WO1999012528A1 - Self-emulsifiable semi-solid capsules with matrix system having prolonged action - Google Patents

Self-emulsifiable semi-solid capsules with matrix system having prolonged action Download PDF

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Publication number
WO1999012528A1
WO1999012528A1 PCT/BE1998/000132 BE9800132W WO9912528A1 WO 1999012528 A1 WO1999012528 A1 WO 1999012528A1 BE 9800132 W BE9800132 W BE 9800132W WO 9912528 A1 WO9912528 A1 WO 9912528A1
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capsule according
hydroxypropylcellulose
derivatives
chosen
active principle
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PCT/BE1998/000132
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French (fr)
Inventor
Antonio Sereno Guerra
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Smb Technology
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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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention relates to semi-solid self-emulsifying matrix capsules with long or controlled action for the oral administration of a medicament.
  • These pharmaceutical capsules make it possible, on the one hand, to increase the bioavailability of the drug to be administered by a pasty self-emulsifying system containing a surfactant and, on the other hand, to prolong its release by the formation of a matrix. lo polymer with hydrophilicity and controlled molecular weight.
  • the fenofibrate capsules based on polyglycosylated glycerides and hydroxypropylcellulose were designed from PCT patent application WO / 96/21439.
  • the hydroxypropylcellulose used is Klucel XHF, that is to say a cellulose with a very high molecular weight. around 1,150,000.
  • this patent application did not provide that the choice of molecular weight of hydroxypropylcellulose could modulate the kinetics of release of the active principle.
  • HLB hydrophilic-lypophilic balance
  • the object of the present invention is to remedy the above-mentioned drawbacks by providing a semi-solid self-emulsifying matrix capsule with prolonged action, comprising an active principle, at least one surfactant capable of self-emulsifying in an aqueous or physiological liquid medium in the presence of the active ingredient, with an HLB value of between 1 and 20 and at least one hydrophilic organic polymer making it possible to form a non-ionizable hydrophilic matrix network in the presence of said liquid medium, the release kinetics of which is controlled by the combination of compatibility characteristics of hydrophilic polymer and of the self-emulsifiable mixture and which exhibits little or no sensitivity to the hydrodynamic test conditions in vitro, whose production method is very simple, economical, easy to insert into conventional pharmaceutical production lines.
  • the abovementioned hydrophilic organic polymer is a hydroxyethylcellulose or hydroxypropylcellulose with a molecular weight of less than 1,000,000 or a mixture of two or more of these substances.
  • the hydroxyethylcellulose or hydroxypropylcellulose has a molecular weight of between 80,000 and 800,000 and it is preferably constituted by a hydroxypropylcellulose with a molecular weight of about 80,000.
  • hydroxypropylcellulose is known under the trade name of Klucel EF or is type M from the company Nisso.
  • the amount by weight of hydroxyethylcellulose and / or hydroxypropylcellulose is from 1 to 40% and preferably from 5 to 25% and the surfactant is chosen from the group comprising ethers and esters polyglycols, lecithin and its derivatives, sucrose esters, partially esterified glycerol derivatives and mixtures thereof.
  • the prolonged or controlled release capsules of the invention used for the oral administration of a medicament make it possible not only to increase its bioavailability by a pasty self-emulsifiable system containing a surfactant but also to prolong its release by the formation of a hydroxyethyl- and / or hydroxypropylcellulosic matrix with controlled hydrophilicity.
  • the active ingredients used will generally be substances whose oral bioavailability of conventional forms is low (equal to or less than 75%) and whose biopharma- ceutiques are such that it is interesting to develop a long-acting form.
  • the poorly water-soluble drugs such as flutamide, nifedipine, theophylline, naphthydrofuryl, acycovir, steroids, anti-inflammatories nonsteroidal drugs, anxiolytics, antimycotics such as ketoconazole and antihyperlipidemic drugs such as fenofibrate and unstable drugs in the gastrointestinal environment such as peptide hormones, amino acid derivatives and peptides such as captopril, cyclosporine and taxol.
  • the capsules will contain an amount of drug sufficient to be pharmacologically active as well as an excipient containing a surfactant or a mixture of surfactants capable of self-emulsifying in water or physiological fluids in the presence of the active ingredient.
  • surfactants that can be used, these will have an HLB value of between 1 and 20 and, in this regard, ethers and esters of polyglycols, ampholytes such as lecithin and its derivatives, sucrose esters, derivatives will be mentioned. partially esterified from glycerol and mixtures thereof.
  • the capsules will also contain an organic hydrophilic polymer of the hydroxyethylcellulose or hydroxypropylcellulose type, dispersed and partially solvated in the mixture of the other excipients, non-ionizable in physiological pH values.
  • This hydroxyethylcellulose or hydroxypropylcellulose in addition to its role as stabilizer of the pharmaceutical form, must be in sufficient quantity to form a hydrophilic matrix network, as soon as the capsule is immersed in an aqueous or physiological medium and that the water has dissolved the gelatin and / or the cellulosic polymer of the envelope thereof.
  • capsules in the context of the present invention corresponds to the definition given by the European Pharmacopoeia - 1997, pages 1859 and 1860 and that therefore this term encompasses the different categories of distinguishable capsules, namely hard-shell capsules or capsules, soft-shell capsules, gastro-resistant capsules and modified release capsules.
  • Hydroxyethylcelluloses (HEC) and hydroxypropylcelluloses (HPC) with a molecular weight of less than 1,000,000 and preferably with a molecular weight of between 80,000 and 800,000 will be used.
  • Particularly suitable are hydroxypropylcellulose with a molecular weight of approximately 80,000 known under the trade name of Klucel EF and hydroxypropylcellulose with a molecular weight of approximately 800,000 corresponding to type M from the company Nisso.
  • These hydroxycellulosic derivatives will be used alone or as a mixture of two or more of these substances in amounts representing between 1 and 40% and preferably between 5 and 25% by weight of the capsular mass.
  • the capsules may also contain an oil, a fatty substance or a water-soluble amphiphilic polymer or a mixture of these, substances intended to dissolve the active principle and / or to increase the final melting point of the mixture ( in order to avoid an additional costly wrapping step) and / or to stabilize the emulsion.
  • oils which may be suitable, mention may be made of pharmaceutically acceptable edible oils, acetylated and / or distilled monoglycerides and diglycerides, triglycerides, waxes and their derivatives, long chain fatty alcohols (C ⁇ 4 -C 20 ) and their mixtures.
  • amphiphilic polymers mention will be made more particularly of polyalkylene glycols such as poioxamers and polyethylene glycols (PEG), polyvinyl pyrrolidone and other water-soluble vinyl derivatives.
  • the amount by total weight of oil, fat and / or amphiphilic polymer constitutes from 1 to 15% of the total mass.
  • a hydrophobic polymer intended to slow the release of the active ingredient, can also be added but in an amount less than the hydroxyethyl- and / or hydroxypropylcellulosic derivative.
  • particularly interesting hydrophobic polymers are ethylcellulose, certain acrylic derivatives such as Eudragit RS (registered trademark) and certain vinyl derivatives.
  • the preferred hydrophobic polymer will be ethylcellulose with a viscosity of less than 15 cps and its amount will be between 2 and 25% by weight of the total mass of the capsule.
  • the capsule of the invention once immersed in an aqueous and / or physiological medium at a temperature of 37 ° C., forms a gelled polymer matrix which allows the mixture of the other excipients and of the active principle to self-emulsify, thus allowing the control of the release of the drug in space (emulsion) and in time (prolonged effect).
  • this type of semi-solid matrix becomes, contrary to what has been published, practically insensitive to the hydrodynamic conditions of in vitro test.
  • the capsule formulations are preferably prepared in the following manner.
  • the surfactant is melted, in the presence, if necessary, of oils, fatty matter, polyalkylene glycol, glycerides, at a temperature defined in a thermostatically controlled system of pharmaceutical homogenization.
  • the polymers are then added with stirring and dispersed homogeneously.
  • the active ingredient is added and dispersed last.
  • the additions of polymers and active ingredient may have to be reversed. Any air trapped in the mass can be extracted by evacuating the preparation tank.
  • an appropriate commercial system for example gelatin capsules filled with Bosch GKF 1500L capsule filler).
  • the filled capsules are finally closed and / or sealed. After cooling, they are packaged in their commercial packaging.
