WO1982001468A1 - New galenical administration form of metoclopramide,method for its preparation and medicament comprising this new form - Google Patents

New galenical administration form of metoclopramide,method for its preparation and medicament comprising this new form Download PDF

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Publication number
WO1982001468A1
WO1982001468A1 PCT/FR1981/000134 FR8100134W WO8201468A1 WO 1982001468 A1 WO1982001468 A1 WO 1982001468A1 FR 8100134 W FR8100134 W FR 8100134W WO 8201468 A1 WO8201468 A1 WO 8201468A1
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metoclopramide
microgranules
new
neutral
weight
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PCT/FR1981/000134
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French (fr)
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Claude Laruelle
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Claude Laruelle
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Priority to DE8181902835T priority Critical patent/DE3175039D1/en
Publication of WO1982001468A1 publication Critical patent/WO1982001468A1/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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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

Definitions

  • METOCLOPRAMIDE has been known for many years. In the form of dihydrochloride or monohydrochloride, it is widely used to treat functional gastrointestinal disturbances such as dyspepsia, peptic and biliary dyskinesia, chronic gastritis, peptic ulcers, nausea and vomiting. Pharmacologically, the action of METOCLOPRAMIDE is both central and peripheral. However, the administration of METOCLOPRAMIDE in its current form has significant drawbacks, limiting the convenience of use.
  • the present invention therefore relates to a new dosage form with delayed programmed release of METOCLOPRAMIDE and is characterized in that it is constituted by microgranules comprising a neutral core consisting of a grain of an inert excipient comprising at least two components of the type belonging to the class consisting of sucrose, starch, talc, drying silica, lactose and stearic acid, this neutral grain being provided with a first layer comprising METOCLOPRAMIDE, then with a second outer layer consisting of a microporous envelope comprising at least one natural and / or synthetic polymer belonging to the class consisting of shellac, gum arabic, gelatin, ethylcellulose, cellulose acetophthalate, cellulose triacetate, polyoxyethylene glycol, methacrylates, styrene-acrylonitrile copolymer and polyvinylpyrrolidone in successive envelopes.
  • a neutral core consisting of a grain of an inert excipient comprising at
  • the microporous envelope can be formed of shellac in a proportion by weight varying between 1 and 10%
  • the inert excipient can be a mixture comprising from 40 to 80% by weight of sucrose and from 10 to 40%. by weight of starch.
  • the first layer may comprise from 1 to 20% by weight of METOCLOPRAMIDE, from 0.01% to 0.5% by weight of stearic acid, from 5 to 15% by weight talc and 2 to 10% by weight of drying silica.
  • the neutral core may include adsorbates of METOCLOPRAMIDE.
  • the subject of the invention is also a process for obtaining the remarkable new galenical form in that neutral sieved and dried microgranules are prepared beforehand, that a solution in absolute alcohol of METOCLOPRAMIDE is projected onto these microgranules, then coating said microgranules to make the first layer in one or more coatings, then forming the microporous envelope by coating with said polymer in solution in a solvent.
  • the present invention relates to medicaments comprising the new form of administration of METOCLOPRAMIDE in the form of active microgranules mixed with neutral uncoated microgranules in order to obtain a predetermined concentration of METOCLOPRAMIDE, this set of microgranules being presented in the form capsules, tablets, suppositories, syrup, granules or powder.
  • METOCLOPRAMIDE The first layer is then made by incorporating the other excipients with the exception of shellac into these microgranules, then the spraying of METOCLOPRAMIDE hydrochloride is restarted, this coating being repeated several times with sieving and drying if necessary between each layer.
  • the microporous outer layer is produced by spraying the shellac with the granules in solution in absolute ethyl alcohol.
  • microporous outer envelope is made so as to allow a prolonged release of theoretical METOCLOPRAMIDE:
  • a disintegration device in which an amount of microgranules corresponding to approximately 50 mg of contact is brought into contact.
  • active principle with artificial liquids the device making it possible to maintain constant agitation and a constant temperature of 37 ° ⁇ 0.5 ° C.
  • Artificial liquids are solutions buffered at successive pH used according to the diagram below.
  • the new dosage form according to the invention was the subject of an in-depth pharmacokinetic study in comparison with the conventional tablet form.
  • the study was carried out in cross-over in humans.
  • Six male subjects received each of the two forms at two-week intervals, one 20 mg capsule of active ingredient containing the microgranules and two 10 mg tablets of the conventional form.
  • the plasma concentration of METOCLOPRAMIDE was determined by means of 10 samples in the interval of 72 hours.
  • the time of appearance of the serum peak increases from 1 hour to 4.5 hours.
  • the half-life duration increases from approximately 3 hours to more than 8 hours.
  • the new dosage presentation leads to a new drug useful for the treatment of gastric disorders in general.
  • FIGURE 1 Plasma concentrations of METOCLOPRAMIDE after an oral cross-over dose in 6 subjects . are healthy
  • FIGURE 2 Plasma concentrations of METOCLOPRAMIDE after an oral dose taken in cross-over in 6 healthy subjects
  • FIGURE 3 METOCLOPRAMIDE plasma concentrations

