EP0065531A1 - New galenic preparation of phenofibrate, method for the obtention thereof, its application as a medicine - Google Patents

New galenic preparation of phenofibrate, method for the obtention thereof, its application as a medicine

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Publication number
EP0065531A1
EP0065531A1 EP81903096A EP81903096A EP0065531A1 EP 0065531 A1 EP0065531 A1 EP 0065531A1 EP 81903096 A EP81903096 A EP 81903096A EP 81903096 A EP81903096 A EP 81903096A EP 0065531 A1 EP0065531 A1 EP 0065531A1
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Prior art keywords
fenofibrate
granules
new
derivatives
polymer
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EP81903096A
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German (de)
French (fr)
Inventor
Claude Laruelle
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DESHORS
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DESHORS
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Classifications

    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

  • New dosage form of fenofibrate its process of obtaining, its application as medicine.
  • the present invention relates to a new galenical form of fenofibrate (DCI) and / or its derivatives, its production process and the medicaments comprising this form.
  • DCI fenofibrate
  • fenofibrate is isopropyl para- (4-chlorobenzoyl) -phenoxyisobutyrate.
  • the expression “fenofibrate and its derivatives” denotes the compounds of formula I
  • R 1 represents a phenyl group or a phenyl group substituted by one or more - CH 3 , CF 3 or halogens (in particular fluorine, chlorine or bromine),
  • R 2 and R 3 independently represent a hydrogen or halogen atom (preferably fluorine, chlorine or bromine), an alkyl or alkoxy group having 1 to 5 C or a -CF 3 group,
  • Y represents a group -OH, a lower alkoxy group, preferably C 1 - C 4 , a group -NR 4 R 5 , a group 4 -ement -NHCH 2 CH 2 NR 4 R 5 or a group -O-alkylene- NR 4 R 5 , the alkylene having in particular 2 to 6 carbon atoms R 4 and R 5 identical or different, each representing a hydrogen atom, a C 1 -C 5 alkyl group, a C 3 cycloalkyy group - C 7 , preferably in C 5 - C 6 an aryl or aryl group substituted on the aromatic residue by one or more halogen groups, methyl or -CF 3 , or else R 4 and R 5 form together with the nitrogen atom to which they are linked, either an n-heterocyclic group having 5 to 7 vertices which may contain a second heteroatom chosen from N, O and S, and which may be substituted, or an amide residue derived from Ivsine
  • fenofibrate is used for the treatment of hyperlipidénaies, hypercholesterolimies and endogenous hypertrigiycéridémies of the adult.
  • fenofibrate at a rate of 300 to 400 mg per day, a reduction of the cholera steremia of 20 to 25% and a reduction of the triglyceridemia of 40 to 50% . This significant action manifests itself from the first month of treatment and persists after 30 months of treatment.
  • hyperiipidemias contribute to the increase in the statistical risk of vascular accident in particular coronary artery.
  • the treatment of hyperipidemia with fenofibrate constitutes a long-term symptomatic treatment which is not without risks.
  • fenofibrate is presented in the form of capsules dosed with 100 mg of active principle: the average daily dosage is 300 to 400 mg, sometimes 600 mg.
  • the subject of the present invention is a new galenical form making it possible to reduce the dosage and the number of administrations thanks to the progressive and delayed release of fenofibrate and / or its derivatives.
  • This form is remarkable in that it consists of granules comprising a neutral core consisting of a grit of an inert excipient comprising at least one constituent chosen from sucrose and lactose, optionally in mixture with starch, said neutral core being coated with a first layer containing fenofibrate and / or its derivatives in admixture with an excipient for the first layer comprising at least a first constituent chosen from talc, silica and their mixtures, and a second constituent which is stearic acid, then a second layer, or outer layer constituted by a microporous envelope comprising at least one polymer compatible with oral administration.
  • the neutral core consists of sucrose, lactose or their mixtures.
  • the neutral core can be a mixture comprising from 20 to 60% by weight of sucrose and / or lactose and from 1 to 40% by weight of starch. These proportions are expressed relative to the total weight of the new dosage form.
  • the new dosage form contains from 0.01 to 1% approximately, and in particular from 0.1 to 0.5% by weight, of stearic acid, from 5 to 15% by weight. weight of talc and 2 to 10% by weight of drying silica.
  • the neutral core can comprise fenibrate adsorbates and / or its derivatives.
  • the new dosage form as defined above contains, relative to its total weight, from 25 to 55% approximately by weight of fenofibrate and / or its derivatives, and from 2 to 10% approximately by weight of polymer constituting the layer external, the rest being constituted by the other inert excipients, present for example in a proportion of 40 to 70% approximately.
  • the neutral core generally represents 15 to 60%.
  • the grain constituting the neutral core has dimensions of the order of 0.1 to 0.5 mm, and the granules, object of the invention, have dimensions not exceeding approximately 2 mm, these dimensions varying for example from 1 mm to 2 mm in most cases.
  • the first layer can itself be composed of several sublayers (generally not more than 4) obtained by successive applications of fenofibrate and / or of its derivatives and of or excipients for said first layer.
  • the invention is not limited to granules having determined proportions of polymer or a determined number of said sublayers, because one of the advantages of the new form of the invention is to produce a drug having a delayed effect controlled by the mixture of granules having different release rates of fenofibrate and / or its derivatives.
  • the subject of the invention is also a process for obtaining the new galenical form which is remarkable in that the neutral granules are prepared beforehand by granulation, that they are dried and sieved, that these granules are impregnated with a solution of fenofibrate and / or its derivatives, which is then coated with said granules with said excipient for the first layer, which is repeated, if desired, the operations of impregnating fenofibrate and coating, then forming the microporeus ⁇ envelope by coating with said polymer in solution in a solvent.
  • a pharmaceutically acceptable organic solvent is used in particular, such as ethane or acetone.
