EP1776093A1 - Compositions containing nicorandil, preparation method and use - Google Patents

Compositions containing nicorandil, preparation method and use

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Publication number
EP1776093A1
EP1776093A1 EP05786080A EP05786080A EP1776093A1 EP 1776093 A1 EP1776093 A1 EP 1776093A1 EP 05786080 A EP05786080 A EP 05786080A EP 05786080 A EP05786080 A EP 05786080A EP 1776093 A1 EP1776093 A1 EP 1776093A1
Authority
EP
European Patent Office
Prior art keywords
composition
nicorandil
parts
premix
tablet
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05786080A
Other languages
German (de)
French (fr)
Inventor
Mathieu Nocent
Thierry Bonhomme
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharma SA
Original Assignee
Rhone Poulenc Rorer SA
Aventis Pharma SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rhone Poulenc Rorer SA, Aventis Pharma SA filed Critical Rhone Poulenc Rorer SA
Publication of EP1776093A1 publication Critical patent/EP1776093A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention particularly relates to Nicorandil-containing compositions, process for their preparation, tablets containing these compositions, and their use as a medicament.
  • the invention relates to a composition containing Nicorandil, which has the advantage of allowing a significant simplification of the industrial process for manufacturing tablets containing it.
  • a process comprising a granulation step is described in EP 0230932 B1.
  • Examples 1, 2, 4, 5, and 6 describe processes implementing a granulation step.
  • the use of a granulation step makes it possible to obtain tablets having a better stability than when this step is absent (Tables 1 to 7, Examples 3, 7, 8). This is one of the reasons why it was chosen to use a granulation process for the commercial product.
  • Example 3 of EP 0230932 B1 describes a process in which, in a first step, the active ingredient is mixed with stearic acid, and then the mixture is micronized. However, the stability of the compositions obtained is not satisfactory (Table 3, page 5: 97.3% after 3 months at 40 ° C., 0% residual moisture). For comparison, Example 2 (99.4%) is the one that has the closest stability to the commercial composition.
  • This direct compression composition comprises active ingredient (Nicorandil) and a saturated higher aliphatic acid or a non-micronized saturated higher alcohol.
  • a saturated higher aliphatic acid or a saturated higher acceptable alcohol must be solid at ambient temperature, that is to say at a temperature close to 20 to 25 ° C.
  • Preferred saturated higher aliphatic acids or alcohols will still be solid at a temperature close to 40 ° C., preferably 50 ° C.
  • Particularly preferred saturated aliphatic acids may be chosen from palmitic acid and stearic acid.
  • Particularly preferred saturated aliphatic alcohols may be selected from hexadecanoic and octadecanoic alcohols, preferably hexadecan-1-ol and octadecan-1-ol.
  • a composition according to the invention advantageously comprises (i) Nicorandil, and (ii) a lubricant chosen from a saturated higher aliphatic acid and its salts and / or saturated higher alcohol, solid at ambient temperature, in which the lubricant is not micronized.
  • a preferred lubricant is stearic acid.
  • a composition according to the invention may further comprise a disintegrant and a diluent.
  • a preferred disintegrant is croscarmellose sodium.
  • a preferred diluent is mannitol.
  • a composition according to the invention advantageously comprises, by weight, 10% Nicorandil, and a lubricant, solid at room temperature, non-micronized.
  • a composition according to the invention preferably comprises 8% non-micronized stearic acid.
  • a composition according to the invention advantageously comprises a disintegrant, preferably 5% of croscarmellose sodium.
  • a composition according to the invention advantageously comprises a diluent, preferably mannitol, in particular 76% by weight.
  • the invention relates to a method for preparing a composition according to its first aspect.
  • the preparation method according to the second aspect of the invention comprises a first step in which, by weight, 30 parts of Nicorandil, 15 parts of croscarmellose sodium, 35 parts of mannitol and 3 parts of corn starch are mixed. to form a first premix.
  • the first premix is preferably calibrated.
  • the method according to the invention may further comprise a second step in which the first calibrated premix is mixed with 193 parts by weight of mannitol to form a second premix.
  • the process according to the invention may further comprise a third step in which the second premix is mixed with 24 parts by weight of non-micronized stearic acid.
  • the invention relates to a composition for direct compression, obtained by a method according to its second aspect.
