EP1087757A1 - Method for making tablets with active principle sustained-release - Google Patents

Method for making tablets with active principle sustained-release

Info

Publication number
EP1087757A1
EP1087757A1 EP99925111A EP99925111A EP1087757A1 EP 1087757 A1 EP1087757 A1 EP 1087757A1 EP 99925111 A EP99925111 A EP 99925111A EP 99925111 A EP99925111 A EP 99925111A EP 1087757 A1 EP1087757 A1 EP 1087757A1
Authority
EP
European Patent Office
Prior art keywords
emulsion
active principle
release
tablets
fatty
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP99925111A
Other languages
German (de)
French (fr)
Inventor
Joseph Joachim
Pascal Prindirre
Nabil Farah
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ethypharm SAS
Gattefosse SA
Original Assignee
Gattefosse SA
Laboratories Prographarm SA
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 Gattefosse SA, Laboratories Prographarm SA filed Critical Gattefosse SA
Publication of EP1087757A1 publication Critical patent/EP1087757A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir

Definitions

  • the invention relates to a process for the manufacture of prolonged-release tablets of active principle (s) as well as to the tablets thus obtained.
  • the expression “prolonged release tablet of active principle” means a tablet capable of increasing the therapeutic effect of the active principle in the tissues or in the blood for an extended period of time.
  • the documents FR-A-2417982 and HU-A-9960 describe a process for the production of delayed-action tablets by wet granulation. More specifically, the powder mixture comprising the active principle and the various adjuvants is mixed with a granulation liquid consisting of an aqueous emulsion based on a hydrophobic component such as stearic acid and nonionic hydrophilic components such as polysorbates. The resulting wet mass is then dried and then passed through a sieve, the granules obtained then being pelletized so as to obtain tablets. The steps of kneading, sieving, drying and pelletizing the powder mixture make it a long and expensive process.
  • document WO 94/06416 describes tablets consisting of a core coated with a double layer, respectively a first layer containing at least one active principle with immediate or modulated release, a second layer with delayed release of active principle and an additional layer of low permeability. There is therefore obtained, by a relatively long process, a tablet having a complex structure, the kinetics of release of the active principle is predetermined during manufacture.
  • document WO 87/04070 describes a process for spraying onto tablets an aqueous dispersion prepared by re-dissolving in water a dried lipid emulsion, based on wax or hydrogenated oils.
  • the document JP-A-53062821 describes a process consisting in emulsifying a lipophilic substance in fusion in an aqueous phase then in coating a pharmaceutical preparation by spraying this emulsion at high temperature, higher than the melting point of the lipophilic substance ( so-called dry-spraying technique). Besides the fact that nothing is indicated concerning the nature of the coated pharmaceutical preparation. This technique has the drawback of leading, during the spraying, to an evaporation of the aqueous phase and thus of modifying the coating conditions.
  • the problem that the invention proposes to solve is therefore to develop prolonged-release tablets of active principle (s), the manufacturing process of which is simple to implement, potentially shorter and consequently less expensive. than the methods proposed in the state of the art.
  • the invention provides a process for the manufacture of prolonged-release tablets of active principle (s) according to which:
  • the emulsion obtained is sprayed on a powder mixture comprising at least the active principle
  • the powder mixture comprises not only the active principle, but also the formulation excipients.
  • formulation excipient is meant the excipients necessary for the formulation of the dosage form envisaged.
  • the compression step can be carried out using any known excipient intended to promote said compression.
  • the spray air temperature is between 20 and 60 ° C, advantageously 25 ° C, the temperature of the emulsion being fixed between 20 and 25 ° C.
  • the initial powder mixture is subjected beforehand to a granulation step in order to obtain granules.
  • said emulsion is advantageously produced in phase inversion, so as to modify the particle size distribution, thus making it possible to reduce the size of the particles and therefore the viscosity of the emulsion.
  • the fluid oil-in-water emulsion comprises from 5 to 35% by weight of fatty substances.
  • concentration of fatty substance is not sufficient to ensure the prolonged release of the active principle.
  • the viscosity is too high to obtain a fluid emulsion.
  • the compression step is difficult.
  • said particles are coated in an amount of 3 to 100% by weight of fluid emulsion, advantageously from 10 to 60%.
  • the tablet becomes too bulky to constitute an appropriate dosage form.
  • the fatty substances are chosen from the group comprising fatty acids, hydrogenated oils, fatty acid esters with glycerin or polyols and natural waxes.
  • the chosen fatty substance is glycerol behenate marketed by the Applicant under the trade name COMPRITOL ® 888 ATO.
  • the fatty substance is glycerol palmitostearate marketed by the Applicant under the trade mark ® Precirol® Ato 5.
  • the emulsion also contains an emulsifier or surfactant.
  • the surfactant used is chosen from nonionic and / or ionic surfactants. More specifically, the emulsifying agent will be chosen so as to ensure the fluidity of the emulsion, its stability and the absence of foaming. In addition, the emulsifier must be pharmaceutically acceptable.
  • the emulsifying agent chosen is polyethylene glycol 4000 palmitostearate.
  • the emulsifying agent is sodium lauryl sulfate used in an amount of 0.5 to 1% by weight of the emulsion. Beyond 10 1%, no improvement in the emulsion is obtained and foaming is observed.
  • the viscosity of the oil-in-water fluid emulsion is chosen between 10 and 15 70 centipoise.
  • the invention also relates to the prolonged-release tablet of active principle (s) capable of being obtained by the process described above.
  • Figure 1 is a representation of the release profile of a tablet with kinetics of dissolution of the active principle of order 0.
  • Figure 2 is a representation of the release profile of a tablet with kinetics of dissolution of the active principle of order 1.
  • FIG. 3 shows the release profile of theophylline granules at a spray air temperature 25 ° C of an emulsion based COMPRITOL ® 888 ATO.
  • Figure 4 shows the release profile of theophylline granules at a spray air temperature of 60 ° C of an emulsion based COMPRITOL ® 888 ATO.
  • FIG. 5 shows the theophylline granules release profile at a spraying air temperature of 25 ° C of an emulsion based on 35 Precirol® ATO 5 ®.