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  • Life Sciences & Earth Sciences (AREA)
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Abstract

Metoclopramide medicament in a new galenical form with latentiation effect. The active principle contained in microgranules incorporated in a capsule is progressively released. By using this new medicament it is possible to decrease the number of daily administrations and to reduce the amount of active principle ingested.

Description

NOUVELLE FORME GALENIQUE D'ADMINISTRATION DU METOCLOPRAMIDE, SON PROCEDE DE PREPARATION ET MEDICAMENT COMPRENANT CETTE NOUVELLE FORME La présente invention concerne une nouvelle préparation galénique du METOCLOPRAMIDE, et le médicament comprenant cette préparation. NOVEL GALENIC FORM OF ADMINISTRATION OF METOCLOPRAMIDE, ITS PREPARATION METHOD AND MEDICINAL PRODUCT COMPRISING THIS NEW FORM The present invention relates to a new galenical preparation of METOCLOPRAMIDE, and the medicament comprising this preparation.
Le METOCLOPRAMIDE est connu depuis de nombreuses années. Sous la forme de dichlorhydrate ou de monochlorhydrate, il est largement utilisé pour traiter les troublés fonctionnels gastro-intestinaux tels que dyspepsies, dyskinésies gastro-duodénales et biliaires, gastrites chroniques, ulcères gastro-duëdonaux, nausées et vomissements. Au plan pharmacologique, l'action du METOCLOPRAMIDE est à la fois centrale et périphérique. Toutefois, l'administration du METOCLOPRAMIDE sous sa forme actuelle présente des inconvénients notables, en limitant la commodité d'emploi.METOCLOPRAMIDE has been known for many years. In the form of dihydrochloride or monohydrochloride, it is widely used to treat functional gastrointestinal disturbances such as dyspepsia, peptic and biliary dyskinesia, chronic gastritis, peptic ulcers, nausea and vomiting. Pharmacologically, the action of METOCLOPRAMIDE is both central and peripheral. However, the administration of METOCLOPRAMIDE in its current form has significant drawbacks, limiting the convenience of use.
Par exemple, on a constaté que la présentation sous forme de comprimés provoque certaines intolérances, en particulier gastriques, ce qui empêche son utilisation par une catégorie importante de malades d'une part, et d'autre part qui limite son utilisation pour les traitements à long terme.For example, it has been found that the presentation in the form of tablets causes certain intolerances, in particular gastric, which prevents its use by a large category of patients on the one hand, and on the other hand which limits its use for treatments to long term.
De plus, on a constaté avec les formes disponiblés, après chaque administration, c'est-à-dire trois ou quatre fois par jour sinon davantage, une succession d'augmentations et de diminutions rapides des taux plasmatiques, l'organisme étant soumis alternativement à des surdosages et à des sous-dosages. Enfin, les inconvénients des formes classiques n'ont pas permis jusqu'à présent le traitement des troubles digestifs nécessitant une administration prolongée, ce qui est au contraire possible avec la nouvelle forme galénique d'administration du METOCLOPRAMIDE ainsi qu'on le démontre ci-après, cette nouvelle forme permettant la libération régulière du médicament dans l'organisme pendant des périodes suffisamment longues pour autoriser simplement la prise journalière d'une seule unité. La présente invention a donc pour objet une nouvelle forme galénique à libération programmée retardée du METOCLOPRAMIDE et est caractérisée en ce qu'elle est constituée par des microgranules comprenant une âme neutre constituée d'un grain d'un excipient inerte comprenant au moins deux composants du type appartenant à la classe constituée par le saccharose, l'amidon, le talc, la silice desséchante, le lactose et l'acide stéarique, ce grain neutre étant muni d'une première couche comprenant le METOCLOPRAMIDE, puis d'une seconde couche extérieure constituëe par une enveloppe microporeuse comprenant au moins un polymère naturel et/ou synthétique appartenant à la classe constituée par la gomme laque, la gomme arabique, la gélatine, l ' éthylcellulose, l ' acétophtalate de cellulose, le triacëtate de cellulose, le