  • the first example relating to a practically insoluble molecule (fenofibrate) in a simply emulsifiable system whose control of the release kinetics is carried out by the choice of the molecular weight of the hydrophilic polymer
  • the second example relates to a very poorly soluble molecule (hydroxyflutamide) in an auto-emulsifiable system whose release is controlled by the quantity of polymer and the choice of its molecular weight.
  • Example 1 Fenofibrate Fenofibrate is an extremely poorly soluble molecule (less than 5 mg / liter) in water, and whose suprabio-available formulation was the subject of patent application WO96 / 21 39.
  • a formula containing a very high molecular weight hydroxypropylcellulose (HPC) (Klucel XHF, registered trademark) was used. If we replace, in this formula, this HPC XHF by Klucel EF (registered trademark) of a weight much lower molecular, we obtain a significant slowing down of the speed of release of the active ingredient.
  • the dissolution test for this sparingly soluble molecule was carried out according to the monograph "Clofibrate capsules" from USP XXIII, pages 399-400 (apparatus II with blades, 100 rpm).
  • the dissolution method uses the rotary vane apparatus of the European Pharmacopoeia 2nd Ed. (V.5.4); the dissolution medium consists of 900 ml of a solution of sodium lauryl sulfate l OO mmolar, the pH of which has been brought down to 7.5 using sulfuric acid.
  • the temperature of the medium is 37 ° C ( ⁇ 0.5)
  • the speed of rotation of the pallets is 100 revolutions per minute and the test of a capsule is carried out six times.
  • the assay is carried out by spectrophotometry. Results
  • This example concerns the formulation in a capsule based on hydroxyflutamide, a sparingly soluble molecule ( ⁇ 1 part / 500 parts of H 2 O). It has been shown that the mixture of this active ingredient with Gelucire and Labrasol was capable of forming a hot microemulsion and the existence of a ternary diagram. The influence of the addition of Nisso type M HPC (hydroxypropylcellulose with an intermediate molecular weight of approximately 800,000) and the amount of this HPC on the dissolution kinetics of hydroxyflutamide has been studied (laboratory code SCH16 ). On the other hand, these formulations were compared with the same formulation containing either HPC XHF (high molecular weight) or a methylcellulose derivative (Methocel - registered trademark).
  • the in vitro dissolution test was carried out according to USP XXIII in a 4-liter vane apparatus (Erweka). The temperature was 37 ° C, the rotation speed 150 revolutions per minute (rpm) and the dissolution medium, 4000 ml of deionized water. The determination of the quantity of active ingredient dissolved was carried out by spectrophotometry at 273 nm.
  • the dissolution results are presented in FIG. 2 and show that the dissolution profile is modified and slowed down by the addition of hydroxypropylcellulose according to its molecular mass (ideally less than 1 million) and the amount added, and that the standard deviations obtained become lower, at the same time as the dissolution profile becomes linear with the largest amount of HPC M (Example 2B - 200 mg HPC).
  • the formula containing HPC XHF does not slow down the kinetics (Example 2D) and that containing Methocel (Example 2E) significantly accelerates it.

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Abstract

The invention concerns a matrix self-emusifiable semi-solid capsule with a matrix system having prolonged action, comprising an active principle, at least a surfactant capable of self-emulsification in an aqueous or physiological medium in the presence of the active principle, of HLB value ranging between 1 and 20 and at least one hydrophilic organic polymer for forming a hydrophilic matrix system non-ionizable in the presence of said liquid mixture, wherein the hydrophilic organic polymer is a hydroxyethylcellulose or hydroxypropylcellulose with molecular weight less than 1,000,000 and preferably between 80,000 and 800,000.

Description

"Capsules semi-solides autoémulsionnables matricielles à action prolongée." "Semi-solid self-emulsifying long-acting matrix capsules."
La présente invention est relative à des capsules semi- solides autoémulsionnables matricielles à action prolongée ou contrôlée 5 pour l'administration orale d'un médicament.The present invention relates to semi-solid self-emulsifying matrix capsules with long or controlled action for the oral administration of a medicament.
Ces capsules pharmaceutiques permettent en fait, d'une part, d'augmenter la biodisponibilité du médicament à administrer par un système pâteux autoémulsionnable contenant un agent tensioactif et, d'autre part, d'en prolonger la libération par la formation d'une matrice l o polymérique à hydrophilie et masse moléculaire contrôlée.These pharmaceutical capsules make it possible, on the one hand, to increase the bioavailability of the drug to be administered by a pasty self-emulsifying system containing a surfactant and, on the other hand, to prolong its release by the formation of a matrix. lo polymer with hydrophilicity and controlled molecular weight.
Ainsi que cela est bien connu, pour présenter une activité thérapeutique, il ne suffit pas qu'une molécule soit pharmacoiogiquement active mais elle doit également auparavant parvenir à son site d'action, à une vitesse et une quantité adéquates. Beaucoup de substancesAs is well known, to present a therapeutic activity, it is not enough for a molecule to be pharmacologically active but it must also beforehand reach its site of action, at an adequate speed and quantity. Lots of substances
15 pharmacoiogiquement actives présentent une résorption orale trop faible. La raison la plus fréquente est une trop faible solubilité dans l'eau. D'autres molécules, bien qu'hydrosolubles sont peu résorbées pour des raisons de sensibilité aux enzymes digestives, d'instabilité dans les fluides gastro-intestinaux et/ou d'ionisation trop importante aux pH15 pharmacologically active have too little oral resorption. The most common reason is too low water solubility. Other molecules, although water-soluble, are poorly resorbed for reasons of sensitivity to digestive enzymes, instability in gastrointestinal fluids and / or excessive ionization at pH
20 physiologiques. Les techniques actuellement les plus utilisées pour augmenter la résorption (biodisponibilité) des médicaments sont résumées dans le Tableau 1 ci-après. Tableau 120 physiological. The techniques currently most used to increase the resorption (bioavailability) of drugs are summarized in Table 1 below. Table 1
Figure imgf000004_0001
Figure imgf000004_0001
Pour ce qui est de la cinétique de résorption, il est fréquemment intéressant d'en contrôler la vitesse par un système galénique gérant la libération du principe actif; ce sont les formes à libération contrôlée dont les avantages sont bien connus et qui ont principalement une meilleure compliance due à une réduction du nombre de prises journalières, une diminution de l'incidence et/ou de l'intensité des effets secondaires, une meilleure sélectivité de l'action pharmacologique et un effet thérapeutique plus constant ou prolongé. Il est toutefois très difficile de développer des formes à action prolongée de molécules de principe actif peu solubles car dans ce cas, ce n'est plus la forme galénique mais le cristal de matière active qui gère la cinétique de libération. Les techniques actuellement utilisées pour réaliser des formes à action prolongée sont reprises dans le Tableau 2 ci-après.As regards the kinetics of resorption, it is frequently advantageous to control the speed thereof by a galenical system managing the release of the active principle; these are the controlled release forms whose advantages are well known and which mainly have better compliance due to a reduction in the number of daily doses, a decrease in the incidence and / or intensity of side effects, better selectivity pharmacological action and a more constant or prolonged therapeutic effect. However, it is very difficult to develop forms with prolonged action of poorly soluble active principle molecules because in this case, it is no longer the galenic form but the crystal of active material which manages the kinetics of release. The techniques currently used to produce long-acting forms are listed in Table 2 below.
Tableau 2Table 2
Figure imgf000005_0001
Figure imgf000005_0001
La technique moderne actuellement la plus étudiée pour augmenter la biodisponibilité est l'utilisation de systèmes micro- émulsionnés et/ou autoémulsionnables contenant le principe actif.The modern technique currently the most studied to increase bioavailability is the use of micro-emulsified and / or self-emulsifying systems containing the active principle.
