Shin-Etsu 1 hydroxypropyl methylcellulose 90 SH4000SR sold by the company Shin-Etsu
2 commercialisée par la société Degussa 2 marketed by Degussa
On a utilisé la méthode de dissolution de l'exemple 1, en modifiant les temps de prélèvement des échantillons, pour déterminer le profil de dissolution des comprimés ainsi préparés. On a obtenu les résultats suivants :The dissolution method of Example 1 was used, by modifying the sample collection times, to determine the dissolution profile of the tablets thus prepared. The following results were obtained:
Figure imgf000015_0002
Figure imgf000015_0002

Claims

Revendications claims
1. Composition pharmaceutique à résidence gastrique, caractérisée en ce qu'elle comprend : (a) un principe actif consistant en un benzamide ou un sel de benzamide,1. Pharmaceutical composition with gastric residence, characterized in that it comprises: (a) an active principle consisting of a benzamide or a benzamide salt,
(b) un système générateur de dioxyde de carbone, et(b) a carbon dioxide generating system, and
(c) un moyen permettant la rétention partielle du dioxyde de carbone généré par ledit système générateur de dioxyde de carbone.(c) means allowing partial retention of the carbon dioxide generated by said carbon dioxide generating system.
2. Composition selon la revendication 1, caractérisée en ce que le benzamide est le tiapride ou l'un de ses sels.2. Composition according to claim 1, characterized in that the benzamide is tiapride or one of its salts.
3. Composition selon l'une des revendications 1 et 2 , caractérisée en ce que le benzamide est le chlorhydrate de tiapride.3. Composition according to one of claims 1 and 2, characterized in that the benzamide is tiapride hydrochloride.
4. Composition selon la revendication 1, caractérisée en ce que le benzamide est l'amisulpride, l'un de ses sels, l'un de ses énantiomères ou un sel de l'un de ses énantiomères tels que le (D) -tartrate du (S) - ( - ) - amisulpride.4. Composition according to claim 1, characterized in that the benzamide is amisulpride, one of its salts, one of its enantiomers or a salt of one of its enantiomers such as (D) -tartrate du (S) - (-) - amisulpride.
5. Composition selon la revendication 1, caractérisée en ce que le benzamide est le sulpiride l'un de ses sels, l'un de ses énantiomères ou un sel de l'un de ses énantiomères.5. Composition according to claim 1, characterized in that the benzamide is sulpiride one of its salts, one of its enantiomers or a salt of one of its enantiomers.
6. Composition selon l'une des revendications 1 à 5, caractérisée en ce que le système générateur de dioxyde de carbone comprend au moins un agent générateur de dioxyde de carbone et au moins un composé acide choisi dans le groupe constitué par les acides monocarboxyliques, les acides polycarboxyliques et les sels partiels d'acides polycarboxyliques .6. Composition according to one of claims 1 to 5, characterized in that the carbon dioxide generating system comprises at least one carbon dioxide generating agent and at least one acid compound chosen from the group consisting of monocarboxylic acids, polycarboxylic acids and partial salts of polycarboxylic acids.
7. Composition selon la revendication 6, caractérisée en ce que l'agent générateur de dioxyde de carbone est un carbonate d'un métal alcalin ou alcalino-terreux, tel le carbonate de calcium, ou un bicarbonate d'un métal alcalin, tel le bicarbonate de sodium.7. Composition according to claim 6, characterized in that the carbon dioxide generating agent is a carbonate of an alkali or alkaline earth metal, such as calcium carbonate, or a bicarbonate of an alkali metal, such as sodium bicarbonate.
8. Composition selon l'une des revendications 6 et 7, caractérisée en ce que le composé acide est l'acide tartrique, l'acide succinique, l'acide citrique ou l'un de leurs sels partiels tels le citrate monosodique.8. Composition according to one of claims 6 and 7, characterized in that the acid compound is tartaric acid, succinic acid, citric acid or one of their partial salts such as monosodium citrate.
9. Composition selon l'une des revendications 1 à 8, caractérisée en ce que ledit moyen permettant la rétention partielle du dioxyde de carbone généré par ledit système générateur de dioxyde de carbone consiste en au moins un polymère hydrophile.9. Composition according to one of claims 1 to 8, characterized in that said means allowing the partial retention of carbon dioxide generated by said carbon dioxide generating system consists of at least one hydrophilic polymer.
10. Composition selon la revendication 9, caractérisée en ce que le polymère hydrophile est un dérivé cellulosique, en particulier 1 ' hydroxypropylcellulose, 1 ' hydroxypropyl- méthylcellulose et leurs mélanges.10. Composition according to claim 9, characterized in that the hydrophilic polymer is a cellulose derivative, in particular 1 hydroxypropylcellulose, 1 hydroxypropylmethylcellulose and mixtures thereof.
11. Composition selon l'une des revendications 1 à 10, caractérisée en ce qu'elle se présente sous la forme d'un comprimé flottant . 11. Composition according to one of claims 1 to 10, characterized in that it is in the form of a floating tablet.
PCT/FR1998/000755 1997-04-18 1998-04-15 Gastric-retained pharmaceutical composition WO1998047506A1 (en)