  • FIG. 6 represents the release profile of theophylline granules at a spray air temperature of 60 ° C. from an emulsion based on
  • FIG. 7 shows the release profile of theophylline tablets a spraying air temperature of 25 ° C of an emulsion based COMPRITOL ® 888 ATO.
  • FIG. 8 shows the release profile of theophylline tablets a spraying air temperature of 60 ° C of an emulsion based COMPRITOL ® 888 ATO.
  • 9 shows Diclofenac tablets release profile made from an emulsion-based COMPRITOL ® 888 ATO or PRECIROL ® ATO 5 to a spray temperature of 25 ° C.
  • Figure 10 shows the release profile of the same batch of tablets of Diclofenac made from an emulsion-based COMPRITOL ® 888 ATO or PRECIROL ® ATO 5 before and after stability at 40 ° C.
  • Diclofenac tablets release profile made from a PRECIROL based emulsion ® ATO 5 at a spraying air temperature of 25 ° C.
  • kinetics of order 1 correspond to a release proportional to the quantity remaining in the dosage form envisaged and which decreases over time exponentially (see FIG. 2).
  • Example 1 the kinetics of in vitro release of the active ingredients is carried out in a dissolumeter (conventional SOTAX) in accordance with European and American pharmacopoeias at pH 1.2.
  • the blade rotation speed is 100 revolutions per minute.
  • Example 1 we compare the theophylline granules coated release profile according to the method of the invention before and after compression with two different fats, namely Compritol ® 888 ® and Precirol® Ato 5 by setting the temperature atomizing air at 25 ° C or 60 ° C.
  • Granules are prepared corresponding to the following formula:
  • the granules are produced by wet granulation in a Guedu type mixer with rotating blades by implementing the following steps:
  • a lipid emulsion comprising:
  • COMPRITOL ® 888 or PRECIROL ® is used as a fatty substance
  • the fatty substance and the surfactant are heated until complete fusion. Distilled water, heated to the same temperature, is added slowly with stirring. The addition of water gradually transforms the initial water-in-oil emulsion into an oil-in-water emulsion. The emulsion is then homogenized with a homogenizer of the POLYTRON type for three minutes in order to reduce and homogenize the size of the oil droplets.
  • sodium lauryl sulfate when sodium lauryl sulfate is used as a surfactant, it is dissolved hot in the aqueous phase.
  • a fluidized air flow device is used, the fluidizing air temperature of which is chosen at 25 ° C. or 60 ° C.
  • the fluidization pressure is chosen to be of the order of 1.5 bar.
  • the spray rate is set at 10 grams per minute.
  • FIGS. 3 and 4 appended show the release profile of theophylline granules coated with a lipid emulsion based on
  • COMPRITOL® 888 for spray air temperatures of 25 ° C ( Figure 3) or 60 ° C ( Figure 4).
  • the proportion of COMPRITOL® 888 varies between 10 and 30% relative to the mass of dry matter used.
  • Figures 5 and 6 show immediate release profiles when the emulsion used is based on PRECIROL ® Ato 5.
  • the method of the invention has the advantage of being able to be implemented at a spraying air temperature of the order of only 25 ° C., which not only facilitates the various operations but also reduces the manufacturing cost, particularly in terms of energy consumed.
  • Diclofenac particles are produced under the same conditions as in Example 1, starting from a diclofenac / bicalcium phosphate mixture in proportions of 50/50.
  • Figure 10 depicts the release profiles of diclofenac tablets coated with lipid emulsions comprising 20% COMPRITOL ® 888 ATO or 20% Precirol® ® Ato 5, before and after twelve months of stability at 40 ° C and 75% relative humidity (accelerated stability).
  • Example 2 does not carry out prior wet granulation of the active principle.
  • the powder mixture consisting of a diclofenac / dicalcium phosphate mixture is then coated in the proportions of 50/50 in order to obtain coated particles having good compressibility properties.
  • the spraying of the emulsion on the particles is carried out under the same conditions as in Example 1 at a spraying air temperature of around 25 ° C.
  • the coated particles are then compressed on an industrial rotary press.
  • the compression characteristics and tablets obtained are as follows:
  • FIG. 11 shows the release profile of diclofenac tablets, the proportion of PRECIROL® ATO 5 relative to the mass of dry matter used is 20%.
  • the kinetics of in vitro release of diclofenac is evaluated in a dissolumeter in accordance with the European, American and Japanese pharmacopoeias at pH 6.8 according to the provisions of the American Pharmacopoeia edition XXIII.
  • the rotation speed of the blades is 50 rotations per minute.
  • the two tests carried out on the same batch show a profile of prolonged release over 12 hours of the active principle.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention concerns a method for making tablets with active principle sustained-release which consists in: preparing a fluid oil-in-water emulsion; spraying the resulting emulsion on a powder mixture containing at least the active principle; subjecting said treated powder to a compressing step, to obtain tablets.

Description

PROCEDE POUR LA FABRICATION DE COMPRIMES A LIBERATTON PROLONGEE DE PRINCIPES ACTIFSPROCESS FOR THE MANUFACTURE OF EXTENDED LIBERATTON TABLETS OF ACTIVE INGREDIENTS
L'invention se rapporte à un procédé pour la fabrication de comprimés à libération prolongée de principe(s) actif(s) de même qu'aux comprimés ainsi obtenus.The invention relates to a process for the manufacture of prolonged-release tablets of active principle (s) as well as to the tablets thus obtained.
Dans la description et dans les revendications, par l'expression «comprimé à libération prolongée de principe actif», on désigne un comprimé susceptible d'allonger l'effet thérapeutique du principe actif dans les tissus ou dans le sang pendant une période de temps prolongée (voir notamment « The Science andIn the description and in the claims, the expression “prolonged release tablet of active principle” means a tablet capable of increasing the therapeutic effect of the active principle in the tissues or in the blood for an extended period of time. (see in particular "The Science and
Practice of Pharmacy », 19ème édition, REMINGTON 1975).Practice of Pharmacy ", 19th edition, REMINGTON 1975).
Plusieurs procédés ont été proposés pour la fabrication de ce type de comprimés.Several methods have been proposed for the manufacture of this type of tablet.