Ces formes pharmaceutiques émulsionnables ont été abondamment illustrées dans la littérature mais celles-ci sont soit à libération trop rapide, c'est-à-dire à libération insuffisamment contrôlée soit donnent des pertes de biodisponibilité et des problèmes de variabilité(s) qui rendent les principes actifs non bioéquivalents aux formes ciblées, ou encore concernent des comprimés dont il est bien connu que la cinétique de libération du principe actif qu'ils contiennent est totalement différente de celle des capsules et la technique utilisée à cet effet donc non applicable. II y a également lieu de noter que les lois de cinétique qui régissent la libération des principes actifs dans les matrices hydrophiles classiques font état de ce qu'une augmentation du poids moléculaire du polymère ralentit la libération. C'est ainsi que dans cet ordre d'idée ont été conçues les capsules au fénofibrate à base de glycérides polyglycosylés et d'hydroxypropylcellulose de la demande de brevet PCT WO/96/21439. En fait, comme le prouve le dossier d'enregistrement et le bulletin d'analyse des matières premières de ces capsules, l'hydroxypropylcellulose utilisée est le Klucel XHF, c'est-à-dire une cellulose d'un poids moléculaire très élevé de l'ordre de 1.150.000. En fait, cette demande de brevet ne prévoyait pas que le choix du poids moléculaire de l'hydroxypropylcellulose pouvait moduler la cinétique de libération du principe actif.These emulsifiable pharmaceutical forms have been abundantly illustrated in the literature but these are either too rapid release, that is to say insufficiently controlled release or give losses of bioavailability and problems of variability (s) which make the active ingredients that are not bioequivalent to the targeted forms, or even concern tablets of which it is well known that the kinetics of release of the active ingredient that they contain is totally different from that of the capsules and the technique used for this purpose therefore not applicable. It should also be noted that the laws of kinetics which govern the release of the active ingredients in conventional hydrophilic matrices state that an increase in the molecular weight of the polymer slows down the release. Thus, in this context, the fenofibrate capsules based on polyglycosylated glycerides and hydroxypropylcellulose were designed from PCT patent application WO / 96/21439. In fact, as the registration dossier and the analysis bulletin for the raw materials of these capsules prove, the hydroxypropylcellulose used is Klucel XHF, that is to say a cellulose with a very high molecular weight. around 1,150,000. In fact, this patent application did not provide that the choice of molecular weight of hydroxypropylcellulose could modulate the kinetics of release of the active principle.
Bien que ces différentes approches aient permis d'augmenter la biodisponibilité de différents principes actifs, tous ces développement ont toutefois mené à des formes à action au moins aussi rapide que les formes conventionnelles. C'est ainsi que, par exemple, les tmax obtenus après administration de fénofibrate (demande de brevet WO96/21439) étaient de l'ordre de 5 heures, quelle que soit la forme administrée (capsule poudre, forme micronisée, forme semi-solide).Although these different approaches have made it possible to increase the bioavailability of different active ingredients, all of these developments have nonetheless led to forms with action at least as rapid as conventional forms. Thus, for example, the t max obtained after administration of fenofibrate (patent application WO96 / 21439) was of the order of 5 hours, whatever the form administered (powder capsule, micronized form, semi-form solid).
Certains auteurs ont également tenté de réaliser des formes semi-solides en gélules à action prolongée, en utilisant des excipients pâteux combinant point de fusion élevé et valeur HLB (balance hydrophile-lypophile) faible destinés à la voie orale. Leur stratégie consiste d'une manière générale en un savant mélange de Gélucire en se basant sur le principe que la libération augmente avec la valeur de HLB et diminue avec le point de fusion. Leur conclusion est que le point de fusion et la valeur HLB ont une importance fondamentale dans le contrôle de la libération du principe actif et que, par conséquent, les dérivés à point de fusion élevé et valeur HLB faible sont ceux qui conviennent le mieux à une libération prolongée. On notera également dans le même ordre d'idée la Thèse de Anne-Marie Mouricout, présentée et soutenue publiquement le 28 juin 1989 pour : "Mise en gélule d'un principe actif basique dans des excipients pâteux : les Gelucire®". On notera toutefois que la doctorante précise à la page 48 de sa thèse que "le Klucel HF (de haut poids moléculaire et de forte viscosité) améliore la tenue en gélule dans des proportions de 1 % à 2,5 %, mais ne modifie pas le profil de dissolution.", que "le Klucel EF (de bas poids moléculaire et donc de faible viscosité) à 10 % prolonge légèrement la libération du pπncipe actif et que "Donc, l'addition de Klucel améliore la conservation des mélanges pâteux en gélule mais influence peu la cinétique de dissolution."Some authors have also attempted to produce semi-solid forms in long-acting capsules, using pasty excipients combining high melting point and low HLB (hydrophilic-lypophilic balance) value intended for the oral route. Their strategy generally consists of a clever mixture of Gelucire based on the principle that the release increases with the value of HLB and decreases with the melting point. Their conclusion is that the melting point and the HLB value are of fundamental importance in controlling the release of the active ingredient and that therefore the derivatives with high melting point and low HLB value are those which best suited for extended release. We will also note in the same vein the Thesis of Anne-Marie Mouricout, presented and publicly supported on June 28, 1989 for: "Putting in gelatin capsules of a basic active principle in pasty excipients: Gelucire®". Note, however, that the doctoral student specifies on page 48 of her thesis that "Klucel HF (high molecular weight and high viscosity) improves the gel strength in proportions of 1% to 2.5%, but does not modify the dissolution profile. ", that" the Klucel EF (of low molecular weight and therefore of low viscosity) at 10% slightly prolongs the release of the active ingredient and that "Therefore, the addition of Klucel improves the preservation of the pasty mixtures in capsule but has little influence on the kinetics of dissolution. "
On peut donc conclure à un effet de ralentissement pour certains types de Gelucire mais dans ce cas les résultats de cinétique de dissolution du principe actif se sont toujours révélés sensibles aux conditions hydrodynamiques de tests comme la vitesse d'agitation avec les inconvénients qui en découlent, c'est-à-dire des dissolutions incomplètes et variables.We can therefore conclude that there is a slowing down effect for certain types of Gelucire, but in this case the results of kinetics of dissolution of the active principle have always been shown to be sensitive to hydrodynamic test conditions such as the stirring speed with the drawbacks which result therefrom, that is, incomplete and variable dissolutions.
La présente invention a pour but de remédier aux inconvé- nients précités en prévoyant une capsule semi-solide autoemulsionnable matricielle à action prolongée, comprenant un principe actif, au moins un agent tensioactif pouvant s'autoémulsionner dans un milieu liquide aqueux ou physiologique en présence du principe actif, d'une valeur HLB comprise entre 1 et 20 et au moins un polymère organique hydrophile permettant de former un réseau matriciel hydrophile non ionisable en présence dudit milieu liquide, dont la cinétique de libération est contrôlée par la conjonction des caractéristiques de compatibilité du polymère hydrophile et du mélange autoemulsionnable et qui présente peu ou pas de sensibilité aux conditions hydrodynamiques de test in vitro, dont la méthode de production est très simple, économique, aisée à insérer dans les lignes classiques de production pharmaceutique.The object of the present invention is to remedy the above-mentioned drawbacks by providing a semi-solid self-emulsifying matrix capsule with prolonged action, comprising an active principle, at least one surfactant capable of self-emulsifying in an aqueous or physiological liquid medium in the presence of the active ingredient, with an HLB value of between 1 and 20 and at least one hydrophilic organic polymer making it possible to form a non-ionizable hydrophilic matrix network in the presence of said liquid medium, the release kinetics of which is controlled by the combination of compatibility characteristics of hydrophilic polymer and of the self-emulsifiable mixture and which exhibits little or no sensitivity to the hydrodynamic test conditions in vitro, whose production method is very simple, economical, easy to insert into conventional pharmaceutical production lines.
A cet effet, suivant l'invention, le polymère organique hydrophile précité est une hydroxyethylcellulose ou hydroxypropylcellulose d'un poids moléculaire inférieur à 1.000.000 ou un mélange de deux ou plusieurs de ces substances.To this end, according to the invention, the abovementioned hydrophilic organic polymer is a hydroxyethylcellulose or hydroxypropylcellulose with a molecular weight of less than 1,000,000 or a mixture of two or more of these substances.
Avantageusement, l'hydroxyéthylcellulose ou hydroxypropylcellulose a un poids moléculaire compris entre 80.000 et 800.000 et elle est constituée de préférence par une hydroxypropylcellulose d'un poids moléculaire d'environ 80.000.Advantageously, the hydroxyethylcellulose or hydroxypropylcellulose has a molecular weight of between 80,000 and 800,000 and it is preferably constituted by a hydroxypropylcellulose with a molecular weight of about 80,000.