  • the present invention relates to medicaments comprising the new form of administration of fenofibrate and / or its derivatives, in the form of active granules optionally mixed with neutral granules not coated with polymer in order to obtain a predetermined concentration in fenofibrate and / or its derivatives, this set of granules being presented in the form of capsules, tablets, suppositories, syrup, granules or powder.
  • the corn starch and the sucrose are mixed and granulated, then the grains are sieved and blended for a long time so as to make them perfectly spherical. We sift again and dry perfectly.
  • an alcoholic solution of fenofibrate is sprayed onto the neutral cores thus obtained.
  • the first layer is then made by incorporating into these granules a part of the mixture of the other excipients (with the exception of shellac) then the spraying of fenofibrate is started again, this coating being repeated several times with sieving and drying if necessary between each undercoat.
  • the microporous outer layer is produced, by spraying the shellac granules with gum shellac in solution in absolute ethyl alcohol, in an amount sufficient to impregnate all of the granules. It is then carefully dried, eliminating the ethyl alcohol remaining, it is again sieved and the title of the granules obtained is checked as below before putting into capsules, after having optionally adjusted the titration by addition and homogenized with neutral granules to arrive at the desired titration.
  • granules according to the invention were prepared by replacing the shellac with polyvinylpyroli dane or with a polymethacrylate.
  • Granules according to the invention have also been prepared in which the neutral core is exclusively made up of sucrose or lactose. Measurement of Fenofibrate Release
  • a disintegration device in which a quantity of granules corresponding to approximately 250 mg of active principle is brought into contact with artificial liquids, the device making it possible to maintain constant agitation and a constant temperature of 37 ° ⁇ 0.5 ° C.
  • Artificial liquids are solutions buffered at successive pH used according to the scheme below. Period Solutions TTeemmppss ddee pH% of principal active release
  • the new dosage form leads to a new, remarkable drug, which is easier to use and whose side effects linked to its use are reduced.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

Le medicament est forme de granules constituees chacune d'un noyau neutre (saccharose + amidon) recouvert d'une premiere couche de fenofibrate en melange avec un excipient, et d'une deuxieme couche exterieure microporeuse d'un polymere comestible. L'administration d'une gelule de 250 mg par jour au lieu de trois prises de 100 mg permet ainsi de reduire le dosage et le nombre d'administrations grace a la liberation progressive et retardee du fenofibrate. On maintient une dose minimale dans le sang, on evite les fortes concentrations temporaires, et on reduit la quantite totale ingeree.The drug is in the form of granules each consisting of a neutral core (sucrose + starch) covered with a first layer of fenofibrate mixed with an excipient, and a second microporous outer layer of an edible polymer. The administration of a 250 mg capsule per day instead of three doses of 100 mg thus makes it possible to reduce the dosage and the number of administrations thanks to the gradual and delayed release of fenofibrate. Maintain a minimum dose in the blood, avoid temporary high concentrations, and reduce the total amount ingested.

Description

Nouvelle forme galénique du fénofibrate, son procédé d'obtention, son application comme médicament. New dosage form of fenofibrate, its process of obtaining, its application as medicine.
La présente invention concerne une nouvelle forme galénique du fénofibrate (DCI) et/ou de ses dérivés, son procédé d'obtention et les médicaments comprenant cette forme.The present invention relates to a new galenical form of fenofibrate (DCI) and / or its derivatives, its production process and the medicaments comprising this form.
On rappelle que le fénofibrate est le para-(4-chlorobenzoyl) -phénoxyisobutyrate d'isopropyie. Dans la présente demande, on dési gne par l'expression "fénofibrate et ses dérivés" les composés de formule IIt is recalled that the fenofibrate is isopropyl para- (4-chlorobenzoyl) -phenoxyisobutyrate. In the present application, the expression “fenofibrate and its derivatives” denotes the compounds of formula I
dans laquelle R1 représente un groupement phénvle ou un groupence nt phényle substitué par un ou plusieurs - CH3, CF3 ou halogènes (notamment fluor, chlore ou brome), in which R 1 represents a phenyl group or a phenyl group substituted by one or more - CH 3 , CF 3 or halogens (in particular fluorine, chlorine or bromine),
R2 et R3 représentent indépendamment un atome d'hydrogène ou d'halogène (de préférence fluor, chlore ou brome), un groupement alkyle ou alkoxy ayant 1 à 5 C ou un groupement -CF3,R 2 and R 3 independently represent a hydrogen or halogen atom (preferably fluorine, chlorine or bromine), an alkyl or alkoxy group having 1 to 5 C or a -CF 3 group,
-SCH3, -SOCH3, -SO2CH3 ou -OH, et-SCH 3 , -SOCH 3 , -SO 2 CH 3 or -OH, and
Y représente un groupement -OH, un groupement alkoxy inférieur, de préférence en C1 - C4, un groupement -NR4R5, un grou4 5 pement -NHCH2 CH2 N R4R5 ou un groupement -O-alkylène-NR4R5, l'alkylène ayant notamment 2 à 6 atomes de carbone R4 et R5 identiques ou différents, représentant chacun un atome d'hydrogène, un grou pement alkyle en C1 - C5, un groupement cycloalkyie en C3 - C7, de préférence enC5 - C6 un groupe aryle ou aryle substitué sur le reste aromatique par un ou plusieurs groupements halogènes, méthyle ou -CF3, ou bien R4 et R5 forment ensemble avec l'atome d'azote auquel ils sont reliés, soit un groupe n-hétérocyclique ayant 5 à 7 sommets pouvant renfermer un second hétéroatome choisi parmi N, O et S, et pouvant être substitué, soit un reste amide dérivé de la Ivsine ou deY represents a group -OH, a lower alkoxy group, preferably C 1 - C 4 , a group -NR 4 R 5 , a group 4 -ement -NHCH 2 CH 2 NR 4 R 5 or a group -O-alkylene- NR 4 R 5 , the alkylene having in particular 2 to 6 carbon atoms R 4 and R 5 identical or different, each representing a hydrogen atom, a C 1 -C 5 alkyl group, a C 3 cycloalkyy group - C 7 , preferably in C 5 - C 6 an aryl or aryl group substituted on the aromatic residue by one or more halogen groups, methyl or -CF 3 , or else R 4 and R 5 form together with the nitrogen atom to which they are linked, either an n-heterocyclic group having 5 to 7 vertices which may contain a second heteroatom chosen from N, O and S, and which may be substituted, or an amide residue derived from Ivsine or from
WEPO cystéine .WEPO cysteine.
