WO2003061650A1 - Orodispersible pharmaceutical composition comprising mitiglinide - Google Patents

Orodispersible pharmaceutical composition comprising mitiglinide Download PDF

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Publication number
WO2003061650A1
WO2003061650A1 PCT/FR2003/000196 FR0300196W WO03061650A1 WO 2003061650 A1 WO2003061650 A1 WO 2003061650A1 FR 0300196 W FR0300196 W FR 0300196W WO 03061650 A1 WO03061650 A1 WO 03061650A1
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Prior art keywords
mitiglinide
pharmaceutical composition
orodispersible
pharmaceutically acceptable
tablet
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PCT/FR2003/000196
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French (fr)
Inventor
Patrick Wuthrich
Hervé Rolland
Marc Julien
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Les Laboratoires Servier
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Publication of WO2003061650A1 publication Critical patent/WO2003061650A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the present invention relates to a solid orodispersible pharmaceutical form for the oral administration of mitiglinide or its pharmaceutically acceptable salts, without simultaneous intake of a glass of water and without swallowing problem.
  • Mitllinide can be taken by mouth as a tablet to be swallowed with half a glass of water.
  • Mitlinlinide is more particularly in the form of the calcium salt dihydrate or bis- ⁇ (2S) -2-benzyl-4 - [(3ai-, 7aS) -octahydro-2H-isoindol-2-yl] -4- oxobutanoate ⁇ calcium, dihydrate.
  • the doses of calcium salt dihydrate of mitlinide used to obtain the desired therapeutic effect generally range from 5 mg to 40 mg per dose, three to four times a day, in the form of an immediate-release tablet.
  • the pharmaceutical compositions of the present invention not only make it possible to remedy the known drawbacks of the swallowed tablet form but also to provide a superior medical service which in particular improves the quality of life of the patients.
  • the orodispersible pharmaceutical composition of mitiglinide has the advantage of rapidly obtaining high plasma levels of active ingredient.
  • the orodispersible pharmaceutical composition according to the invention has the particularity of requiring neither water nor chewing during its administration. It disintegrates very quickly in the mouth, preferably in less than three minutes and even more preferably in less than a minute.
  • This disintegrating agent is essential in the formulation of orodispersible tablets and must be used in conjunction with a direct compression excipient.
  • the difficulties encountered in the manufacture of such tablets lie in the fact that it is very difficult to obtain tablets having constant and reproducible physical characteristics and compatible with the conventional handling constraints of the tablets.
  • oral lyophilisate Other orodispersible forms can be produced by the use of lyophilization, leading to the production of very porous solid forms called "oral lyophilisate". These forms require the use of a very specific industrial process, complicated and time-consuming, giving a medicinal form at high cost price.
  • the present invention overcomes these drawbacks. It relates to a solid orodispersible form of mitiglinide containing a simple excipient, of natural origin allowing rapid disintegration, exhibiting taste neutrality and pleasant texture. This excipient plays the role of both a binder and a disintegrant. It makes it possible to obtain a simple mitlinide formulation, having an excellent capacity for direct compression, leading to tablets of low friability and of hardness compatible with conventional handling techniques.
  • the invention relates to a solid orodispersible pharmaceutical composition of mitiglinide or of a pharmaceutically acceptable salt thereof, characterized in that it contains:
  • the mitlinide is in the form of calcium salt dihydrate.
  • composition according to the invention may also contain, for manufacturing reasons, one or more lubricants and a flow agent as well as flavors, colors and sweeteners, conventionally used.
  • Mitlinlinide may possibly be associated with excipients such as cyclodextrins or coated with excipients by the use of technologies known to those skilled in the art such as coating fluidized air bed, atomization, coacervation, prilling, spray congealing.
  • a subject of the invention is also the use of granules consisting of co-dried lactose and starch for the preparation of solid orodispersible pharmaceutical compositions of mitiglinide.
  • orodispersible is understood to mean solid pharmaceutical compositions which disintegrate in the oral cavity in less than 3 minutes, and preferably in less than a minute.
  • Said granules included in the solid pharmaceutical compositions according to the invention correspond to the compositions described in patent application EP 00 / 402159.8. These granules are characterized by a spherical structure and an advantageous compressibility and are marketed under the name STARLAC.
  • the first is based on the observation that the least water-soluble excipients are the most suitable for the formulation of orodispersible tablets (the solubilization, causing an increase in viscosity of the water, is a brake on its penetration into the tablets. ).
  • said granules comprise a large fraction of lactose very soluble in water.
  • the starch included in said granules is not a "super disintegrating" agent as used and described in the orodispersible forms of the prior art.
  • the second is based on the observation that the disintegration properties of an excipient (used in a tablet) evaluated in water by conventional methods cannot be extrapolated to the behavior of the same tablet in vivo, in saliva. Indeed, the disintegration rates in water are measured (according to the Pharmacopoeia
  • compositions according to the invention are preferably characterized in that they contain, relative to the total weight of the tablet:
  • lubricating agents such as sodium stearyl fumarate or magnesium stearate, preferably from 0.5% to 1.5%, and from 0.1% to 3 % by weight of a flow agent such as colloidal silica, preferably from 0.5% to 1.5%.
  • the tablets are prepared by mixing the constituents followed by direct compression.
  • the hardness of the tablets of Examples 1 and 2 is approximately equal to 20 Newtons.
  • the orodispersible mitlinide tablets described in examples 1 and 2 were placed in the mouth. During these tests, it turned out that for each of the formulations tested, the disintegration time in the mouth was less than 1 minute.