Suivant une forme de réalisation avantageuse de l'invention, l'hydroxypropylcellulose est connue sous la dénomination commerciale de Klucel EF ou est le type M de la société Nisso.According to an advantageous embodiment of the invention, hydroxypropylcellulose is known under the trade name of Klucel EF or is type M from the company Nisso.
Suivant une forme de réalisation particulièrement avantageuse, la quantité en poids d'hydroxyéthylcellulose et/ou d'hydroxypropylcellulose est de 1 à 40 % et de préférence de 5 à 25 % et l'agent tensioactif est choisi dans le groupe comprenant les éthers et esters de polyglycols, la lécithine et ses dérivés, les esters de saccharose, les dérivés partiellement estérifiés du glycérol et leurs mélanges.According to a particularly advantageous embodiment, the amount by weight of hydroxyethylcellulose and / or hydroxypropylcellulose is from 1 to 40% and preferably from 5 to 25% and the surfactant is chosen from the group comprising ethers and esters polyglycols, lecithin and its derivatives, sucrose esters, partially esterified glycerol derivatives and mixtures thereof.
Comme on vient de la préciser, les capsules à libération prolongée ou contrôlée de l'invention utilisées pour l'administration orale d'un médicament permettent non seulement d'en augmenter la biodisponibilité par un système pâteux autoemulsionnable contenant un agent tensioactif mais également d'en prolonger la libération par la formation d'une matrice hydroxyéthyl- et/ou hydroxypropylcellulosique à hydrophilie contrôlée.As has just been specified, the prolonged or controlled release capsules of the invention used for the oral administration of a medicament make it possible not only to increase its bioavailability by a pasty self-emulsifiable system containing a surfactant but also to prolong its release by the formation of a hydroxyethyl- and / or hydroxypropylcellulosic matrix with controlled hydrophilicity.
Les principes actifs utilisés seront d'une manière générale les substances dont la biodisponibilité orale des formes classiques est faible (égale ou inférieure à 75 %) et dont les paramètres biopharma- ceutiques sont tels qu'il est intéressant d'en développer une forme à action prolongée.The active ingredients used will generally be substances whose oral bioavailability of conventional forms is low (equal to or less than 75%) and whose biopharma- ceutiques are such that it is interesting to develop a long-acting form.
Parmi les médicaments et classes chimico-pharma- ceutiques pouvant être formulés suivant l'invention, on citera plus particulièrement les médicaments peu hydrosolubles comme le flutamide, la nifédipine, la théophylline, le naphthydrofuryl, l'acyciovir, les stéroïdes, les anti-inflammatoires non stéroïdiens, les anxiolytiques, les antimycosiques tels que le kétoconazole et les antihyperlipidémiants tels que le fénofibrate et les médicaments peu stables dans le milieu gastro- intestinal comme les hormones peptidiques, les dérivés d'acides aminés et les peptides tels que le captopril, la cyclosporine et le taxol. Les capsules contiendront une quantité de médicament suffisante pour être pharmacoiogiquement actives ainsi qu'un excipient contenant un agent tensioactif ou un mélange d'agents tensioactifs pouvant s'autoémul- sionner dans l'eau ou les liquides physiologiques en présence du principe actif.Among the drugs and chemico-pharmaceutical classes which can be formulated according to the invention, there will be mentioned more particularly the poorly water-soluble drugs such as flutamide, nifedipine, theophylline, naphthydrofuryl, acycovir, steroids, anti-inflammatories nonsteroidal drugs, anxiolytics, antimycotics such as ketoconazole and antihyperlipidemic drugs such as fenofibrate and unstable drugs in the gastrointestinal environment such as peptide hormones, amino acid derivatives and peptides such as captopril, cyclosporine and taxol. The capsules will contain an amount of drug sufficient to be pharmacologically active as well as an excipient containing a surfactant or a mixture of surfactants capable of self-emulsifying in water or physiological fluids in the presence of the active ingredient.
Parmi les agents tensioactifs utilisables, ceux-ci auront une valeur HLB comprise entre 1 et 20 et on citera, à cet égard, les éthers et esters de polyglycols, les ampholytes tels que la lécithine et ses dérivés, les esters de saccharose, les dérivés partiellement estérifiés du glycerol et leurs mélanges. S'avèrent particulièrement avantageux comme agents tensioactifs les glycérides polyglycolysés présentant une valeur HLB comprise entre 6 et 15 comme les Labrafils (marque déposée), Labrasol (marque déposée) et Gélucires (marque déposée) et un point de fusion inférieur à 60°C, leur quantité étant preferentiellement comprise entre 10 et 80 % de la masse capsulaire.Among the surfactants that can be used, these will have an HLB value of between 1 and 20 and, in this regard, ethers and esters of polyglycols, ampholytes such as lecithin and its derivatives, sucrose esters, derivatives will be mentioned. partially esterified from glycerol and mixtures thereof. The polyglycolysed glycerides having an HLB value of between 6 and 15, such as Labrafils (registered trademark), Labrasol (registered trademark) and Gélucires (registered trademark) and a melting point below 60 ° C., are particularly advantageous as surfactants. their amount being preferably between 10 and 80% of the capsular mass.
Les capsules contiendront également un polymère hydrophile organique du type hydroxyethylcellulose ou hydroxypropylcellulose, dispersé et partiellement solvaté dans le mélange des autres excipients, non ionisable dans les valeurs de pH physiologiques. Cette hydroxyéthylcellulose ou hydroxypropylcellulose, outre son rôle de stabilisant de la forme pharmaceutique, devra être en quantité suffisante pour former un réseau matriciel hydrophile, dès que la capsule est plongée dans un milieu aqueux ou physiologique et que l'eau a dissous la gélatine et/ou le polymère cellulosique de l'enveloppe de celle-ci.The capsules will also contain an organic hydrophilic polymer of the hydroxyethylcellulose or hydroxypropylcellulose type, dispersed and partially solvated in the mixture of the other excipients, non-ionizable in physiological pH values. This hydroxyethylcellulose or hydroxypropylcellulose, in addition to its role as stabilizer of the pharmaceutical form, must be in sufficient quantity to form a hydrophilic matrix network, as soon as the capsule is immersed in an aqueous or physiological medium and that the water has dissolved the gelatin and / or the cellulosic polymer of the envelope thereof.
On notera à cet égard que le terme "capsules" dans le cadre de la présente invention correspond à la définition donnée par la Pharmacopée Européenne - 1997, pages 1859 et 1860 et que par conséquent ce terme englobe les différentes catégories de capsules distinguables, à savoir les capsules à enveloppe dure ou gélules, les capsules à enveloppe molle, les capsules gastro-résistantes et les capsules à libération modifiée.It will be noted in this regard that the term "capsules" in the context of the present invention corresponds to the definition given by the European Pharmacopoeia - 1997, pages 1859 and 1860 and that therefore this term encompasses the different categories of distinguishable capsules, namely hard-shell capsules or capsules, soft-shell capsules, gastro-resistant capsules and modified release capsules.
On utilisera les hydroxyéthylcelluloses (HEC) et hydroxy- propylcelluloses (HPC) d'un poids moléculaire inférieur à 1.000.000 et de préférence d'un poids moléculaire compris entre 80.000 et 800.000. Conviennent particulièrement bien l'hydroxypropylcellulose d'un poids moléculaire d'environ 80.000 connue sous la dénomination commerciale de Klucel EF et l'hydroxypropylcellulose d'un poids moléculaire d'environ 800.000 correspondant au type M de la société Nisso. Ces dérivés hydroxycellulosiques seront utilisés seuls ou en mélange de deux ou plusieurs de ces substances en des quantités représentant entre 1 et 40 % et de préférence entre 5 et 25 % en poids de la masse capsulaire.Hydroxyethylcelluloses (HEC) and hydroxypropylcelluloses (HPC) with a molecular weight of less than 1,000,000 and preferably with a molecular weight of between 80,000 and 800,000 will be used. Particularly suitable are hydroxypropylcellulose with a molecular weight of approximately 80,000 known under the trade name of Klucel EF and hydroxypropylcellulose with a molecular weight of approximately 800,000 corresponding to type M from the company Nisso. These hydroxycellulosic derivatives will be used alone or as a mixture of two or more of these substances in amounts representing between 1 and 40% and preferably between 5 and 25% by weight of the capsular mass.