polyoxyéthylèneglycol, les methacrylates, le copolymère styrène-acrylonitrile et le polyvinylpyrrolidone en enveloppes successives.In addition, with the forms available, after each administration, that is to say three or four times a day if not more, there has been a succession of rapid increases and decreases in plasma levels, the organism being subjected alternately overdoses and underdoses. Finally, the drawbacks of conventional forms have not so far made it possible to treat digestive disorders requiring prolonged administration, which is on the contrary possible with the new galenic form of administration of METOCLOPRAMIDE, as demonstrated below. after, this new form allowing the regular release of the drug in the body for periods long enough to simply allow the daily intake of a single unit. The present invention therefore relates to a new dosage form with delayed programmed release of METOCLOPRAMIDE and is characterized in that it is constituted by microgranules comprising a neutral core consisting of a grain of an inert excipient comprising at least two components of the type belonging to the class consisting of sucrose, starch, talc, drying silica, lactose and stearic acid, this neutral grain being provided with a first layer comprising METOCLOPRAMIDE, then with a second outer layer consisting of a microporous envelope comprising at least one natural and / or synthetic polymer belonging to the class consisting of shellac, gum arabic, gelatin, ethylcellulose, cellulose acetophthalate, cellulose triacetate, polyoxyethylene glycol, methacrylates, styrene-acrylonitrile copolymer and polyvinylpyrrolidone in successive envelopes.
En particulier, l'enveloppe microporeuse peut Être formée de gomme laque selon une proportion en poids variant entre 1 et 10 %,et l'excipient inerte peut être un mélange comprenant de 40 à 80 % en poids de saccharose et de 10 à 40 % en poids d'amidon.In particular, the microporous envelope can be formed of shellac in a proportion by weight varying between 1 and 10%, and the inert excipient can be a mixture comprising from 40 to 80% by weight of sucrose and from 10 to 40%. by weight of starch.
Selon une forme de réalisation avantageuse de l'invention, la première couche peut comprendre de 1 à 20 % en poids de METOCLOPRAMIDE, de 0,01 % à 0,5 % en poids d'acide stéarique, de 5 à 15 % en poids de talc et de 2 à 10 % en poids de silice desséchante. En outre, l'âme neutre peut comprendre des adsorbats de METOCLOPRAMIDE. L'invention a également pour objet un procédé d'obtention de la nouvelle forme galénique remarquable en ce qu'on prépare au préalable des microgranules neutres tamisés et séchés, qu'on projette sur ces microgranules une solution dans l'alcool absolu de METOCLOPRAMIDE, qu'on enrobe ensuite lesdits microgranules pour réaliser la première couche en un ou plusieurs enrobages, puis qu'on forme l'enveloppe microporeuse par enrobage à l'aide dudit polymère en solution dans un solvant. De plus, la présente invention a pour objet des médicaments comprenant la nouvelle forme d'administration du METOCLOPRAMIDE sous forme de microgranules actifs mélangés à des microgranules neutres non enrobés afin d'obtenir une concentration prédéterminée en METOCLOPRAMIDE, cet ensemble de microgranules étant présenté sous formes de gélules, de comprimés, de suppositoires, de sirop, de granules ou de poudre.According to an advantageous embodiment of the invention, the first layer may comprise from 1 to 20% by weight of METOCLOPRAMIDE, from 0.01% to 0.5% by weight of stearic acid, from 5 to 15% by weight talc and 2 to 10% by weight of drying silica. In addition, the neutral core may include adsorbates of METOCLOPRAMIDE. The subject of the invention is also a process for obtaining the remarkable new galenical form in that neutral sieved and dried microgranules are prepared beforehand, that a solution in absolute alcohol of METOCLOPRAMIDE is projected onto these microgranules, then coating said microgranules to make the first layer in one or more coatings, then forming the microporous envelope by coating with said polymer in solution in a solvent. In addition, the present invention relates to medicaments comprising the new form of administration of METOCLOPRAMIDE in the form of active microgranules mixed with neutral uncoated microgranules in order to obtain a predetermined concentration of METOCLOPRAMIDE, this set of microgranules being presented in the form capsules, tablets, suppositories, syrup, granules or powder.