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Abstract

The invention relates to an orodispersible solid pharmaceutical composition comprising mitiglinide or one of the pharmaceutically-acceptable salts thereof which is characterised in that it contains mitiglinide or one of the pharmaceutically-acceptable salts thereof and granules consisting of co-dried lactose and starch.

Description

COMPOSITION PHARMACEUTIQUE ORODISPERSIBLE ORODISPERSIBLE PHARMACEUTICAL COMPOSITION
DE MITIGLINIDEFROM MITIGLINIDE
La présente invention a pour objet une forme pharmaceutique orodispersible solide pour l'administration par voie orale de mitiglinide ou de ses sels pharmaceutiquement acceptables, sans prise simultanée d'un verre d'eau et sans problème de déglutition.The present invention relates to a solid orodispersible pharmaceutical form for the oral administration of mitiglinide or its pharmaceutically acceptable salts, without simultaneous intake of a glass of water and without swallowing problem.
Le mitiglinide, ou acide (2S)-2-benzyl-4-[(3ai?,7aS)-octahydro-2H-isoindol-2-yl]-4- oxobutanoïque, est un insulinosécréteur très puissant, utile dans le traitement des diabètes non-insulinodépendants.Mitlinlinide, or (2S) -2-benzyl-4 - [(3ai?, 7aS) -octahydro-2H-isoindol-2-yl] -4- oxobutanoic acid, is a very powerful insulin-secreting agent, useful in the treatment of diabetes non-insulin-dependent.
Le mitiglinide peut être administré par voie orale sous forme de comprimés à avaler avec un demi-verre d'eau.Mitllinide can be taken by mouth as a tablet to be swallowed with half a glass of water.
Le mitiglinide se présente plus particulièrement sous forme de sel de calcium dihydraté ou bis- {(2S)-2-benzyl-4-[(3ai-,7aS)-octahydro-2H-isoindol-2-yl]-4- oxobutanoate} de calcium, dihydraté.Mitlinlinide is more particularly in the form of the calcium salt dihydrate or bis- {(2S) -2-benzyl-4 - [(3ai-, 7aS) -octahydro-2H-isoindol-2-yl] -4- oxobutanoate} calcium, dihydrate.
Les doses de sel de calcium dihydraté de mitiglinide utilisées pour obtenir l'effet thérapeutique souhaité vont généralement de 5 mg à 40 mg par prise, trois à quatre fois par jour, sous la forme de comprimé à libération immédiate.The doses of calcium salt dihydrate of mitlinide used to obtain the desired therapeutic effect generally range from 5 mg to 40 mg per dose, three to four times a day, in the form of an immediate-release tablet.
De nombreuses personnes ont des difficultés pour avaler les comprimés conventionnels souvent de taille non négligeable. Les problèmes liés à l'ingestion de médicaments (étouffement, suffocation par obstruction de la gorge) sont souvent à l'origine d'un mauvais respect des posologies, voire d'un arrêt du traitement.Many people find it difficult to swallow conventional tablets, which are often large. Problems related to the ingestion of drugs (choking, suffocation by obstruction of the throat) are often the cause of poor compliance with dosages, or even stopping treatment.
Les compositions pharmaceutiques de la présente invention permettent non seulement de remédier aux inconvénients connus de la forme comprimé à avaler mais également de proposer un service médical rendu supérieur permettant notamment l'amélioration de la qualité de vie des patients. La composition pharmaceutique orodispersible de mitiglinide présente l'avantage d'une obtention rapide de taux plasmatiques élevés en principe actif.The pharmaceutical compositions of the present invention not only make it possible to remedy the known drawbacks of the swallowed tablet form but also to provide a superior medical service which in particular improves the quality of life of the patients. The orodispersible pharmaceutical composition of mitiglinide has the advantage of rapidly obtaining high plasma levels of active ingredient.
La composition pharmaceutique orodispersible selon l'invention présente la particularité de ne nécessiter ni eau ni mastication au cours de son administration. Elle se désagrège très rapidement dans la bouche, de préférence en moins de trois minutes et de manière encore plus préférentielle en moins d'une minute.The orodispersible pharmaceutical composition according to the invention has the particularity of requiring neither water nor chewing during its administration. It disintegrates very quickly in the mouth, preferably in less than three minutes and even more preferably in less than a minute.