Ainsi par exemple, les documents FR-A-2417982 et HU-A-9960 décrivent un procédé de fabrication de comprimés à action retardée par granulation par voie humide. Plus précisément, le mélange de poudre comprenant le principe actif et les différents adjuvants est malaxé avec un liquide de granulation constitué d'une emulsion aqueuse à base d'un composant hydrophobe tel que l'acide stéarique et de composants hydrophiles non ioniques tels que les polysorbates. La masse humide résultante est ensuite séchée puis passée à travers un tamis, les granulés obtenus étant ensuite pastillés de sorte à obtenir des comprimés. Les étapes de malaxage, de tamisage, de séchage et de pastillage du mélange de poudre en font un procédé long et coûteux.For example, the documents FR-A-2417982 and HU-A-9960 describe a process for the production of delayed-action tablets by wet granulation. More specifically, the powder mixture comprising the active principle and the various adjuvants is mixed with a granulation liquid consisting of an aqueous emulsion based on a hydrophobic component such as stearic acid and nonionic hydrophilic components such as polysorbates. The resulting wet mass is then dried and then passed through a sieve, the granules obtained then being pelletized so as to obtain tablets. The steps of kneading, sieving, drying and pelletizing the powder mixture make it a long and expensive process.
De même, le document WO 94/06416 décrit des comprimés constitués d'un noyau enrobé d'une double couche, respectivement une première couche contenant au moins un principe actif à libération immédiate ou modulée, une seconde couche à libération retardée de principe actif et une couche supplémentaire de faible perméabilité. On obtient donc, par un procédé relativement long, un comprimé présentant une structure complexe, dont la cinétique de libération du principe actif est prédéterminée lors de la fabrication. Par ailleurs, le document WO 87/04070 décrit un procédé de pulvérisation sur des comprimés, d'une dispersion aqueuse préparée par remise en solution dans l'eau d'une emulsion lipidique séchée, à base de cire ou d'huiles hydrogénées.Likewise, document WO 94/06416 describes tablets consisting of a core coated with a double layer, respectively a first layer containing at least one active principle with immediate or modulated release, a second layer with delayed release of active principle and an additional layer of low permeability. There is therefore obtained, by a relatively long process, a tablet having a complex structure, the kinetics of release of the active principle is predetermined during manufacture. Furthermore, document WO 87/04070 describes a process for spraying onto tablets an aqueous dispersion prepared by re-dissolving in water a dried lipid emulsion, based on wax or hydrogenated oils.
Le document JP-A-53062821 décrit un procédé consistant à mettre en emulsion une substance lipophile en fusion dans une phase aqueuse puis d'enrober une préparation pharmaceutique par pulvérisation de cette emulsion à température élevée, supérieure au point de fusion de la substance lipophile (technique dite de dry-spraying). Outre le fait que rien n'est indiqué concernant la nature de la préparation pharmaceutique enrobée. Cette technique présente l'inconvénient de conduire, lors de la pulvérisation à une évaporation de la phase aqueuse et ainsi à modifier les conditions d'enrobage.The document JP-A-53062821 describes a process consisting in emulsifying a lipophilic substance in fusion in an aqueous phase then in coating a pharmaceutical preparation by spraying this emulsion at high temperature, higher than the melting point of the lipophilic substance ( so-called dry-spraying technique). Besides the fact that nothing is indicated concerning the nature of the coated pharmaceutical preparation. This technique has the drawback of leading, during the spraying, to an evaporation of the aqueous phase and thus of modifying the coating conditions.
Le document WO 98/14176 décrit un procédé de fabrication de comprimés à libération prolongée de principe actif obtenus par compression de granulés enrobés à chaud par un agent matriciel lipidique. Cette technique d'enrobage à chaud présente non seulement l'inconvénient de générer une dépense d'énergie supplémentaire mais également de nécessiter une adaptation de l'équipement standard.Document WO 98/14176 describes a process for the production of prolonged-release tablets of active principle obtained by compression of granules coated hot with a lipid matrix agent. This hot coating technique not only has the drawback of generating additional energy expenditure but also of requiring adaptation of the standard equipment.
Le problème que se propose de résoudre l'invention est donc de développer des comprimés à libération prolongée de principe(s) actif(s) dont le procédé de fabrication est simple à mettre en œuvre, potentiellement moins long et par voie de conséquence moins coûteux que les procédés proposés dans l'état de la technique.The problem that the invention proposes to solve is therefore to develop prolonged-release tablets of active principle (s), the manufacturing process of which is simple to implement, potentially shorter and consequently less expensive. than the methods proposed in the state of the art.
Pour ce faire, l'invention propose un procédé pour la fabrication de comprimés à libération prolongée de principe(s) actif(s) selon lequel :To do this, the invention provides a process for the manufacture of prolonged-release tablets of active principle (s) according to which:
- on prépare une emulsion fluide huile dans eau ;- a fluid oil in water emulsion is prepared;
- on pulvérise l'émulsion obtenue sur un mélange de poudre comprenant au moins le principe actif ;- The emulsion obtained is sprayed on a powder mixture comprising at least the active principle;
- on soumet la poudre ainsi traitée à une étape de compression, afin d'obtenir des comprimés.- The powder thus treated is subjected to a compression step, in order to obtain tablets.
On a en effet constaté que de façon tout à fait surprenante, alors que les particules enrobées ne présentaient aucune propriété de libération prolongée, une étape de compression classique ultérieure de ces particules conduisait à l'obtention de comprimés présentant des caractéristiques de libération prolongée.It has in fact been found that, quite surprisingly, while the coated particles exhibited no sustained release property, a subsequent conventional compression step of these particles led to the production of tablets having prolonged release characteristics.
Dans une forme avantageuse de réalisation de l'invention, le mélange de poudre comprend non seulement le principe actif, mais également les excipients de formulation.In an advantageous embodiment of the invention, the powder mixture comprises not only the active principle, but also the formulation excipients.
Par l'expression « excipient de formulation », on désigne les excipients nécessaires à la formulation de la forme galénique envisagée.By the expression "formulation excipient" is meant the excipients necessary for the formulation of the dosage form envisaged.