L'ensemble des caractéristiques et avantages de l'invention seront mieux compris par l'Homme de l'Art en se référant à la description qui va suivre de modes de réalisation particuliers pris à titre d'exemples non limitatifs de la nouvelle forme galénique, de son procédé et de ses applications thérapeutiques, en particulier en relation avec les contrôles pharmacologiques et cliniques effectués en utilisant la nouvelle forme galénique.All of the characteristics and advantages of the invention will be better understood by those skilled in the art with reference to the description which follows of particular embodiments taken by way of nonlimiting examples of the new galenical form, of its process and its therapeutic applications, in particular in relation to the pharmacological and clinical checks carried out using the new galenical form.
EXEMPLE DE PREPARATION DE LA NOUVELLE FORME GALENIQUE : On indique ci-après, l'exemple de fabrication correspondant à 100 000 gélules dosées à 20 mg de chlorhydrate de METOCLOPRAMIDE. a) Formule de fabriçation :EXAMPLE OF PREPARATION OF THE NEW GALENIC FORM: The manufacturing example corresponding to 100,000 capsules containing 20 mg of METOCLOPRAMIDE hydrochloride is indicated below. a) Manufacturing formula:
- METOCLOPRAMIDE (dichlorhydrate monohydrate) .... 2,0 kg- METOCLOPRAMIDE (dihydrochloride monohydrate) .... 2.0 kg
- saccharose- sucrose
- amidon de mais- corn starch
- acide stéarique - gomme laque- stearic acid - shellac
- polymères mêthacryliques- methacrylic polymers
- talc - polyvidone- talc - polyvidone
- édétate de sodium- sodium edetate
- alcool éthylique absolu qs 21, 0 kg b) Procédé de préparation : On granule de l'amidon de mais et du saccharose, puis on tamise et on turbine longuement les grains de façon à les rendre parfaitement sphériques ; on tamise à nouveau et on sèche parfaitement. Dans un mélangeur en acier inoxydable, on projette sur les âmes neutres ainsi obtenues, une solution alcoolique de chlorhydrate de- absolute ethyl alcohol qs 21.0 kg b) Preparation process : Granulate corn starch and sucrose, then sift and turbine the grains for a long time so as to make them perfectly spherical; we sift again and dry perfectly. In an stainless steel mixer, an alcoholic solution of hydrochloride is sprayed onto the neutral cores thus obtained.
METOCLOPRAMIDE. On réalise ensuite la première couche en incorporant à ces microgranules les autres excipients à l'exception de la gomme laque, puis on recommence la pulvérisation de chlorhydrate de METOCLOPRAMIDE, cet enrobage étant recommencé plusieurs fois avec tamisage et séchage si nécessaire entre chaque couche.METOCLOPRAMIDE. The first layer is then made by incorporating the other excipients with the exception of shellac into these microgranules, then the spraying of METOCLOPRAMIDE hydrochloride is restarted, this coating being repeated several times with sieving and drying if necessary between each layer.
Lorsque la première couche contenant le principe actif est terminée, on réalise la couche extérieure microporeuse en projetant sur les granules la gomme laque en solution dans l'alcool éthylique absolu.When the first layer containing the active ingredient is completed, the microporous outer layer is produced by spraying the shellac with the granules in solution in absolute ethyl alcohol.
On sèche ensuite soigneusement en éliminant l'alcool éthylique restant, on tamise à nouveau et on contrôle comme ci-après le titre des microgranules obtenus avant de mettre en gélules après avoir ajusté ëventuel lement le titrage par addition et homogénéisé avec des microgranules neutres pour arriver au titrage désiré de 20 mg de METOCLOPRAMIDE. MESURE DE LA LIBERATION DU METOCLOPRAMIDEIt is then carefully dried, eliminating the remaining ethyl alcohol, it is again sieved and the title of the microgranules obtained is checked as below, before putting into capsules after having possibly adjusted the titration by addition and homogenized with neutral microgranules to arrive at the desired titration of 20 mg of METOCLOPRAMIDE. MEASUREMENT OF METOCLOPRAMIDE RELEASE