De nombreuses formes à dissolution rapide sont décrites dans l'art antérieur. De manière générale, les technologies décrites précédemment ont en commun l'utilisation d'un agent désintégrant comme le Kollidon® CL (polyvinylpyrrolidone réticulée), l'EXPLOTAB® (fécule carboxyméthylée), l'AC DISOL® (carboxyméthylcellulose sodique réticulée).Many rapidly dissolving forms are described in the prior art. In general, the technologies described above have in common the use of a disintegrating agent such as Kollidon ® CL (crosslinked polyvinylpyrrolidone), EXPLOTAB ® the (carboxymethylated starch), AC DISOL ® (crosslinked sodium carboxymethylcellulose).
Cet agent de désintégration est indispensable dans la formulation des comprimés orodispersibles et doit être utilisé conjointement avec un excipient de compression directe. Les difficultés rencontrées pour la fabrication de tels comprimés résident dans le fait qu'il est très difficile d'obtenir des comprimés présentant des caractéristiques physiques constantes et reproductibles et compatibles avec les contraintes de manipulation classiques des comprimés.This disintegrating agent is essential in the formulation of orodispersible tablets and must be used in conjunction with a direct compression excipient. The difficulties encountered in the manufacture of such tablets lie in the fact that it is very difficult to obtain tablets having constant and reproducible physical characteristics and compatible with the conventional handling constraints of the tablets.
En effet, les mélanges classiquement utilisés conduisent à des comprimés de dureté très élevée totalement inadaptée à une désagrégation rapide dans la cavité buccale.Indeed, the mixtures conventionally used lead to tablets of very high hardness totally unsuitable for rapid disintegration in the oral cavity.
D'autres formes orodispersibles sont réalisables par l'utilisation de la lyophilisation aboutissant à l'obtention de formes solides très poreuses dénommées "lyophilisât oral". Ces formes nécessitent l'utilisation d'un procédé industriel très spécifique, compliqué et long de mise en oeuvre, donnant une forme médicamenteuse à prix de revient élevé.Other orodispersible forms can be produced by the use of lyophilization, leading to the production of very porous solid forms called "oral lyophilisate". These forms require the use of a very specific industrial process, complicated and time-consuming, giving a medicinal form at high cost price.
La présente invention permet de remédier à ces inconvénients. Elle concerne une forme solide orodispersible de mitiglinide contenant un excipient simple, d'origine naturelle permettant la désagrégation rapide, présentant une neutralité gustative et de texture agréable. Cet excipient joue le rôle à la fois de liant et de désintégrant. Il permet d'obtenir une formulation de mitiglinide simple, ayant une excellente aptitude à la compression directe conduisant à des comprimés de faible friabilité et de dureté compatible avec les techniques classiques de manipulation.The present invention overcomes these drawbacks. It relates to a solid orodispersible form of mitiglinide containing a simple excipient, of natural origin allowing rapid disintegration, exhibiting taste neutrality and pleasant texture. This excipient plays the role of both a binder and a disintegrant. It makes it possible to obtain a simple mitlinide formulation, having an excellent capacity for direct compression, leading to tablets of low friability and of hardness compatible with conventional handling techniques.
Plus particulièrement, l'invention concerne une composition pharmaceutique solide orodispersible de mitiglinide ou d'un de ses sels pharmaceutiquement acceptables, caractérisée en ce qu'elle contient :More particularly, the invention relates to a solid orodispersible pharmaceutical composition of mitiglinide or of a pharmaceutically acceptable salt thereof, characterized in that it contains:
- du mitiglinide ou un de ses sels pharmaceutiquement acceptables,- mitiglinide or one of its pharmaceutically acceptable salts,
- et des granules consistant en lactose et amidon coséchés.- and granules consisting of co-dried lactose and starch.
De manière préférentielle, le mitiglinide se présente sous forme de sel de calcium dihydraté.Preferably, the mitlinide is in the form of calcium salt dihydrate.
La composition selon l'invention peut également contenir, pour des raisons de fabrication, un ou plusieurs lubrifiants et un agent d'écoulement ainsi que des arômes, des colorants et des édulcorants, classiquement utilisés.The composition according to the invention may also contain, for manufacturing reasons, one or more lubricants and a flow agent as well as flavors, colors and sweeteners, conventionally used.