Les capsules peuvent également contenir, suivant l'invention, une huile, une matière grasse ou un polymère amphiphile hydrosoluble ou un mélange de ceux-ci, substances destinées à solubiliser le principe actif et/ou à augmenter le point de fusion final du mélange (afin d'éviter une étape supplémentaire coûteuse de banderolage) et/ou à stabiliser l'émulsion. Parmi les huiles pouvant convenir, on citera les huiles alimentaires pharmaceutiquement acceptables, les monoglycérides et diglycérides acétylés et/ou distillés, les triglycérides, les cires et leurs dérivés, les alcools gras à longue chaîne (Cι4-C20) et leurs mélanges. Parmi les polymères amphiphiles, on citera plus particulièrement les polyalkylène glycols tels que les poioxamères et les polyéthylène glycols (PEG), la polyvinyl pyrrolidone et autres dérivés vinyliques hydrosolubles. La quantité en poids total d'huile, de matière grasse et/ou de polymère amphiphile constitue de 1 à 15 % de la masse totale.According to the invention, the capsules may also contain an oil, a fatty substance or a water-soluble amphiphilic polymer or a mixture of these, substances intended to dissolve the active principle and / or to increase the final melting point of the mixture ( in order to avoid an additional costly wrapping step) and / or to stabilize the emulsion. Among the oils which may be suitable, mention may be made of pharmaceutically acceptable edible oils, acetylated and / or distilled monoglycerides and diglycerides, triglycerides, waxes and their derivatives, long chain fatty alcohols (Cι 4 -C 20 ) and their mixtures. Among the amphiphilic polymers, mention will be made more particularly of polyalkylene glycols such as poioxamers and polyethylene glycols (PEG), polyvinyl pyrrolidone and other water-soluble vinyl derivatives. The amount by total weight of oil, fat and / or amphiphilic polymer constitutes from 1 to 15% of the total mass.
Dans le cas de principes actifs très hydrosolubles, un polymère hydrophobe, destiné à ralentir la libération du principe actif, peut également être ajouté mais en quantité inférieure au dérivé hydroxyéthyl- et/ou hydroxypropylcellulosique. On citera comme polymères hydrophobes particulièrement intéressants l'éthylcellulose, certains dérivés acryliques comme l'Eudragit RS (marque déposée) et certains dérivés vinyliques. Le polymère hydrophobe préféré sera l'éthylcellulose de viscosité inférieure à 15 cps et sa quantité sera comprise entre 2 et 25 % en poids de la masse totale de la capsule.In the case of highly water-soluble active ingredients, a hydrophobic polymer, intended to slow the release of the active ingredient, can also be added but in an amount less than the hydroxyethyl- and / or hydroxypropylcellulosic derivative. Examples of particularly interesting hydrophobic polymers are ethylcellulose, certain acrylic derivatives such as Eudragit RS (registered trademark) and certain vinyl derivatives. The preferred hydrophobic polymer will be ethylcellulose with a viscosity of less than 15 cps and its amount will be between 2 and 25% by weight of the total mass of the capsule.
Comme on l'a déjà mentionné, la capsule de l'invention, une fois plongée dans un milieu aqueux et/ou physiologique à une température de 37°C, forme une matrice polymérique gélifiée qui permet au mélange des autres excipients et du principe actif de s'autoémul- sionner, permettant ainsi le contrôle de la libération du médicament dans l'espace (émulsion) et le temps (effet prolongé). D'autre part, on a constaté que ce type de matrice semi-solide devenait, contrairement à ce qui a été publié, pratiquement insensible aux conditions hydrodynami- ques de test in vitro.As already mentioned, the capsule of the invention, once immersed in an aqueous and / or physiological medium at a temperature of 37 ° C., forms a gelled polymer matrix which allows the mixture of the other excipients and of the active principle to self-emulsify, thus allowing the control of the release of the drug in space (emulsion) and in time (prolonged effect). On the other hand, it has been found that this type of semi-solid matrix becomes, contrary to what has been published, practically insensitive to the hydrodynamic conditions of in vitro test.
Suivant l'invention les formulations en capsules sont preferentiellement préparées de la façon suivante. L'agent tensioactif est fondu, en présence, si nécessaire, des huile, matière grasse, polyalkylène glycol, glycérides, à une température définie dans un système thermostatise d'homogénéisation pharmaceutique. Le ou les polymères sont ensuite ajoutés sous agitation et dispersés de façon homogène. Le principe actif est ajouté et dispersé en dernier lieu. Selon les cas, on peut devoir inverser les additions de polymères et de principe actif. L'air éventuellement emprisonné dans la masse peut être extrait par mise sous vide de la cuve de préparation. En continuant d'agiter de façon à maintenir le mélange homogène, ce dernier est réparti en capsules à l'aide d'un système commercial approprié (par exemple capsules en gélatine remplies par géluleuse Bosch GKF 1500L). Les capsules remplies sont enfin fermées et/ou scellées. Après refroidissement, elles sont conditionnées dans leur emballage commercial.According to the invention, the capsule formulations are preferably prepared in the following manner. The surfactant is melted, in the presence, if necessary, of oils, fatty matter, polyalkylene glycol, glycerides, at a temperature defined in a thermostatically controlled system of pharmaceutical homogenization. The polymers are then added with stirring and dispersed homogeneously. The active ingredient is added and dispersed last. Depending on the case, the additions of polymers and active ingredient may have to be reversed. Any air trapped in the mass can be extracted by evacuating the preparation tank. By continuing to agitate so as to maintain the homogeneous mixture, the latter is distributed into capsules using an appropriate commercial system (for example gelatin capsules filled with Bosch GKF 1500L capsule filler). The filled capsules are finally closed and / or sealed. After cooling, they are packaged in their commercial packaging.
On donne ci-après quelques exemples non limitatifs couvrant différentes formes de réalisation de la présente invention, le premier exemple se rapportant à une molécule pratiquement insoluble (le fénofibrate) dans un système simplement emulsionnable dont le contrôle de la cinétique de libération est effectué par le choix du poids moléculaire du polymère hydrophile, et le second exemple se rapportant à une molécule très peu soluble (l'hydroxyflutamide) dans un système automicroémulsionnable dont la libération est contrôlée par la quantité de polymère et le choix de son poids moléculaire.Some nonlimiting examples are given below covering various embodiments of the present invention, the first example relating to a practically insoluble molecule (fenofibrate) in a simply emulsifiable system whose control of the release kinetics is carried out by the choice of the molecular weight of the hydrophilic polymer, and the second example relates to a very poorly soluble molecule (hydroxyflutamide) in an auto-emulsifiable system whose release is controlled by the quantity of polymer and the choice of its molecular weight.
Exemple 1 Fénofibrate Le fénofibrate est une molécule extrêmement peu soluble (moins de 5 mg/litre) dans l'eau, et dont la formulation suprabio- disponible a fait l'objet de la demande de brevet WO96/21 39. Comme on le sait, lors de ce développement, une formule contenant une hydroxypropylcellulose (HPC) de très haut poids moléculaire (Klucel XHF, marque déposée) a été utilisée. Si on remplace, dans cette formule, cette HPC XHF par du Klucel EF (marque déposée) d'un poids moléculaire beaucoup plus faible, on obtient un ralentissement sensible de la vitesse de libération du principe actif.Example 1 Fenofibrate Fenofibrate is an extremely poorly soluble molecule (less than 5 mg / liter) in water, and whose suprabio-available formulation was the subject of patent application WO96 / 21 39. As is known , during this development, a formula containing a very high molecular weight hydroxypropylcellulose (HPC) (Klucel XHF, registered trademark) was used. If we replace, in this formula, this HPC XHF by Klucel EF (registered trademark) of a weight much lower molecular, we obtain a significant slowing down of the speed of release of the active ingredient.
On notera que ce phénomène est contraire aux lois des matrices hydrophiles classiques pour lesquelles une augmentation de la masse moléculaire du polymère ralentit la cinétique de libération [voir à cet effet P. Buri et E. Doelker, Pharm. Acta Helv. (1980), volume 55, pages 189-196 et I. Katzhendier et coll., J. Pharm. Sci., volume 86 (1997), pages 110-115].It will be noted that this phenomenon is contrary to the laws of conventional hydrophilic matrices for which an increase in the molecular mass of the polymer slows down the kinetics of release [see for this purpose P. Buri and E. Doelker, Pharm. Acta Helv. (1980), volume 55, pages 189-196 and I. Katzhendier et al., J. Pharm. Sci., Volume 86 (1997), pages 110-115].