De même, l'étape de compression peut être effectuée en mettant en oeuvre tout excipient connu destiné à favoriser ladite compression.Likewise, the compression step can be carried out using any known excipient intended to promote said compression.
Selon une première caractéristique de l'invention, la température d'air de pulvérisation est comprise entre 20 et 60°C , avantageusement 25°C, la température de l'émulsion étant fixée entre 20 et 25°C.According to a first characteristic of the invention, the spray air temperature is between 20 and 60 ° C, advantageously 25 ° C, the temperature of the emulsion being fixed between 20 and 25 ° C.
A une température supérieure à 60°C, le procédé devient économiquement moins intéressant. On note par ailleurs un risque important de dégradation des principes actifs thermosensibles.At a temperature above 60 ° C, the process becomes economically less attractive. There is also a significant risk of degradation of the heat-sensitive active ingredients.
En d'autres termes, outre le fait que ce procédé permet d'obtenir des comprimés à libération prolongée, il présente en outre l'avantage d'être réalisé à température ambiante (la température de l'air de pulvérisation et de l'émulsion est avantageusement égale à 25°C) et est donc moins coûteux.In other words, in addition to the fact that this process makes it possible to obtain prolonged-release tablets, it also has the advantage of being carried out at ambient temperature (the temperature of the spraying air and of the emulsion is advantageously equal to 25 ° C.) and is therefore less expensive.
Dans une forme de réalisation particulière, le mélange de poudre initial est préalablement soumis à une étape de granulation afin d'obtenir des granulés.In a particular embodiment, the initial powder mixture is subjected beforehand to a granulation step in order to obtain granules.
Pour faciliter la pulvérisation de l'émulsion sur le mélange de poudre, ladite emulsion est avantageusement réalisée en inversion de phase, de sorte à modifier la répartition granulométrique, permettant ainsi de diminuer la taille des particules et donc la viscosité de l'émulsion.To facilitate spraying of the emulsion on the powder mixture, said emulsion is advantageously produced in phase inversion, so as to modify the particle size distribution, thus making it possible to reduce the size of the particles and therefore the viscosity of the emulsion.
Selon une autre caractéristique importante de l'invention, l'émulsion fluide huile dans eau comprend de 5 à 35 % en poids de corps gras. Pour une concentration inférieure à 5%, la concentration en corps gras n'est pas suffisante pour assurer la libération prolongée du principe actif.According to another important characteristic of the invention, the fluid oil-in-water emulsion comprises from 5 to 35% by weight of fatty substances. For a concentration of less than 5%, the concentration of fatty substance is not sufficient to ensure the prolonged release of the active principle.
Pour une concentration supérieure à 35%, la viscosité est trop élevée pour obtenir une emulsion fluide. En outre, l'étape de compression est difficile.For a concentration greater than 35%, the viscosity is too high to obtain a fluid emulsion. In addition, the compression step is difficult.
Par ailleurs, pour permettre la compression des particules, lesdites particules sont enrobées à raison de 3 à 100 % en poids d' emulsion fluide, avantageusement de 10 à 60 %.Furthermore, to allow compression of the particles, said particles are coated in an amount of 3 to 100% by weight of fluid emulsion, advantageously from 10 to 60%.
Pour un enrobage inférieur à 3 %, on observe qu'un enrobage partiel des particules.For a coating of less than 3%, it is observed that a partial coating of the particles.
De même, pour un enrobage supérieur à 100 %, le comprimé devient trop volumineux pour constituer une forme galénique appropriée.Likewise, for a coating greater than 100%, the tablet becomes too bulky to constitute an appropriate dosage form.
Afin d'obtenir une libération prolongée du principe actif, les corps gras sont choisis dans le groupe comprenant les acides gras, les huiles hydrogénées, les esters d'acide gras avec de la glycérine ou des polyols et les cires naturelles.In order to obtain a prolonged release of the active principle, the fatty substances are chosen from the group comprising fatty acids, hydrogenated oils, fatty acid esters with glycerin or polyols and natural waxes.
Selon une première forme de réalisation, le corps gras choisi est le béhénate de glycérol commercialisé par le Demandeur sous la marque déposée COMPRITOL® 888 Ato.According to a first embodiment, the chosen fatty substance is glycerol behenate marketed by the Applicant under the trade name COMPRITOL ® 888 ATO.
Selon un autre mode de réalisation de l'invention, le corps gras est le palmitostéarate de glycérol commercialisé par le Demandeur sous la marque déposée PRECIROL® Ato 5.According to another embodiment of the invention, the fatty substance is glycerol palmitostearate marketed by the Applicant under the trade mark ® Precirol® Ato 5.
Pour permettre de réaliser l'émulsion fluide à température ambiante, l'émulsion contient en outre un émulsionnant ou tensio- actif.To allow the fluid emulsion to be produced at room temperature, the emulsion also contains an emulsifier or surfactant.
Le tensio-actif mis en œuvre est choisi parmi les tensio-actifs non ioniques et/ou ioniques. Plus précisément, l'agent émulsionnant sera choisi de sorte à assurer la fluidité de l'émulsion, sa stabilité et l'absence de formation de mousse. En outre, l'agent émulsionnant doit être pharmaceutiquement acceptable.The surfactant used is chosen from nonionic and / or ionic surfactants. More specifically, the emulsifying agent will be chosen so as to ensure the fluidity of the emulsion, its stability and the absence of foaming. In addition, the emulsifier must be pharmaceutically acceptable.
5 Avantageusement, l'agent émulsionnant choisi est le palmitostéarate de polyéthylène glycol 4000.Advantageously, the emulsifying agent chosen is polyethylene glycol 4000 palmitostearate.
Selon une autre forme de réalisation, l'agent émulsionnant est le lauryl sulfate de sodium utilisé à raison de 0,5 à 1% en poids de l'émulsion. Au delà de 10 1%, on n'obtient pas d'amélioration de l'émulsion et on observe la formation de mousse.According to another embodiment, the emulsifying agent is sodium lauryl sulfate used in an amount of 0.5 to 1% by weight of the emulsion. Beyond 10 1%, no improvement in the emulsion is obtained and foaming is observed.