Bien entendu, l' expression fénofibrate et ses dérivés" englobe en outre le s sels d'addition d'acides pharmaceutiquement acce tables, susceptibles d' être obtenus au départ des composés de formule I. Les composés de formule I, ainsi que ces sels d'addition, sont connus et décrits notamment par le brevet français 69 39954 (No. de publication 2. 035. 821) et son certificat d'addition 72 36165 (No. de publication 2. 157. 853) .Of course, the expression fenofibrate and its derivatives "further includes the addition salts of pharmaceutically acceptable acids, capable of being obtained from the compounds of formula I. The compounds of formula I, as well as these salts of addition, are known and described in particular by French patent 69 39954 (Publication No. 2,035,821) and its addition certificate 72 36,165 (Publication No. 2,157,853).
On sait que le fénofibrate est utilisé pour le traitement des hyperlipidénaies, hypercholestérolémies et hypertrigiycéridémies endogènes de l' adulte. Ainsi, on peut observer chez l'homme soumis à un traitement par le fénofibrate, à raison de 300 à 400 mg pa r jour, une réduction de la choie stéroiémie de 20 à 25% et une réduction de la triglycéridémie de 40 à 50% . Cette action significative se manifeste dès le premier mois de tr -aitement et persiste après 30 mois de traitement.We know that fenofibrate is used for the treatment of hyperlipidénaies, hypercholesterolémies and endogenous hypertrigiycéridémies of the adult. Thus, we can observe in humans subjected to treatment with fenofibrate, at a rate of 300 to 400 mg per day, a reduction of the cholera steremia of 20 to 25% and a reduction of the triglyceridemia of 40 to 50% . This significant action manifests itself from the first month of treatment and persists after 30 months of treatment.
En raison de leur fréquence (4 à 5 % de la population) et de leur rôle dans la genèse de l'artériosclérose, les hyperiipidémies contribuent à l'augmentation du risque statistique d'accident vasculaire en particulier coronarien.Because of their frequency (4 to 5% of the population) and their role in the genesis of arteriosclerosis, hyperiipidemias contribute to the increase in the statistical risk of vascular accident in particular coronary artery.
D'une manière générale , le traitement des hyperiipidémies par le fénofibrate constitue un traitement symptomatique à long terme non dénué de risques.In general, the treatment of hyperipidemia with fenofibrate constitutes a long-term symptomatic treatment which is not without risks.
Dans un article intitulé "Drug Plasma Lεveis and Hyt-ocholeεterolemic Effect of Fénofibrate in Patients with Type Ha Hyperlipoproteinemia" , publié dans la revue "Current Therapeutic Research" , vol. 26, No. 3, sept. 1979, les auteurs P. Drouin, L. Méjean, D. Lambert, J . P. Sauvanet, et G. Derby , de l' Université de Nancy I, Inserm U. 59 , et C . Tourne et E. Wûlfert du Centre de Recherche s des Laboratoires Fournier à Dijon, disent : ". . . l'effet hypocholestéroiémiant du fénofibrate est démontré avec des taux plasmatiques allant de moins de 5 //g/ml jusqu' à 35 i/g/ml. . . " et on peut lire un peu plus loin : . . . "En re gard des incertitude s des réactions défavorables dans le s traitements à long terme , les cliniciens doivent établir et mainte nir le taux plasmatique le plus bas compatible avec un effet thérapeutique optimal. Dans le cas du fénofibrate , il e st évident que le s taux plasmatiques circulant ne doivent pas dépasser 10 ug/ml.In an article entitled "Drug Plasma Lεveis and Hyt-ocholeεterolemic Effect of Fenofibrate in Patients with Type Ha Hyperlipoproteinemia", published in the journal "Current Therapeutic Research", vol. 26, No. 3, Sept. 1979, the authors P. Drouin, L. Méjean, D. Lambert, J. P. Sauvanet, and G. Derby, of the University of Nancy I, Inserm U. 59, and C. Tourne and E. Wûlfert of the Research Center of Laboratoires Fournier in Dijon, say: "... The cholesterol-lowering effect of fenofibrate is demonstrated with plasma levels ranging from less than 5 g / ml to 35 i / g / ml ... "and we can read a little more far : . . . "In view of the uncertainty of adverse reactions in long-term treatment, clinicians must establish and maintain the lowest plasma level compatible with an optimal therapeutic effect. In the case of fenofibrate, it is evident that s circulating plasma levels should not exceed 10 ug / ml.
En particulier, on a pu relever de s cas d'atteinte hépatiqu de troubles dige stifs et inte stinaux.In particular, there have been reports of hepatic involvement of stigma and intestinal disorders.
En outre , le risque de lithiase biliaire induit par la prise de fénofibrate n' est pas à exclure . II était donc utile de chercher à réduire les doses adminis trée s.In addition, the risk of cholelithiasis induced by taking fenofibrate cannot be excluded. It was therefore useful to seek to reduce the doses administered.