  • the invention relates to a method for preparing a tablet comprising Nicorandil, comprising a first step (i) in which a composition for direct compression according to its third aspect is disposed in a mold cavity, comprising a second step (ii) in which a counter-cavity of the mold is applied against the impression so that the composition for direct compression is captive in an enclosure of volume V1 of the mold, and further comprising a third step (iii) in wherein the volume V1 of the mold is reduced to a volume VO less than the volume V1 by compression until a tablet is obtained.
  • the method according to its fourth aspect advantageously comprises a fourth step (iv), in which the impression and the counterprint are disjoint and the tablet is extracted from the enclosure.
  • the invention relates to a tablet obtained according to its fourth aspect.
  • the invention relates to a tablet package according to the fifth acceptable aspect, in particular a blister or a bottle.
  • CONTAINER Phase 2 Manufacture of Ikorel tablets
  • composition comprising Nicorandil according to the invention can be prepared as follows: 1) Composition according to the invention:
  • the water content is systematically lower for the batch of product obtained via the process according to the invention.
  • Nicorandil are as stable over time for the tablets according to the invention as for the commercial tablets.
  • Lot LOP107 CD is a batch obtained by the method according to the invention, described above.
  • Figures 1 to 3 are graphical representations of the evolution of the Nicorandil content as a function of time for, respectively, tablets preserved in blisters at 25 ° C, 60% RH; 30 0 C, 65% RH; and 40 0 C, 75% RH; the latter corresponding to the values presented in Table 14.
  • FIGS. 4 to 6 are graphical representations of the evolution of the content of impurities as a function of time for, respectively, tablets preserved in blisters at 25 ° C., 60% RH; 30 0 C, 65% RH; and 40 0 C, 75% RH; the latter corresponding to the values presented in Table 14. Discussion
  • the active ingredient content of the batch obtained by the process according to the invention is equivalent to that measured in the batches obtained by the current process. It is the same for the concentrations of impurities.
  • the active ingredient content of the batch obtained by the process according to the invention is better or equivalent to that measured in the batches obtained by the current process. It is the same for the concentrations of impurities.
  • the tablets according to the invention have qualities of stability quite remarkable vis-à-vis the tablets according to the current method. It is necessary to remember that the stability conditions considered here are drastic conditions for this product, for which strict conservation conditions are recommended (temperature ⁇ 25 ° C.).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention concerns compositions containing Nicorandil, compositions obtained by said method and use thereof. The invention concerns in particular a method for preparing compositions containing Nicorandil, compositions obtained by said method, tablets obtained by direct compression, and their use as medicine.

Description

COMPOSITIONS CONTENANT DU NICORANDIL, PROCEDE DE PREPARATION ET UTILISATION COMPOSITIONS CONTAINING NICORANDIL, PROCESS FOR PREPARATION AND USE
La présente invention concerne notamment des compositions contenant du Nicorandil, leur procédé de préparation, des comprimés contenant ces compositions, et leur utilisation comme médicament.The present invention particularly relates to Nicorandil-containing compositions, process for their preparation, tablets containing these compositions, and their use as a medicament.
Plus particulièrement, et selon un premier aspect, l'invention concerne une composition contenant du Nicorandil, qui a l'avantage de permettre une simplification importante du procédé industriel de fabrication de comprimés le contenant.More particularly, and according to a first aspect, the invention relates to a composition containing Nicorandil, which has the advantage of allowing a significant simplification of the industrial process for manufacturing tablets containing it.
Le procédé utilisé actuellement au niveau industriel pour la préparation de comprimés de Nicorandil (DCI) (Ikorel ®) passe par une étape de granulation précédant l'étape de formation du comprimé.The process currently used industrially for the preparation of Nicorandil (INN) tablets (Ikorel®) passes through a granulation step preceding the tablet forming step.
Un procédé comprenant une étape de granulation est décrit dans le brevet EP 0230932 B1. Dans ce brevet, les exemples 1 , 2, 4, 5, et 6 décrivent des procédés mettant en œuvre une étape de granulation. D'une manière générale, on constate que l'utilisation d'une étape de granulation permet d'obtenir des comprimés ayant une meilleure stabilité que lorsque cette étape est absente (tableaux 1 à 7, exemples 3, 7, 8). C'est d'ailleurs une des raisons pour lesquelles il a été choisi d'utiliser un procédé par granulation pour le produit commercial.A process comprising a granulation step is described in EP 0230932 B1. In this patent, Examples 1, 2, 4, 5, and 6 describe processes implementing a granulation step. In general, it is found that the use of a granulation step makes it possible to obtain tablets having a better stability than when this step is absent (Tables 1 to 7, Examples 3, 7, 8). This is one of the reasons why it was chosen to use a granulation process for the commercial product.