Les formules unitaires en capsules testées sont reprises dans le Tableau 3.The unit formulas in capsules tested are listed in Table 3.
Tableau 3Table 3
Figure imgf000013_0001
Figure imgf000013_0001
Exemple 2 de la demande de brevet WO96/21439 ** Les deux chiffres suivant le mot Gelucire en caractérisent le point de fusion (°C) pour le premier, et la HLB pour le second. *** Masse moléculaire : - Klucel XHF ≈ 1.150.000Example 2 of patent application WO96 / 21439 ** The two digits following the word Gelucire characterize the melting point (° C) for the first, and the HLB for the second. *** Molecular mass: - Klucel XHF ≈ 1,150,000
- Klucel EF ≈ 80.000. Condition de test in vitro :- Klucel EF ≈ 80,000. In vitro test condition:
Le test de dissolution de cette molécule peu soluble a été réalisé selon la monographie "Clofibrate capsules" de l'USP XXIII, pages 399-400 (appareil II à pales, 100 tpm). En résumé, la méthode de dissolution utilise l'appareil à palettes tournantes de la Pharmacopée Européenne 2ème Ed. (V.5.4); le milieu de dissolution est constitué de 900 ml d'une solution de lauryl- sulfate sodique l OO mmolaire dont le pH a été ramené à 7,5 à l'aide d'acide sulfurique. La température du milieu est de 37°C (±0,5), la vitesse de rotation des palettes est de 100 tours par minute et l'essai d'une gélule est réalisé à six reprises. Le dosage est effectué par spectrophotométrie. RésultatsThe dissolution test for this sparingly soluble molecule was carried out according to the monograph "Clofibrate capsules" from USP XXIII, pages 399-400 (apparatus II with blades, 100 rpm). In summary, the dissolution method uses the rotary vane apparatus of the European Pharmacopoeia 2nd Ed. (V.5.4); the dissolution medium consists of 900 ml of a solution of sodium lauryl sulfate l OO mmolar, the pH of which has been brought down to 7.5 using sulfuric acid. The temperature of the medium is 37 ° C (± 0.5), the speed of rotation of the pallets is 100 revolutions per minute and the test of a capsule is carried out six times. The assay is carried out by spectrophotometry. Results
Les courbes de dissolution sont reprises à la figure 1 et montrent l'influence du poids moléculaire sur le ralentissement de la courbe de dissolution. D'autre part, la cinétique de dissolution lors de l'ajout d'éthylcellulose montre une dissolution incomplète et très variable (les coefficients de variation sont >50 % alors qu'ils sont nettement inférieurs à 20 % avec l'HPC). Les résultats chiffrés sont donnés dans le Tableau 4.The dissolution curves are shown in Figure 1 and show the influence of molecular weight on the slowing down of the dissolution curve. On the other hand, the kinetics of dissolution during the addition of ethylcellulose shows an incomplete and very variable dissolution (the coefficients of variation are> 50% while they are clearly less than 20% with HPC). The quantified results are given in Table 4.
Tableau 4Table 4
Figure imgf000014_0001
Exemple 2 Hvdroxyflutamide
Figure imgf000014_0001
EXAMPLE 2 Hvdroxyflutamide
Cet exemple concerne la formulation en capsule à base d'hydroxyflutamide, molécule peu soluble (± 1 partie/500 parties de H2O). Il a été montré que le mélange de ce principe actif avec le Gelucire et le Labrasol était capable de former une microémulsion à chaud et l'existence d'un diagramme ternaire. On a étudié l'influence de l'ajout d'HPC du type M de Nisso (hydroxypropylcellulose de poids moléculaire intermédiaire d'environ 800.000) et de la quantité de cette HPC sur la cinétique de dissolution de l'hydroxyflutamide (code du Laboratoire SCH16). On a d'autre part comparé ces formulations à une même formulation contenant soit de l'HPC XHF (à haut poids moléculaire) soit à un dérivé de méthylcellulose (Méthocel - marque déposée).This example concerns the formulation in a capsule based on hydroxyflutamide, a sparingly soluble molecule (± 1 part / 500 parts of H 2 O). It has been shown that the mixture of this active ingredient with Gelucire and Labrasol was capable of forming a hot microemulsion and the existence of a ternary diagram. The influence of the addition of Nisso type M HPC (hydroxypropylcellulose with an intermediate molecular weight of approximately 800,000) and the amount of this HPC on the dissolution kinetics of hydroxyflutamide has been studied (laboratory code SCH16 ). On the other hand, these formulations were compared with the same formulation containing either HPC XHF (high molecular weight) or a methylcellulose derivative (Methocel - registered trademark).
Les formules en capsules testées sont données dans le Tableau 5.The capsule formulas tested are given in Table 5.
Tableau 5Table 5
Figure imgf000015_0001
Figure imgf000015_0001
® = Marque déposée® = Registered trademark
Le test de dissolution in vitro a été réalisé selon l'USP XXIII dans un appareil à palettes de 4 litres (Erweka). La température était de 37°C, la vitesse de rotation de 150 tours par minute (tpm) et le milieu de dissolution, 4000 ml d'eau désionisée. Le dosage de la quantité de principe actif dissous a été réalisé par spectrophotométrie à 273 nm. Les résultats de dissolution sont présentés à la figure 2 et montrent que le profil de dissolution est modifié et ralenti par l'ajout d'hydroxypropylcellulose en fonction de sa masse moléculaire (idéalement inférieure à 1 million) et de la quantité ajoutée, et que les déviations standards obtenues deviennent plus faibles, en même temps que le profil de dissolution se linéarise avec la quantité la plus importante d'HPC M (Exemple 2B - 200 mg HPC). La formule contenant de l'HPC XHF ne ralentit par la cinétique (Exemple 2D) et celle contenant du Méthocel (Exemple 2E) l'accélère nettement.The in vitro dissolution test was carried out according to USP XXIII in a 4-liter vane apparatus (Erweka). The temperature was 37 ° C, the rotation speed 150 revolutions per minute (rpm) and the dissolution medium, 4000 ml of deionized water. The determination of the quantity of active ingredient dissolved was carried out by spectrophotometry at 273 nm. The dissolution results are presented in FIG. 2 and show that the dissolution profile is modified and slowed down by the addition of hydroxypropylcellulose according to its molecular mass (ideally less than 1 million) and the amount added, and that the standard deviations obtained become lower, at the same time as the dissolution profile becomes linear with the largest amount of HPC M (Example 2B - 200 mg HPC). The formula containing HPC XHF does not slow down the kinetics (Example 2D) and that containing Methocel (Example 2E) significantly accelerates it.
Le même test de dissolution a été réalisé dans des conditions hydrodynamiques d'agitation variables, à savoir 50, 100 etThe same dissolution test was carried out under variable hydrodynamic conditions of agitation, namely 50, 100 and
150 tpm pour le lot "optimal" contenant 200 mg d'hydroxypropylcellulose150 rpm for the "optimal" batch containing 200 mg of hydroxypropylcellulose
(12L96 Exemple 2B). Les résultats montrent que la vitesse d'agitation n'influence pas la cinétique de dissolution de l'hydroxyflutamide (figure(12L96 Example 2B). The results show that the stirring speed does not influence the dissolution kinetics of the hydroxyflutamide (figure
3). Exemple 33). Example 3
ThéophyllineTheophylline
Cet exemple concerne une molécule assez hydrosoluble (1 partie pour 70 parties d'eau), la théophyllineThis example concerns a fairly water-soluble molecule (1 part for 70 parts of water), theophylline
Il a été montré qu'une formulation de théophylline dans du Gelucire 50/13 ralentissait bien la cinétique de dissolution du principe actif mais que ce ralentissement n'était pas stable dû à un réarrangement polymorphique de la base grasse tensioactive. (R. Duddu et coll., Bull. Tech. Gatt. N° 89 - 1996, pages 53-59).It has been shown that a formulation of theophylline in Gelucire 50/13 slowed down the kinetics of dissolution of the active principle but that this slowdown was not stable due to a polymorphic rearrangement of the fatty surfactant base. (R. Duddu et al., Bull. Tech. Gatt. N ° 89 - 1996, pages 53-59).
