WO2002026235A1 - Dispersible pharmaceutical cephalosporin compositions, preparation and use thereof - Google Patents

Dispersible pharmaceutical cephalosporin compositions, preparation and use thereof Download PDF

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Publication number
WO2002026235A1
WO2002026235A1 PCT/FR2001/002959 FR0102959W WO0226235A1 WO 2002026235 A1 WO2002026235 A1 WO 2002026235A1 FR 0102959 W FR0102959 W FR 0102959W WO 0226235 A1 WO0226235 A1 WO 0226235A1
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Prior art keywords
pharmaceutical composition
cephalosporin
dispersible
agents
excipients
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PCT/FR2001/002959
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French (fr)
Inventor
Claude Laruelle
René Gimet
Dominique Toselli
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Cll Pharma
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Publication date
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Priority to AU2001291980A priority Critical patent/AU2001291980A1/en
Publication of WO2002026235A1 publication Critical patent/WO2002026235A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0087Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056Mouth 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the present invention relates to pharmaceutical compositions based on cephalosporins, in particular in the form of dispersible tablets, as well as to their use for improving the sensory perception of patients with the oral administration of such compositions.
  • cephalosporins are very widely used as anti-bacterial agents and are therefore offered by a very large number of chemical suppliers.
  • these cephalosporins there may be mentioned, by way of example, the active ingredients known under the international nonproprietary names (INNs) cefadroxil, cephadrine or even cefalexin.
  • INNs international nonproprietary names
  • cefadroxil the active ingredient known under the international nonproprietary names
  • cefadroxil cephadrine or even cefalexin.
  • cefadroxil has been offered by 28 chemical suppliers alone.
  • Cephalosporins and their derivatives can be produced according to various synthetic processes.
  • a process for the preparation of cephalosporin derivatives which consists in reacting a derivative of 7-aminodeacetoxycephalosporanic acid (7-ADCA) with an acylating agent. comprising an amino function protected by a protective group which may in particular be a t-butyloxycarbonyl group (t-BOC), the expected cephalosporin derivative then being obtained by hydrolysis of the protective group in an inert solvent.
  • a protective group which may in particular be a t-butyloxycarbonyl group (t-BOC)
  • t-BOC t-butyloxycarbonyl group
  • US Patent 3,985,741 describes another process for preparing cephalosporins in which the acylating agent used is chosen from compounds in which the alpha-amino group is protected by a ⁇ -keto group such as for example methyl acetylate .
  • This acetylating agent is a mixed anhydrous acid obtained by reaction between a carboxylic acid salt (Dane salt) and an ethyl chloroformate in the presence of a catalyst, N-methylmorpholine.
  • Another synthetic process schematically consists of a) silylating the 7-ADCA, then b) acylating the silylated 7-ADCA in step a) with D - (-) - ⁇ -amino- ⁇ - (p-hydroxyphenyl) acetyl chloride hydrochloride in the presence of an acid acceptor such as triethylamine, dimethylamine, dimethylaniline, quinoline, lutidine or pyridine , then c) cleaving all the silyl groups from the acylation product of step b) to obtain the desired cephalosporanic acid.
  • an acid acceptor such as triethylamine, dimethylamine, dimethylaniline, quinoline, lutidine or pyridine
  • cephalosporins obtainable by these different processes must then undergo one or more stages of crystallization and purification before they can be incorporated into pharmaceutical compositions.
  • the obtained compounds present notable variations as well from the point of view of their structural characteristics in particular crystallographic as of the degree of purity which they present (presence of traces residual solvents).
  • Medicines based on cephalosporins are generally administered orally and can be presented in various galenical forms such as capsules, granules or powders for oral suspension, dispersible or non-dispersible tablets.
  • cephalosporins in the form of capsules or non-dispersible tablets cannot always be envisaged, especially in children and in people suffering from the upper tract of the digestive tract and having difficulty swallowing.
  • Non-dispersible capsules and tablets also have a bioavailability which may be less than that of dispersible powders and tablets.
  • the administration of cephalosporins in the form of powders or granules for oral suspension requires before use the reconstitution of the suspension by addition of water, the agitation of this suspension before each use and the measurement of the dose. appropriate before each administration. All of these different operations are a source of errors regarding the dose of cephalosporin administered.
  • the dispersible tablet which must be dispersed in water before * ingestion, always corresponds to a single and precise dose of the active ingredient to be administered;