Usuellement, le fénofibrate e st présenté sous forme de gélules dosée s à 100 mg de principe actif : la posologie journalière moyenne est de 300 à 400 mg, parfois 600 mg. La présente invention a pour objet, une nouvelle forme galénique permettant de réduire le dosage et le nombre d'administrations grâce à la libération progressive et retardée de fénofibrate et/ou de ses dérivés. Cette forme est remarquable en ce qu' elle est constituée par des granules comprenant une âme neutre constituée d'un grai d'un excipient inerte comprenant au moins un constituant choisi parmi le saccharose et le lactose, éventuellement en mélange avec de l'amidon, ladite âme neutre étant revêtue d'une première couche contenant le fénofibrate et/ou ses dérivés en mélange avec un excipient pour la première couche comprenant au moins un premier constituant choisi parmi le talc , la silice et leurs mélanges , et un second c o nstituant qui est l'acide stéarique, puis d'une seconde couche , ou couche externe constituée par une enveloppe microporeuse comprenant au moins un polymère compatible avec l'administration par voie orale .Usually, fenofibrate is presented in the form of capsules dosed with 100 mg of active principle: the average daily dosage is 300 to 400 mg, sometimes 600 mg. The subject of the present invention is a new galenical form making it possible to reduce the dosage and the number of administrations thanks to the progressive and delayed release of fenofibrate and / or its derivatives. This form is remarkable in that it consists of granules comprising a neutral core consisting of a grit of an inert excipient comprising at least one constituent chosen from sucrose and lactose, optionally in mixture with starch, said neutral core being coated with a first layer containing fenofibrate and / or its derivatives in admixture with an excipient for the first layer comprising at least a first constituent chosen from talc, silica and their mixtures, and a second constituent which is stearic acid, then a second layer, or outer layer constituted by a microporous envelope comprising at least one polymer compatible with oral administration.
Dans un mode de réalisation particulier , l' âme neutre est constituée par du saccharose , du lactose ou leurs mélanges.In a particular embodiment, the neutral core consists of sucrose, lactose or their mixtures.
Parmi les polymère s compatible s avec l' administration or ale , on citera notamment le s polymère s naturels et/ou synthétiques appartenant à la classe constituée par la gomme laque , la gomme arabique, la gélatine des éthers ou esters de cellulose tels que l' éthyl cellulose , l' acétophtalate de cellulose ou le triacétate de cellulose , le oolvoxvéthvlèneglvcol, les oolyméthacrylates , les copolymères styrèn - acrylonitrile et le polyvinyl pyrrolidone , en enveloppes successives. Selon un autre mode de réalisation particuliers, l' âme neutre peut être un mélange comprenant de 20 à 60% en poids de saccharose et/ou de lactose et de 1 à 40% en poids d'amidon. Ces proportions sont exprimé es par rapport au poids total de la nouvelle form galénique.Among the polymers compatible with oral administration, mention may be made in particular of natural and / or synthetic polymers. belonging to the class consisting of shellac, gum arabic, gelatin of cellulose ethers or esters such as ethyl cellulose, cellulose acetophthalate or cellulose triacetate, oolvoxvethvleneglvcol, oolymethacrylates, styrene copolymers - acrylonitrile and polyvinyl pyrrolidone, in successive envelopes. According to another particular embodiment, the neutral core can be a mixture comprising from 20 to 60% by weight of sucrose and / or lactose and from 1 to 40% by weight of starch. These proportions are expressed relative to the total weight of the new dosage form.
Selon une forme de réalisation de l'invention, la nouvelle forme galénique contient de 0, 01 à 1 % environ, et en particulier de 0, 1 à 0, 5 % en poids, d'acide stéarique , de 5 à 15% en poids de talc et de 2 à 10 % en poids de silice desséchante. En outre, l'âme neutre peut comprendre des adsorbats de fénibrate et/ou ses dérivés.According to one embodiment of the invention, the new dosage form contains from 0.01 to 1% approximately, and in particular from 0.1 to 0.5% by weight, of stearic acid, from 5 to 15% by weight. weight of talc and 2 to 10% by weight of drying silica. In addition, the neutral core can comprise fenibrate adsorbates and / or its derivatives.
Généralement, la nouvelle forme galénique telle que définie précédemment contient par rapport à son poids total, de 25 à 55% envi ron en poids de fénofibrate et/ou de ses dérivés, et de 2 à 10 % environ en poids de polymère constituant la couche externe, le reste étant constitué par les autres excipients inertes, présents par exemple dans une proportion de 40 à 70% environ.Generally, the new dosage form as defined above contains, relative to its total weight, from 25 to 55% approximately by weight of fenofibrate and / or its derivatives, and from 2 to 10% approximately by weight of polymer constituting the layer external, the rest being constituted by the other inert excipients, present for example in a proportion of 40 to 70% approximately.
Par rapport au poids total, l' âme neutre représente généralement de 15 à 60 %.Relative to the total weight, the neutral core generally represents 15 to 60%.
Généralement, le grain constituant l'âme neutre a des dimensions de l'ordre de 0, 1 à 0 , 5 mm, et les granules, objet de l'invention, ont des dimensions n' excédant pas 2 mm environ, ces dimensions variant par exemple de 1 mm à 2 mm dans la plupart des cas.Generally, the grain constituting the neutral core has dimensions of the order of 0.1 to 0.5 mm, and the granules, object of the invention, have dimensions not exceeding approximately 2 mm, these dimensions varying for example from 1 mm to 2 mm in most cases.
Il convient de remarquer que la première couche , telle que définie ci-dessus, peut être elle-même composée ce plusieurs sous-couches (généralement pas plus de 4) obtenues par applications successives de fénofibrate et/ou de se s dérivés et du ou des excipients pour ladite première couche.It should be noted that the first layer, as defined above, can itself be composed of several sublayers (generally not more than 4) obtained by successive applications of fenofibrate and / or of its derivatives and of or excipients for said first layer.