Les formules en capsules testées sont reprises dans le Tableau 6. Tableau 6The capsule formulas tested are listed in Table 6. Table 6
Figure imgf000017_0001
Figure imgf000017_0001
* Formule et courbe de la publication de P. Duddu. ® Marque déposée.* Formula and curve of the publication of P. Duddu. ® Registered trademark.
Le test de dissolution a été réalisé de la façon suivante (selon méthode de Duddu) : Appareil USP XXIII type 2 à palettes (= Ph. Eur. V .5.4)The dissolution test was carried out as follows (according to Duddu method): USP XXIII type 2 apparatus with paddles (= Ph. Eur. V .5.4)
- Milieu de dissolution : 1000 ml d'eau désionisée (Milli Q)- Dissolution medium: 1000 ml of deionized water (Milli Q)
- Température : 37°C- Temperature: 37 ° C
- Vitesse d'agitation : 50 tours par minute- Stirring speed: 50 rpm
- Dosage : Spectrophotometrie (Hewlett Packard 8452) à 272 nm.- Assay: Spectrophotometry (Hewlett Packard 8452) at 272 nm.
Les résultats sont présentés à la figure 4 et dans le Tableau 7 et montrent que l'HPC contrôle la dissolution de la théophylline et améliore nettement la stabilité de celle-ci. The results are presented in FIG. 4 and in Table 7 and show that the HPC controls the dissolution of theophylline and clearly improves its stability.
Tableau 7Table 7
Dissolution de la théophyllineDissolution of theophylline
Figure imgf000018_0001
Figure imgf000018_0001
Il est bien entendu que la présente invention n'est en aucune façon limitée aux formes de réalisation décrites et que bien des modifications peuvent être envisagées sans sortir du cadre du présent brevet. It is understood that the present invention is in no way limited to the embodiments described and that many modifications can be envisaged without departing from the scope of this patent.

Claims

REVENDICATIONS
1. Capsule semi-solide autoemulsionnable matricielle à action prolongée, comprenant un principe actif, au moins un agent tensioactif pouvant s'autoémulsionner dans un milieu liquide aqueux ou physiologique en présence du principe actif, d'une valeur HLB comprise entre 1 et 20 et au moins un polymère organique hydrophile permettant de former un réseau matriciel hydrophile non ionisable en présence dudit milieu liquide, caractérisé en ce que le polymère organique hydrophile est une hydroxyethylcellulose ou hydroxypropylcellulose d'un poids moléculaire inférieur à 1.000.000 ou un mélange de deux ou plusieurs de ces substances.1. Semi-solid self-emulsifying matrix matrix with long-acting action, comprising an active principle, at least one surfactant capable of self-emulsifying in an aqueous or physiological liquid medium in the presence of the active principle, with an HLB value of between 1 and 20 and at least one hydrophilic organic polymer making it possible to form a non-ionizable hydrophilic matrix network in the presence of said liquid medium, characterized in that the hydrophilic organic polymer is a hydroxyethylcellulose or hydroxypropylcellulose with a molecular weight of less than 1,000,000 or a mixture of two or many of these substances.
2. Capsule suivant la revendication 2, caractérisée en ce que l'hydroxyéthylcellulose ou hydroxypropylcellulose a un poids moléculaire compris entre 80.000 et 800.000. 2. Capsule according to claim 2, characterized in that the hydroxyethylcellulose or hydroxypropylcellulose has a molecular weight between 80,000 and 800,000.
3. Capsule suivant la revendication 2, caractérisée en ce qu'elle comprend une hydroxypropylcellulose d'un poids moléculaire d'environ 80.000.3. Capsule according to claim 2, characterized in that it comprises a hydroxypropylcellulose with a molecular weight of about 80,000.
4. Capsule suivant la revendication 3, caractérisée en ce que l'hydroxypropylcellulose est connue sous la dénomination commerciale de Klucel EF.4. Capsule according to claim 3, characterized in that the hydroxypropylcellulose is known under the trade name of Klucel EF.
5. Capsule suivant la revendication 2, caractérisée en ce qu'elle comprend une hydroxypropylcellulose d'un poids moléculaire d'environ 800.000.5. Capsule according to claim 2, characterized in that it comprises a hydroxypropylcellulose with a molecular weight of about 800,000.
6. Capsule suivant la revendication 5, caractérise en ce que l'hydroxypropylcellulose est le type M de la société Nisso.6. Capsule according to claim 5, characterized in that the hydroxypropylcellulose is type M from the company Nisso.
7. Capsule suivant l'une quelconque des revendications 1 à 6, caractérisée en ce qu'elle contient de 1 à 40 % en poids d'hydroxyéthylcellulose et/ou d'hydroxypropylcellulose. 7. Capsule according to any one of claims 1 to 6, characterized in that it contains from 1 to 40% by weight of hydroxyethylcellulose and / or hydroxypropylcellulose.
8. Capsule suivant la revendication 7, caractérisée en ce que la quantité en poids d'hydroxyéthylcellulose et/ou d'hydroxypropylcellulose est de 5 à 25 %.8. Capsule according to claim 7, characterized in that the amount by weight of hydroxyethylcellulose and / or hydroxypropylcellulose is 5 to 25%.
9. Capsule suivant l'une quelconque des revendications 1 à 8, caractérisée en ce que l'agent tensioactif est choisi dans le groupe comprenant les éthers et esters de polyglycols, la lécithine et ses dérivés, les esters de saccharose, les dérivés partiellement estérifiés du glycerol et leurs mélanges.9. Capsule according to any one of claims 1 to 8, characterized in that the surfactant is chosen from the group comprising ethers and esters of polyglycols, lecithin and its derivatives, sucrose esters, partially esterified derivatives glycerol and mixtures thereof.
10. Capsule suivant la revendication 9, caractérisée en ce qu'elle contient, comme dérivé partiellement estérifié du glycerol, un glycéride polyglycolysé présentant une valeur HLB comprise entre 6 et 15.10. Capsule according to claim 9, characterized in that it contains, as a partially esterified derivative of glycerol, a polyglycolysed glyceride having an HLB value of between 6 and 15.
11. Capsule suivant l'une ou l'autre des revendications 10 et 10, caractérisée en ce qu'elle contient de 1 à 80 % en poids d'agent tensioactif.11. Capsule according to either of claims 10 and 10, characterized in that it contains from 1 to 80% by weight of surfactant.
12. Capsule suivant l'une quelconque des revendications 1 à 11 , caractérisée en ce qu'elle comprend de plus au moins une substance choisie parmi une huile, une matière grasse, un polymère amphiphile hydrosoluble et leurs mélanges. 12. Capsule according to any one of claims 1 to 11, characterized in that it further comprises at least one substance chosen from an oil, a fatty substance, a water-soluble amphiphilic polymer and their mixtures.
13. Capsule suivant la revendication 12, caractérisée en ce que l'huile est choisie dans le groupe comprenant les huiles alimentaires pharmaceutiquement acceptables, les monoglycérides et diglycérides acétylés et/ou distillés, les triglycérides, les cires et leurs dérivés, les alcools gras à longue chaîne (C14-C20) et leurs mélanges. 13. Capsule according to claim 12, characterized in that the oil is chosen from the group comprising pharmaceutically acceptable edible oils, acetylated and / or distilled monoglycerides and diglycerides, triglycerides, waxes and their derivatives, fatty alcohols long chain (C 14 -C 20 ) and mixtures thereof.
14. Capsule suivant la revendication 12, caractérisée en ce que le polymère amphiphile est choisi dans le groupe comprenant les polyalkylène glycols, la polyvinylpyrrolidone et les dérivés vinyliques hydrosolubles. 14. Capsule according to claim 12, characterized in that the amphiphilic polymer is chosen from the group comprising polyalkylene glycols, polyvinylpyrrolidone and water-soluble vinyl derivatives.
15. Capsule suivant l'une quelconque des revendications 12 à 14, caractérisée en ce que la quantité en poids totale d'huile, de matière grasse et/ou de polymère amphiphile constitue de 1 à 15 %.15. Capsule according to any one of claims 12 to 14, characterized in that the amount by total weight of oil, fat and / or amphiphilic polymer constitutes from 1 to 15%.