Pour améliorer le masquage d'amertume du mitiglinide, celui-ci pourra éventuellement être associé à des excipients comme les cyclodextrines ou enrobé avec des excipients par l'utilisation de technologies connues de l'Homme de l'Art comme par exemple l'enrobage en lit d'air fluidisé, l'atomisation, la coacervation, le prilling, le spray congealing.To improve the masking of bitterness of Mitlinlinide, it may possibly be associated with excipients such as cyclodextrins or coated with excipients by the use of technologies known to those skilled in the art such as coating fluidized air bed, atomization, coacervation, prilling, spray congealing.
L'invention a également pour objet l'utilisation de granules consistant en lactose et amidon coséchés pour la préparation de compositions pharmaceutiques solides orodispersibles de mitiglinide.A subject of the invention is also the use of granules consisting of co-dried lactose and starch for the preparation of solid orodispersible pharmaceutical compositions of mitiglinide.
On entend par le terme "orodispersible" des compositions pharmaceutiques solides qui se délitent dans la cavité buccale en moins de 3 minutes, et de préférence en moins d'une minute. Lesdits granules compris dans les compositions pharmaceutiques solides selon l'invention correspondent aux compositions décrites dans la demande de brevet EP 00/402159.8. Ces granules sont caractérisés par une structure sphérique et une comprimabilité avantageuse et sont commercialisés sous l'appellation STARLAC .The term "orodispersible" is understood to mean solid pharmaceutical compositions which disintegrate in the oral cavity in less than 3 minutes, and preferably in less than a minute. Said granules included in the solid pharmaceutical compositions according to the invention correspond to the compositions described in patent application EP 00 / 402159.8. These granules are characterized by a spherical structure and an advantageous compressibility and are marketed under the name STARLAC.
Les propriétés désintégrantes desdits granules sont connues pour des comprimés placés dans des volumes de liquides importants, sous agitation. Il est particulièrement surprenant que de tels granules employés pour la fabrication de formes orodispersibles puissent donner des résultats particulièrement satisfaisants en terme de désagrégation en bouche, et ce pour deux raisons.The disintegrating properties of said granules are known for tablets placed in large volumes of liquids, with stirring. It is particularly surprising that such granules used for the manufacture of orodispersible forms can give particularly satisfactory results in terms of disintegration in the mouth, for two reasons.
La première est basée sur le constat que les excipients les moins solubles dans l'eau sont les plus appropriés à la fonnulation de comprimés orodispersibles (la solubilistion, entraînant une augmentation de viscosité de l'eau, est un frein à sa pénétration dans les comprimés). Or lesdits granules comprennent une fraction importante de lactose très soluble dans l'eau. De plus, l'amidon compris dans lesdits granules n'est pas un agent "super désintégrant" tel qu'utilisé et décrit dans les formes orodispersibles de l'art antérieur.The first is based on the observation that the least water-soluble excipients are the most suitable for the formulation of orodispersible tablets (the solubilization, causing an increase in viscosity of the water, is a brake on its penetration into the tablets. ). However, said granules comprise a large fraction of lactose very soluble in water. In addition, the starch included in said granules is not a "super disintegrating" agent as used and described in the orodispersible forms of the prior art.
La deuxième est basée sur le constat que les propriétés de désintégration d'un excipient (utilisé dans un comprimé) évaluées dans l'eau par les méthodes conventionnelles ne sont pas extrapolables au comportement du même comprimé in vivo, dans la salive. En effet, les vitesses de désintégration dans l'eau sont mesurées (selon la PharmacopéeThe second is based on the observation that the disintegration properties of an excipient (used in a tablet) evaluated in water by conventional methods cannot be extrapolated to the behavior of the same tablet in vivo, in saliva. Indeed, the disintegration rates in water are measured (according to the Pharmacopoeia
Européenne) dans une quantité d'eau suffisamment importante pour ne pas atteindre la saturation en terme de solubilisation, alors que in vivo, de par le faible volume de salive, les excipients sont à saturation. De plus, l'agitation à laquelle sont soumis les comprimés lors du test usuel ne reflète pas la désagrégation en bouche. La Demanderesse a ainsi constaté lors d'essais comparatifs que certains excipients connus comme bons désintégrants n'étaient pas adaptés à la préparation de formes orodispersibles. Inversement, certains excipients se désintégrant moyennement dans l'eau peuvent présenter des propriétés avantageuses in vivo.European) in a quantity of water large enough not to reach saturation in terms of solubilization, while in vivo, due to the small volume of saliva, the excipients are at saturation. In addition, the agitation to which the tablets are subjected during the usual test does not reflect the disintegration in the mouth. The Applicant has thus found during comparative tests that certain excipients known as good disintegrants were not suitable for the preparation of orodispersible forms. Conversely, certain excipients which disintegrate moderately in water may have advantageous properties in vivo.