Des excipients commerciaux permettent habituellement d'obtenir des compositions acceptables pour une compression directe. En général, ces excipients sont sous forme granulée, et sont commercialisés sous l'appellation « pour compression directe ». Malheureusement, en raison de problèmes de stabilité inhérents au principe actif, il n'a pas été possible, jusqu'à maintenant, de disposer d'une formulation pour compression directe permettant l'obtention de comprimés suffisamment stables dans le temps. L'exemple 3 du brevet EP 0230932 B1 décrit un procédé dans lequel, lors d'une première étape, le principe actif est mélangé à de l'acide stéarique, puis le mélange est micronisé. Toutefois, la stabilité des compositions obtenues n'est pas satisfaisante (tableau 3, page 5 : 97,3 % après 3 mois à 4O0C, 0 % d'humidité résiduelle). A titre de comparaison, l'exemple 2 (99,4 %) est celui qui a la stabilité la plus proche de la composition commerciale.Commercial excipients usually provide acceptable compositions for direct compression. In general, these excipients are in granulated form, and are marketed under the name "for direct compression". Unfortunately, because of stability problems inherent in the active ingredient, it has not been possible until now to have a formulation for direct compression to obtain tablets sufficiently stable over time. Example 3 of EP 0230932 B1 describes a process in which, in a first step, the active ingredient is mixed with stearic acid, and then the mixture is micronized. However, the stability of the compositions obtained is not satisfactory (Table 3, page 5: 97.3% after 3 months at 40 ° C., 0% residual moisture). For comparison, Example 2 (99.4%) is the one that has the closest stability to the commercial composition.
Dans EP 0230932 B1 , page 2, lignes 32-36, il est écrit qu'une solution acceptable au problème de stabilité des comprimés peut être obtenue par le mélange entre du Nicorandil et un acide ou alcool aliphatique saturé. Toutefois, cette solution ne donne pas pleinement satisfaction, comme on peut le constater à la lecture des résultats de mesure de stabilité, discutés précédemment.In EP 0230932 B1, page 2, lines 32-36, it is written that an acceptable solution to the tablet stability problem can be obtained by mixing between Nicorandil and a saturated aliphatic acid or alcohol. However, this solution does not give full satisfaction, as can be seen from the reading of the stability measurement results, discussed above.
Contre toute attente, il a été trouvé qu'il est possible d'obtenir une composition pour compression directe qui ait une stabilité équivalente à la meilleure composition obtenue via une étape de granulation, qui est la composition commerciale.Surprisingly, it has been found that it is possible to obtain a composition for direct compression which has a stability equivalent to the best composition obtained via a granulation step, which is the commercial composition.
Cette composition pour compression directe comprend du principe actif (Nicorandil) et un acide aliphatique supérieur saturé ou un alcool supérieur saturé non micronisé. Un acide aliphatique supérieur saturé ou un alcool supérieur saturé acceptable doit être solide à température ambiante, c'est à dire à une température proche de 20 à 250C. Des acides ou alcools aliphatiques supérieurs saturés préférés seront encore solides à une température voisine de 400C, de préférence de 5O0C.This direct compression composition comprises active ingredient (Nicorandil) and a saturated higher aliphatic acid or a non-micronized saturated higher alcohol. A saturated higher aliphatic acid or a saturated higher acceptable alcohol must be solid at ambient temperature, that is to say at a temperature close to 20 to 25 ° C. Preferred saturated higher aliphatic acids or alcohols will still be solid at a temperature close to 40 ° C., preferably 50 ° C.
Des acides aliphatiques saturés particulièrement préférés peuvent être choisis parmi l'acide palmitique et l'acide stéarique.Particularly preferred saturated aliphatic acids may be chosen from palmitic acid and stearic acid.
Des alcools aliphatiques saturés particulièrement préférés peuvent être choisis parmi les alcools hexadécanoïques et octadécanoïques, de préférence l'hexadécan-1-ol et Poctadécan-1-ol.Particularly preferred saturated aliphatic alcohols may be selected from hexadecanoic and octadecanoic alcohols, preferably hexadecan-1-ol and octadecan-1-ol.