De même, afin de ne pas obstruer les tubes et la buse de la machine de pulvérisation, la viscosité de l'émulsion fluide huile dans eau est choisie entre 10 et 15 70 centipoises.Similarly, in order not to obstruct the tubes and the nozzle of the spraying machine, the viscosity of the oil-in-water fluid emulsion is chosen between 10 and 15 70 centipoise.
L'invention se rapporte également au comprimé à libération prolongée de principe(s) actif(s) susceptible d'être obtenu par le procédé ci avant décrit.The invention also relates to the prolonged-release tablet of active principle (s) capable of being obtained by the process described above.
20 L'invention et les avantages qui en découlent ressortiront mieux des exemples de réalisation suivants à l'appui des figures annexées dans lesquelles :The invention and the advantages which ensue therefrom will emerge more clearly from the following exemplary embodiments in support of the appended figures in which:
La figure 1 est une représentation du profil de libération d'un comprimé présentant une cinétique de dissolution du principe actif d'ordre 0. 25 La figure 2 est une représentation du profil de libération d'un comprimé présentant une cinétique de dissolution du principe actif d'ordre 1.Figure 1 is a representation of the release profile of a tablet with kinetics of dissolution of the active principle of order 0. Figure 2 is a representation of the release profile of a tablet with kinetics of dissolution of the active principle of order 1.
La figure 3 représente le profil de libération de granulés de théophylline à une température d'air de pulvérisation de 25°C d'une emulsion à base de COMPRITOL® 888 ATO. 30 La figure 4 représente le profil de libération de granulés de théophylline à une température d'air de pulvérisation de 60°C d'une emulsion à base de COMPRITOL® 888 ATO.3 shows the release profile of theophylline granules at a spray air temperature 25 ° C of an emulsion based COMPRITOL ® 888 ATO. 30 Figure 4 shows the release profile of theophylline granules at a spray air temperature of 60 ° C of an emulsion based COMPRITOL ® 888 ATO.
La figure 5 représente le profil de libération de granulés de théophylline à une température d'air de pulvérisation de 25°C d'une emulsion à base de 35 PRECIROL® ATO 5. La figure 6 représente le profil de libération de granulés de théophylline à une température d'air de pulvérisation de 60°C d'une emulsion à base de5 shows the theophylline granules release profile at a spraying air temperature of 25 ° C of an emulsion based on 35 Precirol® ATO 5 ®. FIG. 6 represents the release profile of theophylline granules at a spray air temperature of 60 ° C. from an emulsion based on
PRECIROL® ATO 5.PRECIROL ® ATO 5.
La figure 7 représente le profil de libération de comprimés de théophylline à une température d'air de pulvérisation de 25°C d'une emulsion à base de COMPRITOL® 888 ATO.7 shows the release profile of theophylline tablets a spraying air temperature of 25 ° C of an emulsion based COMPRITOL ® 888 ATO.
La figure 8 représente le profil de libération de comprimés de théophylline à une température d'air de pulvérisation de 60°C d'une emulsion à base de COMPRITOL® 888 ATO. La figure 9 représente le profil de libération de comprimés de Diclofénac fabriqués à partir d'une emulsion à base de COMPRITOL® 888 ATO ou de PRECIROL® ATO 5 à une température de pulvérisation de 25°C.8 shows the release profile of theophylline tablets a spraying air temperature of 60 ° C of an emulsion based COMPRITOL ® 888 ATO. 9 shows Diclofenac tablets release profile made from an emulsion-based COMPRITOL ® 888 ATO or PRECIROL ® ATO 5 to a spray temperature of 25 ° C.
La figure 10 représente le profil de libération du même lot de comprimés de Diclofénac fabriqués à partir d'une emulsion à base de COMPRITOL® 888 ATO ou de PRECIROL® ATO 5 avant et après stabilité à 40°C.Figure 10 shows the release profile of the same batch of tablets of Diclofenac made from an emulsion-based COMPRITOL ® 888 ATO or PRECIROL ® ATO 5 before and after stability at 40 ° C.
La figure 11 représente le profil de libération de comprimés de Diclofénac fabriqués à partir d'une emulsion à base de PRECIROL® ATO 5 à une température d'air de pulvérisation de 25°C.11 shows Diclofenac tablets release profile made from a PRECIROL based emulsion ® ATO 5 at a spraying air temperature of 25 ° C.
Dans les exemples 1 et 2 suivants, on a fabriqué des comprimés selon le procédé de l'invention et dont la cinétique de dissolution du principe actif est dite d'ordre 0.In the following examples 1 and 2, tablets were produced according to the process of the invention and the kinetics of dissolution of the active principle of which is said to be of order 0.
Par l'expression « cinétique de dissolution d'ordre zéro », on désigne la libération constante et régulière du principe actif en fonction du temps. Cette libération peut être représentée graphiquement sous forme d'une droite exprimée par l'équation suivante : dQ/dt = k où Q correspond à la quantité de soluté et k, la constante de vitesse (voir figure 1).The expression “zero order dissolution kinetics” denotes the constant and regular release of the active principle as a function of time. This release can be represented graphically in the form of a straight line expressed by the following equation: dQ / dt = k where Q corresponds to the quantity of solute and k, the speed constant (see Figure 1).
A l'inverse, une cinétique d'ordre 1 correspond à une libération proportionnelle à la quantité restante dans la forme galénique envisagée et qui décroît avec le temps de manière exponentielle (voir figure 2).Conversely, kinetics of order 1 correspond to a release proportional to the quantity remaining in the dosage form envisaged and which decreases over time exponentially (see FIG. 2).
Dans les exemples 1 et 2, la cinétique de libération in vitro des principes actifs est réalisée dans un dissolumètre (SOTAX classique) conforme aux pharmacopées européenne et américaine à pH 1,2. La vitesse de rotation des pâles est de 100 tours par minute.In Examples 1 and 2, the kinetics of in vitro release of the active ingredients is carried out in a dissolumeter (conventional SOTAX) in accordance with European and American pharmacopoeias at pH 1.2. The blade rotation speed is 100 revolutions per minute.