La Demanderesse a alors trouvé que lesdits granules conféraient de façon surprenante aux comprimés de très bonnes aptitudes à se désagréger en bouche, et ce pour une large gamme de duretés de comprimés, tout en conservant une friabilité faible ce qui est particulièrement remarquable. En effet, la plupart des formes orodispersbiles de l'art antérieur qui se délitent rapidement dans la bouche sont très friables, ce qui se traduit par la nécessité d'utiliser un conditionnement spécifique et par des risques de désagrégation du comprimé dès qu'il est manipulé et ôté de son emballage.The Applicant then found that said granules conferred surprisingly tablets with very good ability to disintegrate in the mouth, for a wide range of tablet hardnesses, while retaining low friability, which is particularly remarkable. In fact, most of the orodispersible forms of the prior art which disintegrate quickly in the mouth are very brittle, which results in the need to use specific packaging and in risks of disintegration of the tablet as soon as it is handled and removed from its packaging.
Il est particulièrement remarquable que les critères d'orodispersibilité et de friabilité faible précités soient respectés pour une large gamme de dureté de comprimés, c'est-à- dire pour des comprimés présentant une dureté comprise entre 15 et 30 Newtons.It is particularly noteworthy that the aforementioned orodispersibility and low friability criteria are met for a wide range of tablet hardness, that is to say for tablets having a hardness of between 15 and 30 Newtons.
Les compositions pharmaceutiques selon l'invention sont préférentiellement caractérisées en ce qu'elles contiemient, par rapport au poids total du comprimé :The pharmaceutical compositions according to the invention are preferably characterized in that they contain, relative to the total weight of the tablet:
- de 2,5 % à 20 % en poids de mitiglinide ou d'un de ses sels pharmaceutiquement acceptables,- from 2.5% to 20% by weight of mitiglinide or one of its pharmaceutically acceptable salts,
- de 75 % à 95 % en poids de STARLAC®.- from 75% to 95% by weight of STARLAC ® .
Elles contiendront éventuellement de 0,1 % à 3 % en poids d'agents lubrifiants comme le stéaryl-fumarate de sodium ou le stéarate de magnésium, préférentiellement de 0,5 % à 1,5 %, et de 0,1 % à 3 % en poids d'un agent d'écoulement comme la silice colloïdale, préférentiellement de 0,5 % à 1,5 %.They will optionally contain from 0.1% to 3% by weight of lubricating agents such as sodium stearyl fumarate or magnesium stearate, preferably from 0.5% to 1.5%, and from 0.1% to 3 % by weight of a flow agent such as colloidal silica, preferably from 0.5% to 1.5%.
Les exemples suivants illustrent l'invention mais ne la limitent en aucune façon :The following examples illustrate the invention but do not limit it in any way:
Comprimés orodispersibles de mitiglinideMitlinide orodispersible tablets
EXEMPLE 1 : Formulation : Comprimé terminé à 100 gEXAMPLE 1 Formulation: Tablet finished at 100 g
Figure imgf000006_0001
EXEMPLE 2 :
Figure imgf000006_0001
EXAMPLE 2:
Formulation : Comprimé terminé à 400 mgFormulation: 400 mg finished tablet
Figure imgf000007_0001
Figure imgf000007_0001
Les comprimés sont préparés par mélange des constituants suivi d'une compression directe. La dureté des comprimés des exemples 1 et 2 est environ égale à 20 Newtons.The tablets are prepared by mixing the constituents followed by direct compression. The hardness of the tablets of Examples 1 and 2 is approximately equal to 20 Newtons.
Afin d'évaluer le temps de désagrégation en bouche, les comprimés orodispersibles de mitiglinide décrits dans les exemples 1 et 2 ont été placés dans la bouche. Lors de ces tests, il s'est avéré que pour chacune des formulations testées le temps de désagrégation dans la bouche était inférieur à 1 minute. In order to evaluate the disintegration time in the mouth, the orodispersible mitlinide tablets described in examples 1 and 2 were placed in the mouth. During these tests, it turned out that for each of the formulations tested, the disintegration time in the mouth was less than 1 minute.