L'enveloppe extérieure microporeuse est réalisée de manière à permettre une libération prolongée de METOCLOPRAMIDE théorique :The microporous outer envelope is made so as to allow a prolonged release of theoretical METOCLOPRAMIDE:
1ère heure : libération inférieure à 40 % ; 4ème heure : libération inférieure à 75 % ; 8ème heure : libération supérieure à 80 %. Pour contrôler cette caractéristique, on utilise un appareil à délitement dans lequel on met en contact une quantité de microgranules correspondant à environ 50 mg de principe actif avec des liquides artificiels, l'appareil permettant de maintenir une agitation constante et une température constante de 37° ± 0,5°C. Les liquides artificiels sont des solutions tamponnées à pH successifs utilisés selon le schéma ci-dessous.1st hour: release less than 40%; 4th hour: release less than 75%; 8th hour: release greater than 80%. To control this characteristic, a disintegration device is used in which an amount of microgranules corresponding to approximately 50 mg of contact is brought into contact. active principle with artificial liquids, the device making it possible to maintain constant agitation and a constant temperature of 37 ° ± 0.5 ° C. Artificial liquids are solutions buffered at successive pH used according to the diagram below.
RESULTATS SOLUTIONS TEMPS DE LIBERATION pH THEORIQUES REELSRESULTS SOLUTIONS RELEASE TIMES REAL THEORETICAL pH
25 ml liquide gastrique 1 heure (1ère heure) 1,5 < 40 % 36 % 25 ml liquide intestinal 1 heure (2ème heure) 4,5 > 40 %25 ml gastric fluid 1 hour (1st hour) 1.5 <40% 36% 25 ml intestinal fluid 1 hour (2nd hour) 4.5> 40%
25 ml liquide 2 heures (3ème et intestinal 4ème heures) 6,9 < 75 % 70,8 %25 ml liquid 2 hours (3rd and intestinal 4th hours) 6.9 <75% 70.8%
25 ml liquide 2 heures (5ême et intestinal 6ème heures) 6,9 > 75 % 25 ml liquide 2 heures (7ème et intestinal - 8ème heures) 7,2 > 80 % 92,3 %25 ml liquid 2 hours (5th and intestinal 6th hours) 6.9> 75% 25 ml liquid 2 hours (7th and intestinal - 8th hours) 7.2> 80% 92.3%
La nouvelle forme galénique selon l'invention a fait l'objet d'une étude pharmacocine tique approfondie en comparaison avec la forme comprimé classique. L'étude a été effectuée en cross-over chez l'homme. Six sujets de sexe masculin recevaient chacune des deux formes à deux semaines d'intervalle, une gélule de 20 mg de principe actif contenant les microgranules et 2 comprimés à 10 mg de la forme classique. La détermination de la concentration plasmatique du METOCLOPRAMIDE a été effectuée au moyen de 10 prélèvements dans l'intervalle de 72 heures.The new dosage form according to the invention was the subject of an in-depth pharmacokinetic study in comparison with the conventional tablet form. The study was carried out in cross-over in humans. Six male subjects received each of the two forms at two-week intervals, one 20 mg capsule of active ingredient containing the microgranules and two 10 mg tablets of the conventional form. The plasma concentration of METOCLOPRAMIDE was determined by means of 10 samples in the interval of 72 hours.
Au terme de l'étude, les conclusions sont les suivantes : - la biodisponibilitë relative n'est pas modifiée de manière significative.At the end of the study, the conclusions are as follows: - the relative bioavailability is not significantly modified.
- Le temps d'apparition du pic sérique passe de 1 heure à 4 heures et demie.- The time of appearance of the serum peak increases from 1 hour to 4.5 hours.
- La durée de demi-vie passe de 3 heures environ à plus de 8 heures.- The half-life duration increases from approximately 3 hours to more than 8 hours.
- Les deux formulations sont bio-inéquivalentes.- The two formulations are bio-unequal.
- L'étude des courbes obtenues montre qu'une gélule à 20 mg équivaut à 2 comprimés au minimum, sinon 3 comprimés à 10 mg .- The study of the curves obtained shows that a capsule with 20 mg is equivalent to a minimum of 2 tablets, otherwise 3 10 mg tablets.