Bien entendu, l'invention n'est pas limitée à des granules ayant des proportions déterminées de polymère ou un nombre déterminè desdites sous-couches, car un des intérêts de la nouvelle forme de l'invention est de réaliser un médicament ayant un effet retard contrôlè par le mélange de granules ayant différentes vitesses de libération de fénofibrate et/ou de ses dérivés.Of course, the invention is not limited to granules having determined proportions of polymer or a determined number of said sublayers, because one of the advantages of the new form of the invention is to produce a drug having a delayed effect controlled by the mixture of granules having different release rates of fenofibrate and / or its derivatives.
L'invention a également pour objet un procédé d'obtention de la nouvelle forme galénique remarquable en ce qu'on prépare au préalable par granulation, les granules neutres, qu'on les sèche et les tamise, qu'on imprègne ces granules avec une solution de fénofibrate et/ou de ses dérivés, qu'on enrobe ensuite lesdits granules avec ledit excipient pour la première couche, qu'on répète, si désiré, les opérations d'imprégnation de fénofibrate et d'enrobage, puis qu'on forme l'enveloppe microporeusε par revêtement à l'aide dudit polymère en solution dans un solvant. Pour le fénofibrate et le polymère, on utilise notamment un solvant organique pharmaceutiquement acceptable, tel que l'ethane ou l'acétone. De plus, la présente invention a pour objet des médicaments comprenant la nouvelle forme d' administration du fénofibrate et/ou de ses dérivés, sous forme de granules actifs éventuellement mélangés à des granules neutres non enrobés de polymère afin d'obtenir une concentration prédéterminée en fénofibrate et/ou de ses dérivés, cet ensemble de granules étant présenté sous forme de gélules, de comprimés, de suppositoires, de sirop, de granulés ou de poudre.The subject of the invention is also a process for obtaining the new galenical form which is remarkable in that the neutral granules are prepared beforehand by granulation, that they are dried and sieved, that these granules are impregnated with a solution of fenofibrate and / or its derivatives, which is then coated with said granules with said excipient for the first layer, which is repeated, if desired, the operations of impregnating fenofibrate and coating, then forming the microporeusε envelope by coating with said polymer in solution in a solvent. For fenofibrate and the polymer, a pharmaceutically acceptable organic solvent is used in particular, such as ethane or acetone. In addition, the present invention relates to medicaments comprising the new form of administration of fenofibrate and / or its derivatives, in the form of active granules optionally mixed with neutral granules not coated with polymer in order to obtain a predetermined concentration in fenofibrate and / or its derivatives, this set of granules being presented in the form of capsules, tablets, suppositories, syrup, granules or powder.
L'ensemble des caractéristiques et avantages de l'invention seront mieux compris par l'homme de l'art en se référant à la description qui va suivre de modes de réalisation particuliers pris à titre d'exemples non limitatifs de la nouvelle forme galénique, de son procédé et de ses applications thérapeutiques, en particulier en relation avec les contrôles pharmacologiques et cliniques effectués en utilisant la nouvelle forme galénique .All of the characteristics and advantages of the invention will be better understood by a person skilled in the art by referring to the following description of particular embodiments taken by way of nonlimiting examples of the new galenical form, its process and its therapeutic applications, in particular in relation to the pharmacological and clinical checks carried out using the new dosage form.
Exemple de Préparation de la Nouvelle Forme GaléniqueExample of Preparation of the New Galenic Form
On indique ci-après un exemple de fabrication correspondant à 100 000 gélules dosées à 250 mg. 1) Formule de fabricationA manufacturing example corresponding to 100,000 capsules containing 250 mg is indicated below. 1) Manufacturing formula
. Fénofibrate . .. .. . .. . . . .. ... .. .. .. . .. . . . .. ... .. . 25 kg. Fenofibrate. .. ... ... . . .. ... .. .. ... ... . . .. ... ... 25 kg
. Saccharose , amidon, gomme laque , talc, silice desséchante , acide stéarique .. .. . .. . . . .. ... .. . . . 27 , 5 kg. Sucrose, starch, shellac, talc, drying silica, stearic acid .. ... ... . . .. ... ... . . 27.5kg
. Alcool éthylique absolu .. .. . .. . . . .. ... .. .. .. . .. . q s Les proportions des divers excipients sont les suivantes :. Absolute ethyl alcohol .. ... ... . . .. ... .. .. ... ... q s The proportions of the various excipients are as follows:
- saccharose . .. .. . .. . . . .. ... .. .. .. . .. . . . .. ... .. . 1 3 kg- sucrose. .. ... ... . . .. ... .. .. ... ... . . .. ... ... 1 3 kg
- amidon . ...... ...... ... ...... ... ... ... ...... ......... ...... ...... ...... ... ...... ... .. 6 k g- starch. ...... ...... ... ...... ... ... ... ...... ......... ..... . ...... ...... ... ...... ... .. 6 kg
- talc . .. .. . .. . . . .. ... .. .. .. . .. . . . .. ... .. .. . . . . . . 3., 5 kg- talc. .. ... ... . . .. ... .. .. ... ... . . .. ... .. ... . . . . . 3.5 kg
- silice . .. .. . .. . . . .. ... .. .. .. . .. . . . .. ... .. . .. . . . 2 , 5 kg - acide stéariq.u.e . .. . .. . . . .. ... .. .. .. . .. . . . .. ... .. . 0 , 5 kg- silica. .. ... ... . . .. ... .. .. ... ... . . .. ... ... ... . . 2.5 kg - stearic acid u.e. ... ... . . .. ... .. .. ... ... . . .. ... ... 0.5 kg
- gomme laque . .. .. . .. . . . .. , ... .. .. .. . .. . . . .. ... .. .2 kg- shellac. .. ... ... . . .., ... .. .. ... ... . . .. ... .. .2 kg
On mélange et granule1 l'amidon de mais et le saccharose puis on tamise et on turbine longuement les grains de façon à les rendre parfaitement sphériques. On tamise à nouveau et on sèche parfaitement.The corn starch and the sucrose are mixed and granulated, then the grains are sieved and blended for a long time so as to make them perfectly spherical. We sift again and dry perfectly.