  • dispersible tablets contain 1 g of active ingredient (cefadroxil) in combination with various excipients necessary for this type of formulation, among which we can notably cite crosslinked polyvinylpyrrolidone (known under the trade name crospovidone ®) and which is a disintegrating agent, cellulose. microcrystalline (binding agent), magnesium stearate (lubricating agent), sweeteners such as gluconate or sodium cyclamate or sodium saccharin and flavors such as orange and grapefruit flavors.
  • active ingredient cefadroxil
  • excipients necessary for this type of formulation among which we can notably cite crosslinked polyvinylpyrrolidone (known under the trade name crospovidone ®) and which is a disintegrating agent, cellulose. microcrystalline (binding agent), magnesium stearate (lubricating agent), sweeteners such as gluconate or sodium cyclamate or sodium saccharin and flavors such as orange and grapefruit flavors.
  • ORACEFAL ® in the form of dispersible tablets is poorly tolerated from a sensory point of view (odor and taste) when ingested. It is in order to remedy these problems that the inventors have developed what is the subject of the invention.
  • the inventors therefore set themselves the objective of providing a dispersible pharmaceutical composition based on cephalosporin having all the advantages of this type of galenical formulation as well as an improved odor and taste.
  • the present invention therefore relates to a pharmaceutical composition dispersible in a liquid comprising at least one cephalosporin as active ingredient, alone or in combination with another active ingredient, and at least one disintegrating agent, characterized in that said cephalosporin has an N, N-dimethylacetamide (DMAC) impurity level of less than 21.4 ppm and that said disintegrating agent is crosslinked sodium carboxymethylcellulose (croscarmellose® sodium).
  • DMAC N, N-dimethylacetamide
  • compositions in accordance with the invention have the additional advantage of disintegrating completely in less than 3 minutes when they are brought into contact with a liquid such as water and thus leading to an oral suspension whose homogeneity can be easily obtained by stirring.
  • the pharmaceutical composition according to the invention can be in the form of dispersible tablets or dispersible granules.
  • the DMAC impurity level of the cephalosporins is less than 5 ppm.
  • cephalosporins which can be used as active principle in the pharmaceutical composition in accordance with the invention are preferably chosen from cefadroxil, cephadrine, cefalexin, cefatrizin and cefixime.
  • cephalosporins must be prepared according to a synthetic process which does not require the use of dimethylaniline. However, they are preferably prepared according to a synthetic process using a Dane salt, as described for example in US patent 3,985,741.
  • croscarmellose ® sodium preferably represents from 1 to 25% by weight approximately of the total weight of the pharmaceutical composition and even more particularly from 2 to 10% by weight.
  • the pharmaceutical composition in accordance with the invention may also contain one or more excipients which can be chosen from flow agents, lubricating agents, binding agents, sweeteners, flavoring agents, flavorings, etc.
  • flow agents which can be used in the pharmaceutical composition in accordance with the invention, mention may in particular be made of precipitated silica dioxide, colloidal silica, talc, stearic acid, magnesium stearate and their mixtures, particularly preferred precipitated silica dioxide.
  • These flow agents are used to prevent the components of the tablets or granules from forming aggregates during the preparation of these tablets or granules and also to reduce friction during compression operations. They are generally present in proportions of between 0.1 and 3% of the total weight of the pharmaceutical composition.
  • binding agents which can be used in the pharmaceutical composition in accordance with the invention, mention may in particular be made of microcrystalline cellulose, lactose, hydroxypropylmethylcellulose (HPC), pregelatinized starch and their mixtures, microcrystalline cellulose being particularly preferred. Binding agents facilitate the compression operations necessary to obtain tablets and give adequate hardness to them.
  • these binding agents preferably represent from 5 to 60% of the total weight of the pharmaceutical composition.
  • the sweeteners can in particular be chosen from aspartame, sodium saccharin, sodium cyclamate, potassium acesulfame, ammonium glycerinate and their mixtures. These sweeteners preferably represent from 1 to 20% of the total weight of the pharmaceutical composition.
  • the pharmaceutical composition in accordance with the invention has an improved odor and taste compared to the compositions of the prior art based on cephalosporin, it may nevertheless contain one or more aromas, these being in particular able to be chosen from the aromas fruits such as strawberry, lemon, raspberry, grapefruit, orange, etc. and the aromas of mint, chocolate, vanilla, strawberry, licorice and their mixtures