Une composition selon l'invention comprend avantageusement (i) du Nicorandil, et (ii) un lubrifiant choisi parmi un acide aliphatique supérieur saturé et ses sels et/ou alcool supérieur saturé, solide à température ambiante, dans laquelle le lubrifiant n'est pas micronisé.A composition according to the invention advantageously comprises (i) Nicorandil, and (ii) a lubricant chosen from a saturated higher aliphatic acid and its salts and / or saturated higher alcohol, solid at ambient temperature, in which the lubricant is not micronized.
Un lubrifiant préféré est de l'acide stéarique.A preferred lubricant is stearic acid.
Une composition selon l'invention peut en outre comprendre un désintégrant et un diluant. Un désintégrant préféré est du croscarmellose sodique.A composition according to the invention may further comprise a disintegrant and a diluent. A preferred disintegrant is croscarmellose sodium.
Un diluant préféré est du mannitol.A preferred diluent is mannitol.
Une composition selon l'invention comprend avantageusement, en poids, 10 % de Nicorandil, et un lubrifiant, solide à température ambiante, non micronisé.A composition according to the invention advantageously comprises, by weight, 10% Nicorandil, and a lubricant, solid at room temperature, non-micronized.
Une composition selon l'invention comprend de préférence 8 % d'acide stéarique non micronisé.A composition according to the invention preferably comprises 8% non-micronized stearic acid.
Une composition selon l'invention comprend avantageusement un désintégrant, de préférence 5 % de croscarmellose sodique.A composition according to the invention advantageously comprises a disintegrant, preferably 5% of croscarmellose sodium.
Une composition selon l'invention comprend avantageusement un diluant, de préférence du mannitol, en particulier 76 % en poids.A composition according to the invention advantageously comprises a diluent, preferably mannitol, in particular 76% by weight.
Selon un second aspect, l'invention concerne un procédé de préparation d'une composition selon son premier aspect.According to a second aspect, the invention relates to a method for preparing a composition according to its first aspect.
En particulier, le procédé de préparation selon le second aspect de l'invention comprend une première étape dans laquelle, en poids, 30 parties de Nicorandil, 15 parties de croscarmellose sodique, 35 parties de mannitol et 3 parties d'amidon de maïs sont mélangées pour former un premier pré¬ mélange.In particular, the preparation method according to the second aspect of the invention comprises a first step in which, by weight, 30 parts of Nicorandil, 15 parts of croscarmellose sodium, 35 parts of mannitol and 3 parts of corn starch are mixed. to form a first premix.
Le premier pré-mélange est, de préférence, calibré.The first premix is preferably calibrated.
Le procédé selon l'invention peut comprendre en outre une deuxième étape dans laquelle le premier pré-mélange calibré est mélangé à 193 parties en poids de mannitol pour former un deuxième pré-mélange.The method according to the invention may further comprise a second step in which the first calibrated premix is mixed with 193 parts by weight of mannitol to form a second premix.
Le procédé selon l'invention peut comprendre en outre une troisième étape dans laquelle le deuxième pré-mélange est mélangé à 24 parties en poids d'acide stéarique non micronisé.The process according to the invention may further comprise a third step in which the second premix is mixed with 24 parts by weight of non-micronized stearic acid.
Selon un troisième aspect, l'invention concerne une composition pour compression directe, obtenue par un procédé selon son second aspect. Selon un quatrième aspect, l'invention concerne un procédé de préparation d'un comprimé comprenant du Nicorandil, comprenant une première étape (i) dans laquelle une composition pour compression directe selon son troisième aspect est disposée dans une empreinte d'un moule, comprenant une seconde étape (ii) dans laquelle une contre-empreinte du moule est appliquée contre l'empreinte de sorte que la composition pour compression directe est captive dans une enceinte de volume V1 du moule, et comprenant en outre une troisième étape (iii) dans laquelle le volume V1 du moule est réduit à un volume VO inférieur au volume V1 par compression jusqu'à l'obtention d'un comprimé.According to a third aspect, the invention relates to a composition for direct compression, obtained by a method according to its second aspect. According to a fourth aspect, the invention relates to a method for preparing a tablet comprising Nicorandil, comprising a first step (i) in which a composition for direct compression according to its third aspect is disposed in a mold cavity, comprising a second step (ii) in which a counter-cavity of the mold is applied against the impression so that the composition for direct compression is captive in an enclosure of volume V1 of the mold, and further comprising a third step (iii) in wherein the volume V1 of the mold is reduced to a volume VO less than the volume V1 by compression until a tablet is obtained.