Dans un mélangeur en acier inoxydable , on projette sur les âmes neutres ainsi obtenues , une solution alcoolique de fénofibrate. On réalise ensuite la première couche en incorporant à ces granules une partie du mélange des autres excipients (à l' exception de la gomme laque) puis on recommence la pulvérisation de fénofibrate, cet enrobage étant recommencé plusieurs fois avec tamisage et séchage si nécessaire entre chaque sous-couche.In an stainless steel mixer, an alcoholic solution of fenofibrate is sprayed onto the neutral cores thus obtained. The first layer is then made by incorporating into these granules a part of the mixture of the other excipients (with the exception of shellac) then the spraying of fenofibrate is started again, this coating being repeated several times with sieving and drying if necessary between each undercoat.
Lorsque la première couche contenant le principe actif est ierminée , on réalise la couche extérieure microporeuse , en projetant sur les granule s la gomme laque en solution dans l'alcool éthylique absolu, en quantité suffisante pour imprégner l' ensemble des granules. On sèche ensuite soigneusement en éliminant l'alcool éthylique restant, on tamise à nouveau et on contrôle comme ci-après le titre des granule s obtenus avant de mettre en gélules, après avoir ajusté évent uellement le titrage par addition et homogénéisé avec des granules neutres pour arriver au titrage désiré. En opérant de façon analogue à celle décrite dans l' exemple précédent, on a préparé de s granules selon l'invention en rempla çant la gomme laque par la polyvinylpyroli dane ou par un polyméthacrylate .When the first layer containing the active principle is finished, the microporous outer layer is produced, by spraying the shellac granules with gum shellac in solution in absolute ethyl alcohol, in an amount sufficient to impregnate all of the granules. It is then carefully dried, eliminating the ethyl alcohol remaining, it is again sieved and the title of the granules obtained is checked as below before putting into capsules, after having optionally adjusted the titration by addition and homogenized with neutral granules to arrive at the desired titration. By operating in a similar manner to that described in the previous example, granules according to the invention were prepared by replacing the shellac with polyvinylpyroli dane or with a polymethacrylate.
On a également préparé des granules selon l'invention dans lesquels l' âme neutre e st exclusivement constituée de saccharose ou de lactose. Mesure de la Libération du FénofibrateGranules according to the invention have also been prepared in which the neutral core is exclusively made up of sucrose or lactose. Measurement of Fenofibrate Release
Avec le s granules de l'invention, on peut par exemple assurer une libération retardée de fénofibrate théorique : . 1 ère heure : libération égale à 40 %With the granules of the invention, it is possible, for example, to ensure a delayed release of theoretical fenofibrate:. 1st hour: release equal to 40%
. 4è heure : libération égale à 80 % . 8è heure : libération égale à 100 %. 4th hour: release equal to 80%. 8th hour: release equal to 100%
Pour contrôler cette caractéristique , on utilise un appareil à délite ment dans lequel on met en contact une quantité de granules correspondant à environ 250 mg de principe actif avec des liquides artificiels , l'appareil permettant de maintenir une agitation constante et une- température constante de 37° ± 0 , 5° C . Les liquides artificiels sont des solutions tamponnées à pH successifs utilisées selon le schéma cidessous. Période Solutions TTeemmppss ddee pH % de princip libération actifTo control this characteristic, a disintegration device is used in which a quantity of granules corresponding to approximately 250 mg of active principle is brought into contact with artificial liquids, the device making it possible to maintain constant agitation and a constant temperature of 37 ° ± 0.5 ° C. Artificial liquids are solutions buffered at successive pH used according to the scheme below. Period Solutions TTeemmppss ddee pH% of principal active release
1 25 ml liquide gastrique 1 h (l e heure) 1 , 5 40% 2 25 ml liquide intestinal 1 h (2e heure) 4 , 5 > 40% 3 25 ml liquide intestinal 2 h (3&4è heu) 6, 9 80 %1 25 ml gastric fluid 1 h (1 hour) 1, 5 40% 2 25 ml intestinal fluid 1 h (2nd hour) 4, 5> 40% 3 25 ml intestinal fluid 2 h (3 & 4 hrs) 6, 9 80%
4 25 ml liquide inte stinal 2 h (5&6 heur) 6, 9 > 80% 5 2 5 ml liquide inte stinal 2 h (7 &8è heu) 7 , 2 100% Mesure de Biodisponibilité de la Nouvelle Présentation4 25 ml inte stinal liquid 2 h (5 & 6 hours) 6, 9> 80% 5 2 5 ml inte stinal liquid 2 h (7 & 8 hours) 7, 2 100% New Presentation Bioavailability Measure
Afin de préciser l'intérêt pratique de la nouvelle présentation galénique , il est indispensable de vérifier que la mise à disposition du fénofibrate par la nouvelle présentation conduit à un taux plasmatique d'acide fénofibrique, chez l' homme aya nt une signification thérapeutique.In order to clarify the practical interest of the new galenic presentation, it is essential to verify that the provision of fenofibrate by the new presentation leads to a plasma level of fenofibric acid, in man has a therapeutic significance.
Dans le cadre de la présente invention, il était donc nécessaire de vérifier la bioéquivalence de la forme connue et de la nouvelleù présentation et d' effectuer une étude pharmaco cinétique. La technique de dosage selon Desager (Journal of Chromato graphy , 1978 , p. 1 60- 64) du métabolite principal, l'acide fénofibrique utilise la chromato graphie liquide à haute pression : l'étalon interne étant l'acide cloribrique , métabolite principal du clofibrate (DCI) .In the context of the present invention, it was therefore necessary to verify the bioequivalence of the known form and the new presentation and to carry out a pharmacokinetic study. The assay technique according to Desager (Journal of Chromato graphy, 1978, p. 1 60-64) of the main metabolite, fenofibric acid uses liquid chromatography at high pressure: the internal standard being cloribric acid, main metabolite clofibrate (DCI).