Exemple 1 Dans cet exemple, on compare le profil de libération de granulés de théophylline enrobés selon le procédé de l'invention avant et après compression avec deux corps gras différents, à savoir le COMPRITOL® 888 et le PRECIROL® Ato 5 en fixant la température d'air de pulvérisation à 25°C ou 60°C.Example 1 In this example, we compare the theophylline granules coated release profile according to the method of the invention before and after compression with two different fats, namely Compritol ® 888 ® and Precirol® Ato 5 by setting the temperature atomizing air at 25 ° C or 60 ° C.
1 - Préparation des granulés1 - Preparation of the granules
On prépare des granulés correspondant à la formule suivante :Granules are prepared corresponding to the following formula:
- théophylline monohydratée : 30 grammes- theophylline monohydrate: 30 grams
- lactose : 41 grammes- lactose: 41 grams
- amidon de blé : 16 grammes - carboxyméthyl cellulose sodique : 1 gramme- wheat starch: 16 grams - sodium carboxymethyl cellulose: 1 gram
- cellulose micro-cristalline : 12 grammes- micro-crystalline cellulose: 12 grams
Les granulés sont fabriqués par granulation par voie humide dans un mélangeur granulateur type Guedu à pâles tournantes en mettant en œuvre les étapes suivantes :The granules are produced by wet granulation in a Guedu type mixer with rotating blades by implementing the following steps:
- tamisage préalable de la théophylline monohydratée- preliminary sieving of theophylline monohydrate
- mélange de l'ensemble des constituants dans le mélangeur pendant trois minutes ;- mixing of all the constituents in the mixer for three minutes;
- malaxage pendant cinq minutes avec 1500 ml d'eau distillée pour cinq kilos du mélange initial ;- mixing for five minutes with 1500 ml of distilled water for five kilos of the initial mixture;
- calibration des granulés semi-humides avec un tamis de maille 1,25 mm ;- calibration of semi-wet granules with a 1.25 mm mesh screen;
- séchage final à l'étuve à 50°C.- final drying in an oven at 50 ° C.
2 - Préparation de l 'emulsion On prépare une emulsion lipidique comprenant :2 - Preparation of the emulsion A lipid emulsion is prepared comprising:
- de 10 à 30 % de corps gras ;- from 10 to 30% of fatty substances;
- 4 % de stéarate 4000 (agent tensioactif) ;- 4% stearate 4000 (surfactant);
- complément à 100 % d'eau distillée.- complement to 100% distilled water.
On utilise en tant que corps gras le COMPRITOL® 888 ou le PRECIROL® COMPRITOL ® 888 or PRECIROL ® is used as a fatty substance
Ato 5. Le corps gras et l'agent tensioactif sont chauffés jusqu'à fusion complète. L'eau distillée, chauffée à la même température, est ajoutée lentement sous agitation. L'ajout d'eau transforme au fur et à mesure l'émulsion initiale eau dans huile en une emulsion huile dans eau. L'émulsion est ensuite homogénéisée avec un homogénéiseur du type POLYTRON pendant trois minutes afin de réduire et d'homogénéiser la taille des gouttelettes d'huile.Ato 5. The fatty substance and the surfactant are heated until complete fusion. Distilled water, heated to the same temperature, is added slowly with stirring. The addition of water gradually transforms the initial water-in-oil emulsion into an oil-in-water emulsion. The emulsion is then homogenized with a homogenizer of the POLYTRON type for three minutes in order to reduce and homogenize the size of the oil droplets.
Toutefois, lorsqu'on utilise en tant que tensio-actif le lauryl sulfate de sodium, il est dissout à chaud dans la phase aqueuse.However, when sodium lauryl sulfate is used as a surfactant, it is dissolved hot in the aqueous phase.
3 - Pulvérisation de l'émulsion sur les granulés préalablement obtenus3 - Spraying the emulsion on the granules previously obtained
On utilise un appareil à débit d'air fluidisé dont la température d'air de fluidisation est choisie à 25°C ou 60°C. La pression de fluidisation est choisie de l'ordre de 1,5 bar. De même, le débit de pulvérisation est réglé à 10 grammes par minute.A fluidized air flow device is used, the fluidizing air temperature of which is chosen at 25 ° C. or 60 ° C. The fluidization pressure is chosen to be of the order of 1.5 bar. Likewise, the spray rate is set at 10 grams per minute.
Comme déjà dit, les figures 3 et 4 annexées représentent le profil de libération des granulés de théophylline enrobés d'une emulsion lipidique à base deAs already said, FIGS. 3 and 4 appended show the release profile of theophylline granules coated with a lipid emulsion based on
COMPRITOL® 888 pour des températures d'air de pulvérisation de 25°C (figure 3) ou 60°C (figure 4). La proportion de COMPRITOL® 888 varie entre 10 et 30% relativement à la masse de matière sèche mise en oeuvre.COMPRITOL® 888 for spray air temperatures of 25 ° C (Figure 3) or 60 ° C (Figure 4). The proportion of COMPRITOL® 888 varies between 10 and 30% relative to the mass of dry matter used.
Comme le montrent ces deux figures, quelle que soit la température d'air de pulvérisation, entre 80 et 90 % du principe actif est dissout dans un délai de trente minutes à compter de l'ingestion. On en conclut que les granulés ne présentent pas de caractéristiques de libération prolongée.As these two figures show, whatever the spraying air temperature, between 80 and 90% of the active principle is dissolved within thirty minutes of ingestion. It is concluded that the granules do not exhibit sustained release characteristics.
Les figures 5 et 6 représentent des profils à libération immédiate lorsque l'émulsion utilisée est à base de PRECIROL® Ato 5.Figures 5 and 6 show immediate release profiles when the emulsion used is based on PRECIROL ® Ato 5.
Comme précédemment, on constate qu'entre 80 et 95 % du principe actif contenu dans les granulés enrobés est libéré en trente minutes.As before, it can be seen that between 80 and 95% of the active principle contained in the coated granules is released in thirty minutes.