Afin d ' illustrer les caractéristiques de l ' invention rapportée ci-dessus , 3 graphiques sont présentés. En outre , l ' étude toxicologique eff ectuée sur le rat a permis de déterminer la dose léthale 50 % lorsque les microgranules sont administrés par voie orale :In order to illustrate the characteristics of the invention reported above, 3 graphics are presented. In addition, the toxicological study carried out on the rat made it possible to determine the lethal dose 50% when the microgranules are administered orally:
- chez les femelles, la mortalité est de 50 % à 9,2 g/kg;- in females, the mortality is 50% at 9.2 g / kg;
- chez les mâles, la mortalité est de 40 % à 20 g/kg. Au plan clinique, la tolérance de la nouvelle présentation a été bonne dans l'ensemble et supérieure à la présentation classique. Elle permet ainsi de pratiquer des traitements de longue durée sans inconvénient notable pour le patient. De plus, du fait de l'économie de 35 % à 50 % en dosage de principe actif, on obtient donc une utilisation thérapeutique améliorée justifiant l'intérêt de la nouvelle présentation galénique.- in males, mortality is 40% at 20 g / kg. Clinically, the tolerance of the new presentation was generally good and superior to the classic presentation. It thus makes it possible to practice long-term treatments without significant disadvantage for the patient. In addition, due to the savings of 35% to 50% in dosage of active principle, an improved therapeutic use is therefore obtained, justifying the advantage of the new galenic presentation.
Par conséquent, on peut affirmer que la nouvelle présentation galénique conduit à un nouveau médicament utile pour le traitement des troubles gastriques en général.Therefore, it can be said that the new dosage presentation leads to a new drug useful for the treatment of gastric disorders in general.
Elle permet d'assurer une libération du METOCLOPRAMIDE de façon contrôlée et indépendamment de la façon dont les microgranules sont administrés avec une courbe de libération du principe actif constante d'un malade à l'autre et d'une prise à l'autre.It makes it possible to ensure release of METOCLOPRAMIDE in a controlled manner and independently of the way in which the microgranules are administered with a release curve of the active principle which is constant from one patient to another and from one intake to another.
Enfin, elle permet une mise en gélules et assure la stabilité du METOCLOPRAMIDE, ce qui est une amélioration industrielle et médicale importante.Finally, it allows capsules and ensures the stability of METOCLOPRAMIDE, which is an important industrial and medical improvement.
Bien entendu, l'Homme de l'Art pourra trouver d'autres avantages et variantes de l'invention, en particulier en ce qui concerne le procédé d'obtention des microgranules ou les modifications de dosage, sans pour cela sortir du cadre et de la portée de la présente invention. EXPLICATIONS DES FIGURES FIGURE 1 : Concentrations plasmatiques de METOCLOPRAMIDE après une prise orale effectuée en cross-over chez 6 suj.ets sainsOf course, those skilled in the art will be able to find other advantages and variants of the invention, in particular with regard to the process for obtaining microgranules or the modifications of dosage, without thereby departing from the scope and the scope of the present invention. EXPLANATION OF FIGURES FIGURE 1: Plasma concentrations of METOCLOPRAMIDE after an oral cross-over dose in 6 subjects . are healthy
- 2 comprimés à 10 mg ( )- 2 tablets of 10 mg ()
- 1 gélule retard à 20 mg ( )- 1 20 mg retard capsule ()
FIGURE 2 : Concentrations plasmatiques de METOCLOPRAMIDE après une prise orale effectuée en cross-over chez 6 sujets sainsFIGURE 2: Plasma concentrations of METOCLOPRAMIDE after an oral dose taken in cross-over in 6 healthy subjects
- gélule retard à 20 mg ( )- 20 mg delay capsule ()
- comprimé à 10 mg ( )- 10 mg tablet ()
FIGURE 3 : Concentrations plasmatiques de METOCLOPRAMIDEFIGURE 3: METOCLOPRAMIDE plasma concentrations
- après trois prises orales à 7 H, 13 H, 19 H d'un comprimé à 10 mg ( )- after three oral doses at 7 a.m., 1 p.m., 7 p.m. of a 10 mg tablet ()
- après une prise orale à 7 H d'une gélule retard à 20 mg ( ) - after a 7 mg oral capsule taken at 20 mg ()