Claims

REVENDICATIONS
1- Composition pharmaceutique solide orodispersible de mitiglinide ou de ses sels pharmaceutiquement acceptables, caractérisée en ce qu'elle comprend :1- Solid orodispersible pharmaceutical composition of mitiglinide or its pharmaceutically acceptable salts, characterized in that it comprises:
- du mitiglinide, ou un de ses sels pharmaceutiquement acceptables, - des granules consistant en lactose et amidon coséchés.- mitiglinide, or one of its pharmaceutically acceptable salts, - granules consisting of co-dried lactose and starch.
2- Composition pharmaceutique selon la revendication 1 caractérisée en ce qu'elle comprend, par rapport au poids total de la composition :2- Pharmaceutical composition according to claim 1 characterized in that it comprises, relative to the total weight of the composition:
- de 2,5 % à 20 % en poids de mitiglinide ou d'un de ses sels pharmaceutiquement acceptables, - de 75 % à 95 % en poids de granules consistant en lactose et amidon coséchés.- from 2.5% to 20% by weight of mitiglinide or a pharmaceutically acceptable salt thereof, - from 75% to 95% by weight of granules consisting of co-dried lactose and starch.
3- Composition pharmaceutique selon la revendication 2 caractérisée en ce qu'elle comprend de 5 % à 10 % en poids de mitiglinide ou d'un de ses sels pharmaceutiquement acceptables.3- Pharmaceutical composition according to claim 2 characterized in that it comprises from 5% to 10% by weight of mitiglinide or one of its pharmaceutically acceptable salts.
4- Composition pharmaceutique selon la revendication 1 caractérisée en ce qu'elle comprend également un ou plusieurs lubrifiants, et un agent d'écoulement.4- Pharmaceutical composition according to claim 1 characterized in that it also comprises one or more lubricants, and a flow agent.
5- Composition pharmaceutique selon la revendication 1 caractérisée en ce qu'elle se présente sous forme de comprimé.5- Pharmaceutical composition according to claim 1 characterized in that it is in the form of tablet.
6- Comprimé selon la revendication 5 caractérisé en ce qu'il est obtenu par compression directe.6- Tablet according to claim 5 characterized in that it is obtained by direct compression.
7- Comprimé selon la revendication 6 caractérisé en ce que sa dureté est comprise entre 15 et 50 Newtons.7- Tablet according to claim 6 characterized in that its hardness is between 15 and 50 Newtons.
8- Comprimé selon la revendication 7 caractérisé en ce que sa dureté est environ égale à 20 Newtons. 9- Utilisation de granules consistant en lactose et amidon coséchés dans la fabrication des compositions solides orodispersibles de mitiglinide se délitant en bouche en moins de trois minutes et de préférence en moins d'une minute.8- Tablet according to claim 7 characterized in that its hardness is approximately equal to 20 Newtons. 9- Use of granules consisting of co-dried lactose and starch in the manufacture of solid orodispersible compositions of mitiglinide disintegrating in the mouth in less than three minutes and preferably in less than a minute.
10- Composition pharmaceutique solide orodispersible de mitiglinide ou d'un de ses sels pharmaceutiquement acceptables, selon la revendication 1, utile pour le traitement du diabète. 10- solid orodispersible pharmaceutical composition of mitiglinide or a pharmaceutically acceptable salt thereof, according to claim 1, useful for the treatment of diabetes.
PCT/FR2003/000196 2002-01-23 2003-01-22 Orodispersible pharmaceutical composition comprising mitiglinide WO2003061650A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0200794A FR2834892B1 (en) 2002-01-23 2002-01-23 ORODISPERSIBLE PHARMACEUTICAL COMPOSITION OF MITIGLINIDE
FR0200794 2002-01-23