Le procédé selon son quatrième aspect comprend avantageusement une quatrième étape (iv), dans laquelle l'empreinte et la contre-empreinte sont disjointes et le comprimé est extrait de l'enceinte.The method according to its fourth aspect advantageously comprises a fourth step (iv), in which the impression and the counterprint are disjoint and the tablet is extracted from the enclosure.
Selon un cinquième aspect, l'invention concerne un comprimé obtenu selon son quatrième aspect.According to a fifth aspect, the invention relates to a tablet obtained according to its fourth aspect.
Selon un sixième aspect, l'invention concerne un conditionnement pour comprimés selon le cinquième aspect acceptable, en particulier un blister ou un flacon.According to a sixth aspect, the invention relates to a tablet package according to the fifth acceptable aspect, in particular a blister or a bottle.
Les avantages de l'invention seront plus particulièrement illustrés par l'exemple suivant :The advantages of the invention will be more particularly illustrated by the following example:
Une composition acceptable comprenant du Nicorandil selon l'état de la technique peut être préparée comme suit :An acceptable composition comprising Nicorandil according to the state of the art can be prepared as follows:
1) Composition commerciale :1) Commercial composition:
Tableau 1Table 1
2) Procédé de préparation de l'état de la technique (procédé commercial)2) Preparation method of the state of the art (commercial process)
Phase 1 : Préparation du granule neutre Ikorel (tableau 2, ci-après) Phase 1: Preparation of Ikorel Neutral Granule (Table 2, below)
Tableau 2Table 2
Matières Quantités OpérationsSubjects Quantities Operations
- Mannitol simple 430,379 kg- Mannitol single 430,379 kg
PESEE DES MATIERES - Amidon de maïs 5,640 kg PREMIERES - Acide stéarique 33,981 kgWEIGHTS - Corn Starch 5.640 kg FIRST - Stearic Acid 33.981 kg
- Mannitol + Acide stéarique 464,360 kg MELANGE et PRECHAUFFAGE- Mannitol + stearic acid 464,360 kg MIXING and PREHEATING
- Eau purifiée froide 7,527 kg- Purified cold water 7.527 kg
PREPARATION DE LA - Eau purifiée en ébullition 82,735 kg SOLUTION DE MOUILLAGE - Amidon de maïs 5,640 kgPREPARATION OF - Purified water boiling 82.735 kg WETTING SOLUTION - Corn starch 5.640 kg
N.A 470 kg GRANULATIONN.A 470 kg GRANULATION
470 kg SECHAGE ET RE¬470 kg DRYING AND RE¬
N.A FROIDISSEMENTN. COOLING
EnvironAbout
N.A CALIBRAGE 470 kgN.A CALIBRATION 470 kg
N. A 400 kg (élimination duN. At 400 kg (elimination of
CHARGEMENT EN surplus) CONTAINER Phase 2 : Fabrication des comprimés d'IkorelLOADING IN EXCESS) CONTAINER Phase 2: Manufacture of Ikorel tablets
Tableau 3Table 3
Une composition acceptable comprenant du Nicorandil selon l'invention peut être préparée comme suit : 1) Composition selon l'invention .:An acceptable composition comprising Nicorandil according to the invention can be prepared as follows: 1) Composition according to the invention:
Tableau 4Table 4
2) Procédé de préparation selon l'invention :2) Preparation process according to the invention
Tableau 5Table 5
Comparaison entre la stabilité de la composition commerciale et de la composition selon l'invention lorsque les compositions sont sous forme de comprimés en yrac, stockés en minibag:Comparison between the stability of the commercial composition and the composition according to the invention when the compositions are in the form of tablets in bulk, stored in minibag:
1) Composition commerciale :1) Commercial composition:
Tableau 6 2) Composition selon l'invention :Table 6 2) Composition according to the invention
Tableau 7Table 7
Discussion :Discussion
Les comprimés en vrac obtenus par le procédé selon l'invention sont plus stables que les comprimés commerciaux.Bulk tablets obtained by the process according to the invention are more stable than commercial tablets.