Selon Desager (Int. J. Clin. Pharmacology - 1978 - p. 570 74) un traitement au long cours par le fénofibrate à raison de 300 à 600 mg par jour en 3 à 6 prises conduit à une concentration à l' équilibre du métabolite actif voisine de 10 microgrammes par litre de plasma. Toutefois , comme cela a été rappelé ci-dessus, il est établi que l'activité thérapeutique du fénofibrate est obtenue lorsque la concentration à l' équilibre se situe dans l'intervalle 5 à 10 microgrammes par litre de plasma.According to Desager (Int. J. Clin. Pharmacology - 1978 - p. 570 74) long-term treatment with fenofibrate at a rate of 300 to 600 mg per day in 3 to 6 doses leads to a balanced concentration of the metabolite active near 10 micrograms per liter of plasma. However, as recalled above, it is established that the therapeutic activity of fenofibrate is obtained when the concentration at equilibrium is in the range 5 to 10 micrograms per liter of plasma.
Ce résultat à l' équilibre est obtenu par la forme galénique nouvelle du fénofibrate présenté en granules lorsque la concentration est de 200 à 300 mg, préférentlellement 250 mg, de principe actif. Des tests ont été pratiqués sur sept sujets. Les sujets ont ingéré chaque matin à 8h une gélule de 250 mg de fénofibrate retard selon l'invention. Les analyses ont été pratiquées à partir du onzième jour et ont donné les résultats suivants (moyenne des 7 sujets) ll é jour 8 heures 3, 88 ug/ml 9 heures 4 , 25 "This equilibrium result is obtained by the new dosage form of fenofibrate presented in granules when the concentration is from 200 to 300 mg, preferably 250 mg, of active principle. Tests were carried out on seven subjects. The subjects ingested each morning at 8:00 a 250 mg capsule of fenofibrate retard according to the invention. The analyzes were carried out from the eleventh day and gave the following results (average of the 7 subjects) ll day 8 hours 3.88 u g / ml 9 hours 4.25 "
10 " 6, 25 "10 "6.25"
11 " 6, 95 " 11é jour 12 heures 7,76μg/ml11 "6, 95" 11th day 12 hours 7.76μg / ml
13 II 8,9 II13 II 8.9 II
14 ll 8,83 II14 ll 8.83 II
16 II 8,15 II16 II 8.15 II
18 II 7,5 II18 II 7.5 II
20 ll 5,8 l!20 ll 5.8 l!
12è jour 8 heures 3,95 μ/g/ml12th day 8 hours 3.95 μ / g / ml
12 Il 8,46 ll12 Il 8.46 ll
20 II 6,57 ll 13è jour 8heures 3,43 /g/ml20 II 6.57 ll 13th day 8 hours 3.43 / g / ml
12 II 8,43 ll l0 ll 5,76 ll12 II 8.43 ll l0 ll 5.76 ll
Ces résultats sont rassemblés sur le graphique donné en annexe à la présente description. Pour le 12è et le 13è jour, la courbe est simplifiée en raison du moindre nombre de relevés. On constate un bon étalement dans le temps du taux plasmatique circulant. Le taux ne dépasse pas 10 ug/nal et ne descend pas en-dessous de 3, 5. En particulier, dans la journée, le taux reste au-dessus de 6 , de 8 h à 20 heures. La nouvelle forme galénique permet donc d'obtenir, avec une seule prise quotidienne et une diminution notable de la quantité de principe actif ingéré, un effet préférable à celui obtenu à l'aide des traitements classiques.These results are collated on the graph given in the appendix to this description. For the 12th and 13th day, the curve is simplified due to the lower number of readings. There is a good spread over time of the circulating plasma level. The rate does not exceed 10 ug / nal and does not drop below 3, 5. In particular, during the day, the rate remains above 6, from 8 am to 8 pm. The new dosage form therefore makes it possible to obtain, with a single daily intake and a significant reduction in the amount of active principle ingested, an effect preferable to that obtained with the aid of conventional treatments.
Par conséquent, on peut affirmer que la nouvelle forme galénique conduit à un nouveau médicament, remarquable, d'un maniement plus aisé et dont les effets secondaires liés à son utilisation sont diminués.Consequently, it can be said that the new dosage form leads to a new, remarkable drug, which is easier to use and whose side effects linked to its use are reduced.
Bien entendu, l'homme de l'art pourra trouver d'autres avantages et variantes de l'invention, en particulier en ce qui concerne le procédé d'obtention des granules ou les modifications de dosage, sans pour cela sortir du ca.dre et de la portée de la présente invention. Of course, those skilled in the art will be able to find other advantages and variants of the invention, in particular with regard to the process for obtaining granules or the modifications of dosage, without thereby departing from the scope. and the scope of the present invention.

Claims

REVENDICATIONS
1. Nouvelle forme galénique du fénofibrate et/ou de ses dérivés , caractérisé en ce qu' elle est constituée par des granules comprenant une âme neutre constituée d'un grain d'un excipient inerte comprenant au moins un constituant choisi parmi le saccharose et le lactose , éventuellement en mélange avec de l' amidon, ladite âme neutre étant revêtue d'une première couche contenant le fénofibrate et/ou ses dérivés en mélange avec un excipient pour la première couche comprenant au moins un premier constituant choisi parmi le talc, la silice et leurs mélanges, et un second co nstituant qui est l'acide stéarique, puis d'une seconde couche , ou couche externe constituée par une enveloppe microporeuse comprenant au moins un polymère compatible avec l'administration par voie orale.1. New dosage form of fenofibrate and / or its derivatives, characterized in that it consists of granules comprising a neutral core consisting of a grain of an inert excipient comprising at least one constituent chosen from sucrose and lactose, optionally in admixture with starch, said neutral core being coated with a first layer containing fenofibrate and / or its derivatives in admixture with an excipient for the first layer comprising at least one first constituent chosen from talc, the silica and their mixtures, and a second constituent which is stearic acid, then a second layer, or external layer constituted by a microporous envelope comprising at least one polymer compatible with oral administration.