Claims

REVENDICATIONS 1°- Nouvelle forme galénique du METOCLOPRAMIDE, caractérisée en ce qu'elle est constituée par des microgranules comprenant une âme neutre constituée d'un grain d'un excipient inerte comprenant au moins deux composants du type appartenant à la classe constituée par le saccharose, l'amidon, le talc, la silice desséchante, le lactose et l'acide stéarique, ce grain neutre étant muni d'une première couche comprenant le METOCLOPRAMIDE , puis d'une seconde couche extérieure constituée par une enveloppe microporeuse comprenant au moins un polymère naturel et/ou synthétique appartenant à la classe constituée par la gomme laque, la gomme arabique, la gélatine, l'ëthylcellulose, l'acétophtaïate de cellulose, le triacétate de cellulose, le polyoxyéthylèneglycol, les methacrylates, le copolymère styrène-acrylonitrile et la polyvinylpyrrolidone.1 ° - New dosage form of METOCLOPRAMIDE, characterized in that it consists of microgranules comprising a neutral core consisting of a grain of an inert excipient comprising at least two components of the type belonging to the class constituted by sucrose , starch, talc, drying silica, lactose and stearic acid, this neutral grain being provided with a first layer comprising METOCLOPRAMIDE, then with a second outer layer constituted by a microporous envelope comprising at least one natural and / or synthetic polymer belonging to the class consisting of shellac, gum arabic, gelatin, ethylcellulose, cellulose acetophtaiate, cellulose triacetate, polyoxyethylene glycol, methacrylates, styrene-acrylonitrile copolymer and polyvinylpyrrolidone.
2°- Nouvelle forme galénique du METOCLOPRAMIDE selon la Revendication 1, caractérisée en ce que l'enveloppe microporeuse est formée de gomme laque selon une proportion en poids comprise entre 1 et 10 %.2 ° - New dosage form of METOCLOPRAMIDE according to Claim 1, characterized in that the microporous envelope is formed of shellac in a proportion by weight of between 1 and 10%.
3°- Nouvelle forme galénique du METOCLOPRAMIDE selon les Revendications 1 ou 2 , caractérisée en ce que l'excipient inerte de l'âme neutre est un mélange comprenant de 40 à 80 % en poids de saccharose et de 10 à 40 % en poids d'amidon.3 ° - New dosage form of METOCLOPRAMIDE according to Claims 1 or 2, characterized in that the inert excipient of the neutral core is a mixture comprising from 40 to 80% by weight of sucrose and from 10 to 40% by weight of 'starch.
4°- Nouvelle forme selon l'une quelconque des Revendications 1 à 3, caractérisée en ce que la première couche comprend de 1 à 20 % en poids de METOCLOPRAMIDE, de 0,01 à 0,5 % en poids d'acide stéarique, de 5 à 15 % en poids de talc.4 ° - New form according to any one of Claims 1 to 3, characterized in that the first layer comprises from 1 to 20% by weight of METOCLOPRAMIDE, from 0.01 to 0.5% by weight of stearic acid, from 5 to 15% by weight of talc.
5°- Nouvelle forme selon l'une quelconque des Revendications 1 à 4, caractérisée en ce que l'âme neutre comprend des adsorbats de METOCLOPRAMIDE. 6°- Procédé d'obtention de la nouvelle forme galénique selon l'une quelconque des Revendications 1 à 5, caractérisé en ce qu'on prépare des microgranules neutres tamisés et séchés, qu'on projette sur ces microgranules neutres une solution dans l'alcool absolu de METOCLOPRAMIDE sous forme de microgranules conformes à l'une des Revendications 1 à 5, et en ce que lesdits microgranules sont mélangés avec des microgranules neutres non enrobés afin d'obtenir une concentration prédéterminée en METOCLOPRAMIDE.5 ° - New form according to any one of Claims 1 to 4, characterized in that the neutral core comprises adsorbates of METOCLOPRAMIDE. 6 ° - Process for obtaining the new dosage form according to any one of Claims 1 to 5, characterized in that neutral microgranules are prepared sieved and dried, sprayed on these neutral microgranules with an absolute alcohol solution of METOCLOPRAMIDE in the form of microgranules in accordance with one of Claims 1 to 5, and in that said microgranules are mixed with uncoated neutral microgranules in order to obtain a predetermined concentration of METOCLOPRAMIDE.
7°- Médicaments caractérisés en ce qu'ils comprennent la nouvelle forme galénique d'administration du METOCLOPRAMIDE sous forme de microgranules conformes à l'une quelconque des Revendications 1 à 5, et en ce que lesdits microgranules sont mélangés avec des microgranules neutres non enrobés afin d'obtenir une concentration prédéterminée en METOCLOPRAMIDE.7 ° - Medicaments characterized in that they comprise the new galenical form of administration of METOCLOPRAMIDE in the form of microgranules in accordance with any one of Claims 1 to 5, and in that said microgranules are mixed with uncoated neutral microgranules in order to obtain a predetermined concentration of METOCLOPRAMIDE.
8°- Médicaments utilisés en médecine humaine, destinés au traitement des troubles gastriques, selon la Revendication 7, caractérisés en ce qu'ils se présentent sous forme de gélules, de comprimés, de suppositoires, de sirop, de granules ou de poudre. 8 ° - Medicines used in human medicine, intended for the treatment of gastric disorders, according to Claim 7, characterized in that they are in the form of capsules, tablets, suppositories, syrup, granules or powder.
PCT/FR1981/000134 1980-10-28 1981-10-22 New galenical administration form of metoclopramide,method for its preparation and medicament comprising this new form WO1982001468A1 (en)

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FR8023028A FR2492661A1 (en) 1980-10-28 1980-10-28 NOVEL GALENIC FORM OF ADMINISTRATION OF METOCLOPRAMIDE, ITS PREPARATION METHOD AND MEDICINAL PRODUCT COMPRISING THIS NOVEL FORM
FR8023028801028 1980-10-28