Les teneurs en eau, facteur important de stabilité, sont systématiquement plus faibles pour le lot de produit obtenu via le procédé selon l'invention.The water content, an important factor of stability, is systematically lower for the batch of product obtained via the process according to the invention.
Les quantités de Nicorandil sont aussi stables dans le temps pour les comprimés selon l'invention que pour les comprimés commerciaux.The amounts of Nicorandil are as stable over time for the tablets according to the invention as for the commercial tablets.
On note des valeurs d'impuretés plus élevées à t = 0 pour les comprimés selon l'invention par rapport aux comprimés commerciaux. Toutefois, l'augmentation du taux d'impuretés est plus lente au cours du temps pour les comprimés selon l'invention. Ainsi, à cinq mois, des valeurs d'impuretés hors- normes sont obtenues pour le lot commercial, ce qui n'est pas le cas du lot selon l'invention.Higher impurity values are noted at t = 0 for tablets according to the invention compared with commercial tablets. However, the increase in the level of impurities is slower over time for the tablets according to the invention. Thus, at five months, non-standard impurity values are obtained for the commercial batch, which is not the case with the batch according to the invention.
Enfin, les valeurs de dissolution sont stables dans les deux cas. Stabilité comparée des comprimés en fonction des conditions de stockage, à 6 mois, 400C, 75 % HR, en blistβrs :Finally, the dissolution values are stable in both cases. Comparative stability of the tablets according to the storage conditions, at 6 months, 40 ° C., 75% RH, in blisters:
Tableau 14Table 14
Les lots 20, 21 , et 22 CMP sont obtenus par le procédé commercial actuel. Le lot LOP107 CD est un lot obtenu par le procédé selon l'invention, décrit plus haut.Batches 20, 21, and 22 CMP are obtained by the current commercial process. Lot LOP107 CD is a batch obtained by the method according to the invention, described above.
Les figures 1 à 3 sont des représentations graphiques de l'évolution de la teneur en Nicorandil en fonction du temps, pour, respectivement des comprimés conservés en blisters .à 25°C, 60 % HR ; 300C, 65 % HR ; et 400C, 75 % HR ; ces dernières correspondant aux valeurs présentées dans le tableau 14.Figures 1 to 3 are graphical representations of the evolution of the Nicorandil content as a function of time for, respectively, tablets preserved in blisters at 25 ° C, 60% RH; 30 0 C, 65% RH; and 40 0 C, 75% RH; the latter corresponding to the values presented in Table 14.
Les figures 4 à 6 sont des représentations graphiques de l'évolution de la teneur en impuretés en fonction du temps, pour, respectivement des comprimés conservés en blisters à 250C, 60 % HR ; 300C, 65 % HR ; et 400C, 75 % HR ; ces dernières correspondant aux valeurs présentées dans le tableau 14. Discussion :FIGS. 4 to 6 are graphical representations of the evolution of the content of impurities as a function of time for, respectively, tablets preserved in blisters at 25 ° C., 60% RH; 30 0 C, 65% RH; and 40 0 C, 75% RH; the latter corresponding to the values presented in Table 14. Discussion
Que ce soit à 250C, 60 % HR, ou à 3O0C, 65 % HR à t = 6 mois, la teneur en principe actif du lot obtenu par le procédé selon l'invention est équivalente à celle mesurée dans les lots obtenus par le procédé actuel. Il en est de même pour les concentrations en impuretés.Whether at 25 ° C., 60% RH or at 30 ° C., 65% RH at t = 6 months, the active ingredient content of the batch obtained by the process according to the invention is equivalent to that measured in the batches obtained by the current process. It is the same for the concentrations of impurities.
A 4O0C, 75 % HR, à t = 6 mois, la teneur en principe actif du lot obtenu par le procédé selon l'invention est meilleure ou équivalente à celle mesurée dans les lots obtenus par le procédé actuel. Il en est de même pour les concentrations en impuretés.At 40 ° C., 75% RH, at t = 6 months, the active ingredient content of the batch obtained by the process according to the invention is better or equivalent to that measured in the batches obtained by the current process. It is the same for the concentrations of impurities.
Conclusion :Conclusion:
Les comprimés en vrac, fabriqués selon le procédé par compression directe, et stockés en minibag, sont plus stables que les comprimés commerciaux.Bulk tablets, manufactured using the direct compression process, and stored in minibag, are more stable than commercial tablets.