4 - Etape de compression Les granulés enrobés de COMPRITOL® sont ensuite soumis à une étape de compression au moyen d'une comprimeuse alternative Frogerais type OA de poinçons de taille référencée D10-R10. On utilise, en tant qu'excipient de compression, un mélange de talc et de stéarate de magnésium représentant chacun 1 % en poids du poids total des granulés. Les comprimés obtenus ont un poids moyen de 402 mg et une dureté moyenne de 5,7 kg.4 - Compression step The granules coated with COMPRITOL® are then subjected to a compression step using an alternative Frogerais OA type compression machine. punches of size referenced D10-R10. A mixture of talc and magnesium stearate, each representing 1% by weight of the total weight of the granules, is used as the compression excipient. The tablets obtained have an average weight of 402 mg and an average hardness of 5.7 kg.
Comme le montrent les figures 7 et 8, les comprimés obtenus à partir des granulés fabriqués à une température de pulvérisation de 25°C (figure 7) ou de 60°C (figure 8), présentent une cinétique d'ordre zéro pour une concentration en COMPRITOL® dans l'émulsion égale à 30 %.As shown in Figures 7 and 8, the tablets obtained from the granules produced at a spraying temperature of 25 ° C (Figure 7) or 60 ° C (Figure 8), exhibit zero order kinetics for a concentration in COMPRITOL ® in the emulsion equal to 30%.
Par ailleurs, le procédé de l'invention présente l'avantage de pouvoir être mis en œuvre à une température d'air de pulvérisation de l'ordre de seulement 25°C, ce qui non seulement facilite les différentes opérations mais en outre diminue le coût de la fabrication, notamment en terme d'énergie consommée.Furthermore, the method of the invention has the advantage of being able to be implemented at a spraying air temperature of the order of only 25 ° C., which not only facilitates the various operations but also reduces the manufacturing cost, particularly in terms of energy consumed.
Exemple 2 - Comprimés de diclofénacExample 2 Tablets of Diclofenac
1 - Préparation des granulés On réalise dans les mêmes conditions qu'à l'exemple 1 des particules de diclofénac, en partant d'un mélange diclofénac/phosphate bicalcique dans des proportions de 50/50.1 - Preparation of the granules Diclofenac particles are produced under the same conditions as in Example 1, starting from a diclofenac / bicalcium phosphate mixture in proportions of 50/50.
2 et 3 - Préparations de l'émulsion et pulvérisation On enrobe ensuite les granulés d'une emulsion dans les mêmes conditions que dans l'exemple 1 à une température d'air de pulvérisation de 25°C, en faisant varier la nature et la concentration de la substance lipidique mise en œuvre. On utilise ainsi une proportion de 20 ou 30 % de PRECIROL® Ato ou 30 % de COMPRITOL®, relativement à la masse de matière sèche mise en oeuvre.2 and 3 - Preparation of the emulsion and spraying The granules are then coated with an emulsion under the same conditions as in Example 1 at a spraying air temperature of 25 ° C., varying the nature and the concentration of the lipid substance used. Is thus used a proportion of 20 or 30% Precirol® Ato ® or 30% COMPRITOL ®, relative to the dry matter mass implementation.
4 - Etape de compression4 - Compression step
Sur la même comprimeuse que précédemment, on procède à l'étape de compression des granulés enrobés. Les caractéristiques de compression et des comprimés obtenus sont regroupées dans ce tableau ci-après. On the same compressor as before, the coated granules are compressed. The compression characteristics and tablets obtained are grouped in this table below.
Comme le montre la figure 9, on obtient une cinétique d'ordre zéro dans les trois cas.As shown in Figure 9, we obtain zero order kinetics in all three cases.
Enfin, sur la figure 10, on a représenté les profils de libération des comprimés de diclofénac enrobés avec des émulsions lipidiques comprenant 20 % de COMPRITOL® 888 ATO ou 20 % de PRECIROL® Ato 5, avant et après douze mois de stabilité à 40°C et 75% d'humidité relatif (stabilité accélérée).Finally, Figure 10 depicts the release profiles of diclofenac tablets coated with lipid emulsions comprising 20% COMPRITOL ® 888 ATO or 20% Precirol® ® Ato 5, before and after twelve months of stability at 40 ° C and 75% relative humidity (accelerated stability).
On constate que le principe actif est resté stable et que l'on conserve une stabilité très satisfaisante des cinétiques de dissolution des comprimés de diclofénac.It is found that the active principle has remained stable and that a very satisfactory stability of the kinetics of dissolution of the diclofenac tablets is maintained.
Exemple 3 - Comprimés de diclofénacEXAMPLE 3 Diclofenac Tablets
A la différence de l'exemple 2, on ne réalise pas dans cet exemple de granulation humide préalable du principe actif.Unlike Example 2, this example does not carry out prior wet granulation of the active principle.
1 - Préparation de l'émulsion fluide On prépare une emulsion fluide à 10 % de corps gras identique dans les mêmes conditions que celle préparée dans les exemples 1 et 2. 2 - Pulvérisation1 - Preparation of the fluid emulsion A fluid emulsion containing 10% of identical fatty substance is prepared under the same conditions as that prepared in Examples 1 and 2. 2 - Spraying
On enrobe ensuite le mélange de poudre constituée d'un mélange de diclofénac/phosphate dicalcique dans les proportions de 50/50 afin d'obtenir des particules enrobées ayant de bonnes propriétés de compressibilité.The powder mixture consisting of a diclofenac / dicalcium phosphate mixture is then coated in the proportions of 50/50 in order to obtain coated particles having good compressibility properties.
La pulvérisation de l'émulsion sur les particules est effectuée dans les mêmes conditions que dans l'exemple 1 à une température d'air de pulvérisation d'environ 25° C.The spraying of the emulsion on the particles is carried out under the same conditions as in Example 1 at a spraying air temperature of around 25 ° C.
3 - Etape de compression3 - Compression step
On procède à l'étape de compression des particules enrobées sur une comprimeuse rotative industrielle. Les caractéristiques de compression et des comprimés obtenus sont les suivantes :The coated particles are then compressed on an industrial rotary press. The compression characteristics and tablets obtained are as follows:
- Particule enrobée 92 %- Coated particle 92%
- Encompress 6 %- Encompress 6%
- Talc 1 %- Talc 1%
- Stéarate de magnésium 1 %- Magnesium stearate 1%
- Poids du comprimé moyen 280 mg- Average tablet weight 280 mg
- Dureté 33 Newtons- Hardness 33 Newtons
Sur la figure 11, on a représenté le profil de libération de comprimés de diclofénac dont la proportion en PRECIROL ® ATO 5 relativement à la masse de matière sèche mise en oeuvre est de 20 %.FIG. 11 shows the release profile of diclofenac tablets, the proportion of PRECIROL® ATO 5 relative to the mass of dry matter used is 20%.