2. Nouvelle forme galénique selon la revendication 1 , caractérisé en ce que ledit polymère appartient à la classe constituée par la gomme laque , la gomme arabique , la gélatine , les éthers et esters de cellulose , tels que l'éthylcelluiose, l'acétophtalate de cellulose ou le triacétate de cellulose , le polyéthylènegiycol, les poly-méthacrylates , les copolymères styrène -a crylonitrite et la polyvinylpyrrolidone .2. New dosage form according to claim 1, characterized in that said polymer belongs to the class consisting of shellac, gum arabic, gelatin, cellulose ethers and esters, such as ethylcelluiose, acetophthalate cellulose or cellulose triacetate, polyethylene glycol, poly-methacrylates, styrene-a crylonitrite copolymers and polyvinylpyrrolidone.
3. Nouvelle forme galénique selon une des revendications 1 ou 2 , caractérisée en ce que ledit polymère représente une proportion en poids variant de 2 à 10 % environ.3. New dosage form according to one of claims 1 or 2, characterized in that said polymer represents a proportion by weight varying from 2 to 10% approximately.
4. Nouvelle forme galénique selon une des revendications précédentes, caractérisée en ce qu' elle contient environ de 25 à 55 % de fénofibrate et/ou de ses dérivés.4. New dosage form according to one of the preceding claims, characterized in that it contains approximately 25 to 55% of fenofibrate and / or its derivatives.
5. Nouvelle forme galénique selon une des revendications précédentes, caractérisée en ce que les excipients autres que le polymère , représentent de 40 à 70 % en poids environ.5. New dosage form according to one of the preceding claims, characterized in that the excipients, other than the polymer, represent from 40 to 70% by weight approximately.
6. Nouvelle forme selon une des revendications précédentes, caractérisée en ce que l'âme neutre représente 1 5 à 60 % du poids total.6. New form according to one of the preceding claims, characterized in that the neutral core represents 1 5 to 60% of the total weight.
7. Nouvelle forme selon une des revendications précédentes , caractérisée en ce que la première couche contient en poids de 5 à 1 5 % de talc , de 2 à 10 % de silice et de 0, 01 à 1 % d'acide stéarique , par rapport au poids total de la composition.7. New form according to one of the preceding claims, characterized in that the first layer contains by weight from 5 to 15% of talc, from 2 to 10% of silica and from 0.01 to 1% of stearic acid, by relative to the total weight of the composition.
8. Nouvelle forme selon une des revendicat ions précédentes, caractérisée en ce que l'ame neutre comprend des adsorbats de fénofibrat et/ou de ses dérivés.8. New form according to one of the preceding claims, characterized in that the neutral core comprises adsorbates of fenofibrat and / or its derivatives.
9. Procédé d' obtention de la nouvelle forme galénique selon une des revendications précédentes , caractérisé en ce qu' on prépare au préalable par granulation les granule s neutres , qu'on les sèche et les tamise , qu'on imprègne ces- granules avec une solution de fénofibrate et/ou de ses dérivés, qu' on enrobe ensuite le sdits granules avec ledit excipient pour la première couche , qu' on répète , si désiré, les opérations d'imprégnation de fénofibrate et d' enrobage, puis qu' on forme l' enveloppe microporeuse par revêtement à l'aide dudit polymère en solution dans un solvant.9. Method for obtaining the new dosage form according to one of the preceding claims, characterized in that the neutral granules are prepared beforehand by granulation, that they are dried and sieved, that these granules are impregnated with a solution of fenofibrate and / or its derivatives, which is then coated with said granules with said excipient for the first layer, which is repeated, if desired, the operations of impregnation of fenofibrate and of coating, then that the microporous envelope is formed by coating with said polymer in solution in a solvent.
10. Médicaments caractérisés en ce qu'ils comprennent la nouvelle forme galénique d' administration du fénofibrate et/ou de ses dérivés sous forme de granules conformes à une des revendications 1 à 8, les dits granules étant éventuellement mélangés avec granules neutres non enrobés de polymère afin d' obtenir une concen tration prédéterminée en fénofibrate et/ou de ses dérivés. 10. Medicaments characterized in that they comprise the new galenic form of administration of fenofibrate and / or its derivatives in the form of granules according to one of claims 1 to 8, said granules being optionally mixed with neutral granules not coated with polymer in order to obtain a predetermined concentration of fenofibrate and / or its derivatives.
I I . Médicaments selon la revendication 10 , caractérisés en ce qu'ils se présentent sous forme de gélules contenant 200 à 300 mg de fénofibrate. II. Medicines according to claim 10, characterized in that they are in the form of capsules containing 200 to 300 mg of fenofibrate.
12. Médicaments selon la revendication 10 , caractérisés en ce qu'ils se présentent sous forme de comprimés, de suppositoires, de sirop, de granulés , ou de poudre. 12. Medicines according to claim 10, characterized in that they are in the form of tablets, suppositories, syrup, granules, or powder.
EP81903096A 1980-11-19 1981-11-18 New galenic preparation of phenofibrate, method for the obtention thereof, its application as a medicine Withdrawn EP0065531A1 (en)

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WO1982001649A1 (en) 1982-05-27
IT8125185A0 (en) 1981-11-19
DE3152519T1 (en) 1983-12-29
NL8120434A (en) 1982-10-01
FR2494112A1 (en) 1982-05-21
DE3152519C2 (en) 1990-11-22
ATA906481A (en) 1988-07-15
BE891129A (en) 1982-05-17
AT387517B (en) 1989-02-10
IT1144948B (en) 1986-10-29
FR2494112B1 (en) 1986-01-10

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