De cette étude additionnelle, il apparaît que les comprimés selon l'invention présentent des qualités de stabilité tout à fait remarquables vis-à-vis des comprimés selon le procédé actuel. Il est nécessaire de rappeler que les conditions de stabilité considérées ici sont des conditions drastiques pour ce produit, pour lequel des conditions strictes de conservation sont préconisées (température < 250C). From this additional study, it appears that the tablets according to the invention have qualities of stability quite remarkable vis-à-vis the tablets according to the current method. It is necessary to remember that the stability conditions considered here are drastic conditions for this product, for which strict conservation conditions are recommended (temperature <25 ° C.).

Claims

REVENDICATIONS
1. Composition comprenant (i) du Nicorandil, et (ii) un lubrifiant choisi parmi un acide aliphatique supérieur saturé et ses sels et/ou alcool supérieur saturé, solide à température ambiante, caractérisée en ce que le lubrifiant n'est pas micronisé.A composition comprising (i) Nicorandil, and (ii) a lubricant selected from a saturated higher aliphatic acid and its salts and / or saturated higher alcohol, solid at room temperature, characterized in that the lubricant is not micronized.
2. Composition selon la revendication 1 , caractérisée en ce que le lubrifiant est de l'acide stéarique.2. Composition according to claim 1, characterized in that the lubricant is stearic acid.
3. Composition selon la revendication 1 , caractérisée en ce qu'elle comprend en outre un désintégrant et un diluant.3. Composition according to claim 1, characterized in that it further comprises a disintegrant and a diluent.
4. Composition selon la revendication 3, caractérisée en ce que le désintégrant est du croscarmellose sodique.4. Composition according to claim 3, characterized in that the disintegrant is croscarmellose sodium.
5. Composition selon la revendication 3, caractérisée en ce que le diluant est du mannitol.5. Composition according to claim 3, characterized in that the diluent is mannitol.
6. Composition comprenant, en poids, 10 % de Nicorandil, et un lubrifiant, solide à température ambiante, non micronisé.6. Composition comprising, by weight, 10% Nicorandil, and a lubricant, solid at room temperature, non-micronized.
7. Composition selon la revendication 6, comprenant 8 % d'acide stéarique non micronisé.The composition of claim 6 comprising 8% non-micronized stearic acid.
8. Composition selon la revendication 6, comprenant en outre un désintégrant.The composition of claim 6, further comprising a disintegrant.
9. Composition selon la revendication 8, comprenant 5 % de croscarmellose sodique.The composition of claim 8 comprising 5% croscarmellose sodium.
10. Composition selon la revendication 6, comprenant en outre un diluant.The composition of claim 6, further comprising a diluent.
11. Composition selon la revendication 10, comprenant 76 % de mannitoi.11. Composition according to claim 10, comprising 76% of mannitoi.
12. Procédé de préparation d'une composition selon l'une quelconque des revendications précédentes, caractérisé en ce qu'il comprend une première étape dans laquelle, en poids, 30 parties de Nicorandil, 15 parties de croscarmellose sodique, 35 parties de mannitol et 3 parties d'amidon de maïs sont mélangées pour former un premier pré-mélange. 12. Process for the preparation of a composition according to any one of the preceding claims, characterized in that it comprises a first step in which, by weight, 30 parts of Nicorandil, 15 parts of croscarmellose sodium, 35 parts of mannitol and 3 parts of corn starch are mixed to form a first premix.
13. Procédé selon la revendication 12, caractérisé en ce le premier pré¬ mélange est calibré.13. The method of claim 12, characterized in that the first premix is calibrated.
14. Procédé selon la revendication 13, caractérisé en ce qu'il comprend une deuxième étape dans laquelle le premier pré-mélange calibré est mélangé à 193 parties en poids de mannitol pour former un deuxième pré¬ mélange.14. The method of claim 13, characterized in that it comprises a second step in which the first calibrated premix is mixed with 193 parts by weight of mannitol to form a second premix.
15. Procédé selon la revendication 14, caractérisé en ce qu'il comprend une troisième étape dans laquelle le deuxième pré-mélange est mélangé à 24 parties en poids d'acide stéarique non micronisé.15. The method of claim 14, characterized in that it comprises a third step in which the second premix is mixed with 24 parts by weight of non-micronized stearic acid.