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KR1019997009438A KR20010006353A (en) 1997-04-18 1998-04-15 Gastric-retained pharmaceutical composition
CA002286081A CA2286081A1 (en) 1997-04-18 1998-04-15 Gastric-retained pharmaceutical composition
AU73416/98A AU737634B2 (en) 1997-04-18 1998-04-15 Pharmaceutical composition for gastric residence
IL13199598A IL131995A0 (en) 1997-04-18 1998-04-15 Gastric-retained pharmaceutical compositions
NZ500288A NZ500288A (en) 1997-04-18 1998-04-15 Gastric-retained pharmaceutical composition comprising benzamide as the active principle and a carbon dioxide generating system
PL98336273A PL336273A1 (en) 1997-04-18 1998-04-15 Pharmaceutic composition active in stomach portion of gastrointestinal system
EP98920623A EP0983065A1 (en) 1997-04-18 1998-04-15 Gastric-retained pharmaceutical composition
JP54514398A JP2001523241A (en) 1997-04-18 1998-04-15 Gastric retention pharmaceutical composition
NO995039A NO995039L (en) 1997-04-18 1999-10-15 Gastric retained pharmaceutical preparation

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FR9704803A FR2762213B1 (en) 1997-04-18 1997-04-18 PHARMACEUTICAL COMPOSITION WITH GASTRIC RETENTION
FR97/04803 1997-04-18

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US09/886,991 Continuation US20010046473A1 (en) 1997-04-18 2001-06-25 Gastric-retained pharmaceutical composition and method for its use

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WO2000003740A2 (en) * 1998-07-14 2000-01-27 Sanofi-Synthelabo Use of (s) (-)-amisulpride for the manufacture of a medicament for the treatment of schizophrenia
US7838028B2 (en) 2001-03-31 2010-11-23 Jagotec Ag Pharmaceutical tablet system that floats on gastric fluid for multipulse release of active substance, and respective processes of producing same and a cup-shaped envelope of same
US10369134B2 (en) 2017-12-05 2019-08-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10377708B2 (en) 2017-12-05 2019-08-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11160758B2 (en) 2019-06-04 2021-11-02 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof
WO2023214018A1 (en) 2022-05-06 2023-11-09 Galenix Innovations Gastro-retentive swellable sustained release composition

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FR2790388B1 (en) * 1999-03-04 2001-04-13 Synthelabo PHARMACEUTICAL COMPOSITIONS COMPRISING A BENZAMIDE AND AT LEAST ONE ABSORPTION PROMOTER
WO2009157711A2 (en) * 2008-06-24 2009-12-30 Park Eun-Seok Gastro-retentive porous tablet and method for preparing same
FR2949061B1 (en) * 2009-08-12 2013-04-19 Debregeas Et Associes Pharma FLOATING MICROGRANULES
HUE025008T2 (en) 2012-10-12 2016-04-28 Omya Int Ag Gastroretentive drug formulation and delivery systems and their method of preparation using functionalized calcium carbonate
JP7044649B2 (en) * 2018-06-28 2022-03-30 株式会社ファンケル Intragastric floating tablets

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000003740A2 (en) * 1998-07-14 2000-01-27 Sanofi-Synthelabo Use of (s) (-)-amisulpride for the manufacture of a medicament for the treatment of schizophrenia
WO2000003740A3 (en) * 1998-07-14 2000-05-18 Sanofi Synthelabo Use of (s) (-)-amisulpride for the manufacture of a medicament for the treatment of schizophrenia
US7838028B2 (en) 2001-03-31 2010-11-23 Jagotec Ag Pharmaceutical tablet system that floats on gastric fluid for multipulse release of active substance, and respective processes of producing same and a cup-shaped envelope of same
US10800738B2 (en) 2017-12-05 2020-10-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10377708B2 (en) 2017-12-05 2019-08-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10577317B2 (en) 2017-12-05 2020-03-03 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10576058B2 (en) 2017-12-05 2020-03-03 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10660875B1 (en) 2017-12-05 2020-05-26 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10369134B2 (en) 2017-12-05 2019-08-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10874639B2 (en) 2017-12-05 2020-12-29 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US11370753B2 (en) 2017-12-05 2022-06-28 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11517558B2 (en) 2017-12-05 2022-12-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US11767293B2 (en) 2017-12-05 2023-09-26 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11160758B2 (en) 2019-06-04 2021-11-02 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof
US11654113B2 (en) 2019-06-04 2023-05-23 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof
WO2023214018A1 (en) 2022-05-06 2023-11-09 Galenix Innovations Gastro-retentive swellable sustained release composition

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