La cinétique de libération in vitro du diclofénac est évaluée dans un dissolumètre conforme aux pharmacopées européenne, américaine et japonaise à pH 6,8 selon les dispositions de la pharmacopée américaine édition XXIII. La vitesse de rotation des pâles est de 50 rotations par minute.The kinetics of in vitro release of diclofenac is evaluated in a dissolumeter in accordance with the European, American and Japanese pharmacopoeias at pH 6.8 according to the provisions of the American Pharmacopoeia edition XXIII. The rotation speed of the blades is 50 rotations per minute.
Comme le montre la figure 11, les deux essais réalisés sur le même lot montrent un profil de libération prolongée sur 12 heures du principe actif.As shown in FIG. 11, the two tests carried out on the same batch show a profile of prolonged release over 12 hours of the active principle.
Les avantages de l'invention ressortent bien de la description. On notera notamment que le procédé de l'invention permet d'obtenir des comprimés à libération prolongée sur 12 heures permettant d'adapter les posologies à deux prises par jour.The advantages of the invention appear clearly from the description. It will be noted in particular that the method of the invention makes it possible to obtain tablets for prolonged release over 12 hours making it possible to adapt the dosages to two doses per day.
On notera par ailleurs la facilité de mise en œuvre du procédé consistant en la pulvérisation d'une emulsion lipidique à des températures variant entre 20 et 60°C contribuant en outre à diminuer le coût en énergie des opérations.Note also the ease of implementation of the method consisting in spraying a lipid emulsion at temperatures varying between 20 and 60 ° C. further contributing to reducing the energy cost of the operations.
On constate enfin que les comprimés obtenus présentent une stabilité très satisfaisante à long terme. Finally, it is found that the tablets obtained have very satisfactory long-term stability.

Claims

REVENDICATIONS
1/ Procédé pour la fabrication de comprimés à libération prolongée de principe(s) actif(s) selon lequel : - on prépare une emulsion fluide huile dans eau ;1 / Process for the manufacture of prolonged-release tablets of active principle (s) according to which: - a fluid oil-in-water emulsion is prepared;
- on pulvérise l'émulsion obtenue sur un mélange de poudre comprenant au moins le principe actif ;- The emulsion obtained is sprayed on a powder mixture comprising at least the active principle;
- on soumet la poudre ainsi traitée à une étape de compression, afin d'obtenir des comprimés.- The powder thus treated is subjected to a compression step, in order to obtain tablets.
2/ Procédé selon la revendication 1, caractérisé en ce que la température d'air de pulvérisation est comprise entre 20 et 60°C .2 / A method according to claim 1, characterized in that the spray air temperature is between 20 and 60 ° C.
3/ Procédé selon l'une des revendications 1 à 2, caractérisé en ce que l'émulsion fluide huile dans eau comprend de 5 à 35 % en poids de corps gras.3 / Method according to one of claims 1 to 2, characterized in that the fluid oil-in-water emulsion comprises from 5 to 35% by weight of fatty substance.
4/ Procédé selon la revendication 3, caractérisé en ce que les corps gras sont choisis dans le groupe comprenant comprenant les acides gras, les huiles hydrogénées, les esters d'acide gras avec de la glycérine ou des polyols et les cires naturelles.4 / A method according to claim 3, characterized in that the fatty substances are chosen from the group comprising fatty acids, hydrogenated oils, fatty acid esters with glycerin or polyols and natural waxes.
5/ Procédé selon la revendication 4, caractérisé en ce que le corps gras est le béhénate de glycérol.5 / A method according to claim 4, characterized in that the fatty substance is glycerol behenate.
6/ Procédé selon la revendication 4, caractérisé en ce que le corps gras est le palmitostéarate de glycérol.6 / A method according to claim 4, characterized in that the fatty substance is glycerol palmitostearate.
Il Procédé selon l'une des revendications 1 à 6, caractérisé en ce que l'émulsion fluide huile dans eau comprend en outre un agent émulsionnant choisi dans le groupe des tensio-actifs non ioniques et ou ioniques.Il Method according to one of claims 1 to 6, characterized in that the fluid oil-in-water emulsion further comprises an emulsifying agent chosen from the group of nonionic and or ionic surfactants.
8/ Procédé selon la revendication 7, caractérisé en ce que l'agent émulsionnant est le palmito-stéarate de polyéthylène glycol 4000. 9/ Procédé selon l'une des revendication 1 à 8, caractérisé en ce que l'émulsion fluide huile dans eau présente une viscosité comprise entre 10 et 70 centipoises.8 / A method according to claim 7, characterized in that the emulsifying agent is palmito-stearate of polyethylene glycol 4000. 9 / A method according to one of claims 1 to 8, characterized in that the fluid oil in water emulsion has a viscosity between 10 and 70 centipoises.
10/ Procédé selon l'une des revendication 1 à 9, caractérisé en ce que l'émulsion fluide huile dans eau est pulvérisée sur le mélange de poudre à raison de 3 à 100 % en poids.10 / A method according to one of claims 1 to 9, characterized in that the oil-in-water fluid emulsion is sprayed onto the powder mixture in an amount of 3 to 100% by weight.
11/ Comprimé à libération prolongée de ρrincipe(s) actif(s) susceptible d'être obtenu par le procédé selon l'une des revendications 1 à 10. 11 / prolonged-release tablet of active principle (s) obtainable by the process according to one of claims 1 to 10.
EP99925111A 1998-06-16 1999-06-16 Method for making tablets with active principle sustained-release Withdrawn EP1087757A1 (en)

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FR2779651B1 (en) 2001-04-20
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US20010003590A1 (en) 2001-06-14
WO1999065471A1 (en) 1999-12-23

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