16. Composition pour compression directe, obtenue par un procédé selon l'une quelconque des revendications 12 à 15.16. Composition for direct compression, obtained by a process according to any one of claims 12 to 15.
17. Procédé de préparation d'un comprimé comprenant du Nicorandil, caractérisé en ce qu'il comprend une première étape (i) dans laquelle une composition pour compression directe selon la revendication 16 est disposée, à température ambiante, dans une empreinte d'un moule, en ce qu'il comprend une seconde étape (ii) dans laquelle une contre-empreinte du moule est appliquée contre l'empreinte de sorte que la composition pour compression directe est captive dans une enceinte de volume V1 du moule, et en ce qu'il comprend en outre une troisième étape (iii) dans laquelle le volume V1 du moule est réduit à un volume VO inférieur au volume V1 par compression jusqu'à l'obtention d'un comprimé.Process for the preparation of a tablet comprising Nicorandil, characterized in that it comprises a first step (i) in which a composition for direct compression according to claim 16 is placed, at ambient temperature, in a cavity of one mold, in that it comprises a second step (ii) in which a counterprint of the mold is applied against the impression so that the composition for direct compression is captive in a chamber of volume V1 of the mold, and in that it further comprises a third step (iii) in which the volume V1 of the mold is reduced to a volume VO less than the volume V1 by compression until a tablet is obtained.
18. Procédé selon la revendication 17, caractérisé en ce qu'il comprend en outre une quatrième étape (iv), dans laquelle l'empreinte et la contre- empreinte sont disjointes et le comprimé est extrait de l'enceinte.18. The method of claim 17, characterized in that it further comprises a fourth step (iv), in which the impression and the counterprint are disjoint and the tablet is extracted from the enclosure.
19. Comprimé obtenu selon la revendication 18. 19. A tablet obtained according to claim 18.
EP05786080A 2004-07-08 2005-07-05 Compositions containing nicorandil, preparation method and use Withdrawn EP1776093A1 (en)

Applications Claiming Priority (2)

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FR0407590A FR2872705B1 (en) 2004-07-08 2004-07-08 COMPOSITIONS CONTAINING NICORANDIL, PROCESS FOR PREPARATION AND USE
PCT/FR2005/001730 WO2006016040A1 (en) 2004-07-08 2005-07-05 Compositions containing nicorandil, preparation method and use

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KR (1) KR20070030262A (en)
CN (1) CN100591356C (en)
AU (1) AU2005271131B2 (en)
BR (1) BRPI0513005A (en)
CA (1) CA2570863A1 (en)
EA (1) EA012967B1 (en)
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HK (1) HK1107256A1 (en)
IL (1) IL180285A0 (en)
MA (1) MA28783B1 (en)
MX (1) MXPA06015151A (en)
NO (1) NO20070186L (en)
NZ (1) NZ552983A (en)
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EP2098249B1 (en) 2008-03-05 2012-10-24 Rivopharm SA Nicorandil carriers with enhanced stability
CN115429763B (en) * 2021-06-02 2024-01-02 北京四环科宝制药股份有限公司 Nicotil tablet and preparation method thereof
CN114732792A (en) * 2022-03-25 2022-07-12 北京诺康达医药科技股份有限公司 Nicorandil orally disintegrating tablet and preparation method thereof

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FR2872705A1 (en) 2006-01-13
ZA200700704B (en) 2008-10-29
JP2008505873A (en) 2008-02-28
AU2005271131A1 (en) 2006-02-16
WO2006016040A1 (en) 2006-02-16
NZ552983A (en) 2010-07-30
NO20070186L (en) 2007-01-31
US20070190134A1 (en) 2007-08-16
KR20070030262A (en) 2007-03-15
HK1107256A1 (en) 2008-04-03
MXPA06015151A (en) 2007-03-26
EA012967B1 (en) 2010-02-26
EA200700191A1 (en) 2007-06-29
IL180285A0 (en) 2007-07-04
CN1980644A (en) 2007-06-13
MA28783B1 (en) 2007-08-01
CN100591356C (en) 2010-02-24
CA2570863A1 (en) 2006-02-16
BRPI0513005A (en) 2008-04-22
FR2872705B1 (en) 2008-07-18
AU2005271131B2 (en) 2010-04-29

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