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FR2534139A1 (en) * 1982-10-07 1984-04-13 Laruelle Claude NEW GALENIC FORM OF SULPIRIDE, PROCESS FOR PREPARING SAME, AND MEDICAMENT COMPRISING SAID NEW FORM
EP0115976A1 (en) * 1983-01-28 1984-08-15 Elf Sanofi Drug with programmed release containing acetylsalicylic acid
GB2151920A (en) * 1983-12-23 1985-07-31 Ile De France Oral compositions containing sulpiride
EP0163000A2 (en) * 1984-02-01 1985-12-04 3 M Medica GmbH Pharmaceutical product in pellet form with a continuous sustained release
EP0177000A1 (en) * 1984-10-02 1986-04-09 EURAND ITALIA S.p.A. Process to obtain a sustained release formulation of water soluble components
WO1987001588A1 (en) * 1985-09-12 1987-03-26 Societe D'etudes Scientifiques Et Industrielles De Retardation preparation for a medicine
DE4131276B4 (en) * 1990-09-28 2007-07-19 Solvay Pharmaceuticals Gmbh Perorally administrable metoclopramide solutions

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GB8412585D0 (en) * 1984-05-17 1984-06-20 Beecham Group Plc Composition
LU86077A1 (en) * 1985-09-18 1987-04-02 Pharlyse Sa NEW GALENIC FORMS OF VERAPAMIL, THEIR MANUFACTURE AND THE MEDICINAL PRODUCTS CONTAINING THESE NEW GALENIC FORMS
DE3712095A1 (en) * 1987-04-10 1988-10-20 Lentia Gmbh BINDER-FREE GRANULES WITH DELAYED DELIVERY OF ACTIVE SUBSTANCES
US5286495A (en) * 1992-05-11 1994-02-15 University Of Florida Process for microencapsulating cells
EP1202745A4 (en) * 1999-08-16 2004-09-22 Henceforth Hibernia Inc Therapeutic and prophylactic compositions including catalytic biomimetic solids and methods to prepare and use them
EP1429746B1 (en) * 2001-09-28 2008-08-13 McNEIL-PPC, INC. Dosage forms having an inner core and outer shell
MX2008004267A (en) * 2008-03-28 2009-09-28 Posi Visionary Solutions Llp 24-hour sustained-release metoclopramide.
MX2008004268A (en) * 2008-03-28 2009-09-28 Posi Visionary Solutions Llp 24-hour sustained-release metoclopramide.

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FR2534139A1 (en) * 1982-10-07 1984-04-13 Laruelle Claude NEW GALENIC FORM OF SULPIRIDE, PROCESS FOR PREPARING SAME, AND MEDICAMENT COMPRISING SAID NEW FORM
EP0107557A1 (en) * 1982-10-07 1984-05-02 Societe D'etudes Scientifiques Et Industrielles De L'ile-De-France Galenic of sulpiride, process for its preparation and medicament comprising it
EP0115976A1 (en) * 1983-01-28 1984-08-15 Elf Sanofi Drug with programmed release containing acetylsalicylic acid
GB2151920A (en) * 1983-12-23 1985-07-31 Ile De France Oral compositions containing sulpiride
EP0163000A2 (en) * 1984-02-01 1985-12-04 3 M Medica GmbH Pharmaceutical product in pellet form with a continuous sustained release
EP0163000A3 (en) * 1984-02-01 1986-12-30 Kettelhack Riker Pharma Gmbh Pharmaceutical product in pellet form with a continuous sustained release
EP0177000A1 (en) * 1984-10-02 1986-04-09 EURAND ITALIA S.p.A. Process to obtain a sustained release formulation of water soluble components
WO1987001588A1 (en) * 1985-09-12 1987-03-26 Societe D'etudes Scientifiques Et Industrielles De Retardation preparation for a medicine
DE4131276B4 (en) * 1990-09-28 2007-07-19 Solvay Pharmaceuticals Gmbh Perorally administrable metoclopramide solutions

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FR2492661B1 (en) 1983-07-18
AU555512B2 (en) 1986-09-25
ES8301633A1 (en) 1983-01-01
ZA816993B (en) 1982-09-29
EP0063132A1 (en) 1982-10-27
CA1166574A (en) 1984-05-01
BE890808A (en) 1982-04-21
ES506654A0 (en) 1983-01-01
GR74683B (en) 1984-07-03
EP0063132B1 (en) 1986-07-30
US4656024A (en) 1987-04-07
JPH0428685B2 (en) 1992-05-15
FR2492661A1 (en) 1982-04-30
CH650922A5 (en) 1985-08-30
JPS57502121A (en) 1982-12-02
AU7720481A (en) 1982-05-21
IT1139645B (en) 1986-09-24
IT8124601A0 (en) 1981-10-21

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