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FR (1) FR2834892B1 (en)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1552830A1 (en) * 2002-06-28 2005-07-13 Kissei Pharmaceutical Co., Ltd. Drug composition for prevention or inhibition of advance of diabetic complication
WO2008018371A1 (en) 2006-08-08 2008-02-14 Kissei Pharmaceutical Co., Ltd. Oral disintegrating tablet having masked bitter taste and method for production thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0192080A2 (en) * 1985-02-22 1986-08-27 Meggle Milchindustrie GmbH & Co. KG Instant pelleting agent
EP0745382A1 (en) * 1994-01-31 1996-12-04 Yamanouchi Pharmaceutical Co. Ltd. Intraorally soluble compressed molding and process for producing the same
FR2765578A1 (en) * 1997-07-03 1999-01-08 Adir PROCESS FOR THE PREPARATION OF A SUBSTITUTED PERHYDROISOINDOLE
EP1175899A1 (en) * 2000-07-27 2002-01-30 Roquette Frˬres Starch and lactose granulate

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0192080A2 (en) * 1985-02-22 1986-08-27 Meggle Milchindustrie GmbH & Co. KG Instant pelleting agent
EP0745382A1 (en) * 1994-01-31 1996-12-04 Yamanouchi Pharmaceutical Co. Ltd. Intraorally soluble compressed molding and process for producing the same
FR2765578A1 (en) * 1997-07-03 1999-01-08 Adir PROCESS FOR THE PREPARATION OF A SUBSTITUTED PERHYDROISOINDOLE
EP1175899A1 (en) * 2000-07-27 2002-01-30 Roquette Frˬres Starch and lactose granulate

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1552830A1 (en) * 2002-06-28 2005-07-13 Kissei Pharmaceutical Co., Ltd. Drug composition for prevention or inhibition of advance of diabetic complication
EP1552830A4 (en) * 2002-06-28 2007-07-18 Kissei Pharmaceutical Drug composition for prevention or inhibition of advance of diabetic complication
WO2008018371A1 (en) 2006-08-08 2008-02-14 Kissei Pharmaceutical Co., Ltd. Oral disintegrating tablet having masked bitter taste and method for production thereof
JP2013127009A (en) * 2006-08-08 2013-06-27 Kissei Pharmaceutical Co Ltd Oral disintegrating tablet having masked bitter taste and method for producing the same
JP5237098B2 (en) * 2006-08-08 2013-07-17 キッセイ薬品工業株式会社 Orally disintegrating tablet masking bitterness and method for producing the same

Also Published As

Publication number Publication date
AR038208A1 (en) 2005-01-05
FR2834892B1 (en) 2004-02-27
FR2834892A1 (en) 2003-07-25

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