16. Capsule suivant l'une quelconque des revendications 1 à 15, caractérisée en ce que le principe actif est peu hydrosoluble et est choisi dans le groupe comprenant le flutamide, la nifédipine, la théophylline, le naphthydrofuryl, l'acyclovir, les stéroïdes, les antiinflammatoires non stéroïdiens, les anxiolytiques, les antimycosiques tels que le kétoconazole et les antihyperlipidémiants tels que le fénofibrate. 16. Capsule according to any one of claims 1 to 15, characterized in that the active principle is not very water-soluble and is chosen from the group comprising flutamide, nifedipine, theophylline, naphthydrofuryl, acyclovir, steroids, non-steroidal anti-inflammatory drugs, anxiolytics, antimycotics such as ketoconazole and antihyperlipidemic agents such as fenofibrate.
17. Capsule suivant l'une quelconque des revendications 1 à 15, caractérisée en ce que le principe actif est peu stable dans le milieu gastro-intestinal et est choisi dans le groupe comprenant les hormones peptidiques, les dérivés d'acides aminés et les peptides tels que le captopril, la cyclosporine et le taxol. 17. Capsule according to any one of claims 1 to 15, characterized in that the active principle is not very stable in the gastrointestinal environment and is chosen from the group comprising peptide hormones, amino acid derivatives and peptides such as captopril, cyclosporine and taxol.
18. Capsule suivant l'une quelconque des revendications 7 à 15, caractérisée en ce que le principe actif est très hydrosoluble et elle comprend en outre un polymère hydrophobe en une quantité inférieure à la quantité d'hydroxyéthylcellullose et/ou d'hydroxypropylcellulose.18. Capsule according to any one of claims 7 to 15, characterized in that the active principle is very water-soluble and it further comprises a hydrophobic polymer in an amount less than the amount of hydroxyethylcellullose and / or hydroxypropylcellulose.
19. Capsule suivant la revendication 18, caractérisée en ce que le polymère hydrophobe est choisi dans le groupe comprenant l'éthylcellulose, les dérivés acryliques et les dérivés vinyliques.19. Capsule according to claim 18, characterized in that the hydrophobic polymer is chosen from the group comprising ethylcellulose, acrylic derivatives and vinyl derivatives.
20. Capsule suivant l'une ou l'autre des revendications 18 et 19, caractérisée en ce que la quantité en poids de polymère hydrophobe est comprise entre 2 et 25 %. 20. Capsule according to either of claims 18 and 19, characterized in that the amount by weight of hydrophobic polymer is between 2 and 25%.
PCT/BE1998/000132 1997-09-11 1998-09-08 Self-emulsifiable semi-solid capsules with matrix system having prolonged action WO1999012528A1 (en)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2782006A1 (en) * 1998-08-07 2000-02-11 Gattefosse Ets Sa SUSTAINED RELEASE COMPOSITION CAPABLE OF FORMING MICRO-EMULSION
WO2000057918A2 (en) * 1999-03-31 2000-10-05 Abbott Laboratories Novel formulations comprising lipid-regulating agents
FR2803203A1 (en) * 1999-12-31 2001-07-06 Fournier Ind & Sante NEW GALENIC FORMULATIONS OF FENOFIBRATE
WO2003013500A1 (en) * 2001-08-07 2003-02-20 Laboratoires Smb Sa Improved pharmaceutical composition containing a ppar alpha agent and a process for preparing it
WO2003013501A1 (en) * 2001-08-07 2003-02-20 Laboratoires Smb Sa Improved pharmaceutical composition containing a ppar alpha agent and a process for preparing it
WO2005009409A2 (en) * 2003-07-17 2005-02-03 Banner Pharmacaps, Inc. Controlled release preparations
EP1829541A1 (en) * 2002-12-17 2007-09-05 Abbott GmbH & Co. KG Formulation comprising fenofibric acid or a physiologically acceptable salt thereof
EP1951208A2 (en) * 2005-10-26 2008-08-06 Banner Pharmacaps Inc. Lipophilic vehicle-based dual controlled release matrix system as capsule fill
EP1959935A2 (en) * 2005-10-26 2008-08-27 Banner Pharmacaps Inc. Hydrophilic vehicle-based dual controlled release matrix system as capsule fill
CN108186593A (en) * 2018-02-06 2018-06-22 南京百思福医药科技有限公司 A kind of Nifedipine sustained release tablets and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0222614A2 (en) * 1985-11-12 1987-05-20 Eli Lilly And Company Orally administerable sustained release pharmaceutical formulations
WO1996021439A1 (en) * 1995-01-10 1996-07-18 Galephar P.R. Inc. Pharmaceutical composition containing fenofibrate and polyglycolized glycerides
EP0806202A1 (en) * 1996-05-06 1997-11-12 Adir Et Compagnie Controlled release pharmaceutical composition containing stabilized lipophilic matrices

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0222614A2 (en) * 1985-11-12 1987-05-20 Eli Lilly And Company Orally administerable sustained release pharmaceutical formulations
WO1996021439A1 (en) * 1995-01-10 1996-07-18 Galephar P.R. Inc. Pharmaceutical composition containing fenofibrate and polyglycolized glycerides
EP0806202A1 (en) * 1996-05-06 1997-11-12 Adir Et Compagnie Controlled release pharmaceutical composition containing stabilized lipophilic matrices

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2782006A1 (en) * 1998-08-07 2000-02-11 Gattefosse Ets Sa SUSTAINED RELEASE COMPOSITION CAPABLE OF FORMING MICRO-EMULSION
WO2000007573A1 (en) * 1998-08-07 2000-02-17 Gattefosse S.A. Composition with prolonged release of active principle capable of forming a micro-emulsion
US6309665B2 (en) 1998-08-07 2001-10-30 Gattefosse S.A. Composition with sustained release of active principle, capable of forming a microemulsion
WO2000057918A2 (en) * 1999-03-31 2000-10-05 Abbott Laboratories Novel formulations comprising lipid-regulating agents
WO2000057918A3 (en) * 1999-03-31 2001-01-18 Abbott Lab Novel formulations comprising lipid-regulating agents
FR2803203A1 (en) * 1999-12-31 2001-07-06 Fournier Ind & Sante NEW GALENIC FORMULATIONS OF FENOFIBRATE
WO2001049262A1 (en) * 1999-12-31 2001-07-12 Fournier Industrie Et Sante Fenofibrate galenic formulations and method for obtaining same
WO2003013501A1 (en) * 2001-08-07 2003-02-20 Laboratoires Smb Sa Improved pharmaceutical composition containing a ppar alpha agent and a process for preparing it
WO2003013500A1 (en) * 2001-08-07 2003-02-20 Laboratoires Smb Sa Improved pharmaceutical composition containing a ppar alpha agent and a process for preparing it
EP1829541A1 (en) * 2002-12-17 2007-09-05 Abbott GmbH & Co. KG Formulation comprising fenofibric acid or a physiologically acceptable salt thereof
EP1832285A1 (en) * 2002-12-17 2007-09-12 Abbott GmbH & Co. KG Formulation comprising fenofibric acid or a physiologically acceptable salt thereof
WO2005009409A2 (en) * 2003-07-17 2005-02-03 Banner Pharmacaps, Inc. Controlled release preparations
WO2005009409A3 (en) * 2003-07-17 2005-08-11 Banner Pharmacaps Inc Controlled release preparations
JP2007523872A (en) * 2003-07-17 2007-08-23 バナー ファーマキャップス，インコーポレイティド Controlled release formulation
EP1951208A2 (en) * 2005-10-26 2008-08-06 Banner Pharmacaps Inc. Lipophilic vehicle-based dual controlled release matrix system as capsule fill
EP1959935A2 (en) * 2005-10-26 2008-08-27 Banner Pharmacaps Inc. Hydrophilic vehicle-based dual controlled release matrix system as capsule fill
CN108186593A (en) * 2018-02-06 2018-06-22 南京百思福医药科技有限公司 A kind of Nifedipine sustained release tablets and preparation method thereof
CN108186593B (en) * 2018-02-06 2020-11-03 南京百思福医药科技有限公司 Nifedipine sustained release tablet and preparation method thereof

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