  • the invention also relates to a process for the preparation of a dispersible pharmaceutical composition as defined above, said process being characterized in that it comprises: a) a step of premixing at least one cephalosporin having a impurity of N, N-dimethylacetamide less than 21.4 ppm with crosslinked sodium carboxymethylcellulose in the presence, optionally, of a binding agent and / or a flow agent, to obtain a premix (A), b ) a step of mixing any additional excipients such as binding agents, lubricating agents, sweetening agents, flavorings, to obtain a mixture of excipients (B), c) a step of final mixing of the premix (A) and of the mixture of excipients (B), to obtain a final mixture (C), d) a granulation and / or compression step of the final mixture (C) resulting.
  • steps a) to c) of the process described above are preferably carried out with stirring and can include sub-sieving operations of the various ingredients used and / or mixtures obtained.
  • Step d) of granulation or compression can be carried out conventionally according to known methods of granulation or compression.
  • the subject of the invention is the use of at least one dispersible pharmaceutical composition as defined above to improve the sensory perception (olfactory and gustatory) of a patient during the oral administration of such a composition.
  • the invention also comprises other arrangements which will emerge from the description which follows, which refers to an example of demonstration of the improvement of sensory perception during the oral administration of a composition.
  • pharmaceutical according to the invention compared to the administration of pharmaceutical compositions not forming part of the invention.
  • Dispersible tablets having the compositions listed in Table I below were prepared (the quantities are given in mg):
  • Comparative composition not forming part of the invention Composition according to the present invention
  • a CD 1 dispersible tablet which serves as a reference and which corresponds to the formulation of the ORACEFAL® 1000 dispersible tablets of the 1996 edition of the VIDAL® dictionary containing 1000 mg of cefadroxil monohydrate, was also studied.
  • the different excipients mentioned for the CD 4 dispersible tablet correspond to those present in the CD 1 dispersible tablet of ORACEFAL ® 1000.
  • the CD 2 to CD 4 tablets above were prepared as follows: a) Preparation of a premix A
  • microcrystalline cellulose The remaining 20% of microcrystalline cellulose, sweetening agents, anhydrous citric acid and the flavors were sieved on an oscillating calibrator equipped with a 0.5 mm grid.
  • the mixtures A and B obtained in the preceding steps were calibrated separately on an oscillating calibrator equipped with a 1 mm grid operating at 110 oscillations / minute.
  • the mixtures A and B thus calibrated, as well as the second half of the silica, were introduced into the tank of a mobile tank mixer of the TUMBLER type and mixed for 30 minutes at a speed of 19 revolutions / minute. c.2) Screening of the flow agent
  • the flow agent namely magnesium stearate, was sieved on an oscillating calibrator fitted with a 0.25 mm grid. c.3) Lubrication step
  • step c The final mixture obtained above in step c was then compressed in a rotary tableting machine of the FETTE P2100 type with punches with a diameter of 23 mm, bi-plane faceted with a breakable bar.
  • the machine was adjusted so as to obtain a tablet mass equal to 2500 mg of hardness between 60 and 180 N, and having the following characteristics:
  • the total disintegration time of each of the above CD 1 to CD 4 tablets was determined after immersion in 100 ml of water per tablet.
  • Each person blindly tests the four CD1 to CD4 tablets, each dispersed in half a glass of water, both from the olfactory point of view of the suspension before ingestion and from the point of view of its overall appreciation. (taste, finesse, presence or absence of aftertaste, etc.) during ingestion. Each person assigns a score ranging from 1 to 10 for the olfactory assessment and a score ranging from 1 to 10 for the overall assessment.
  • This evaluation test makes it possible to take into account the odor after disintegration of the tablet in water. This factor is important because it reflects the desire to bring the glass to the mouth and administer the product.
  • CD 2 dispersible tablet according to the invention that is to say containing the combination of a cephalosporin having a DMAC impurity level of less than 21.4 ppm as a principle active and croscarmellose ® sodium as a disintegrating agent, leads to better results, both from the point of view of odor and of overall appreciation after ingestion, than those obtained with the dispersible tablets CD 1, CD 3 or CD 4 not forming part of the invention.
  • a tablet containing the combination of a cephalosporin having a DMAC impurity level greater than 21.4 ppm, in combination with croscarmellose ® sodium as a disintegrating agent gives results. generally equivalent to the reference (CD 1 tablet).
  • a tablet containing the combination of a cephalosporin having a DMAC impurity level of less than 21.4 ppm, in combination with crospovidone ® as a disintegrating agent CD 4 tablet

Abstract

The invention concerns dispersible cephalosporin compositions, in particular in the form of tablets, their preparation method and their use for improving sensory perception of patients when such compositions are orally administered.

Description

COMPOSITIONS PHARMACEUTIQUES DISPERSIBLES A BASE DE CEPHALOSPORINES, LEUR PROCÉDÉ DE PRÉPARATION ET LEUR DISPERSIBLE PHARMACEUTICAL COMPOSITIONS BASED ON CEPHALOSPORINS, THEIR PREPARATION METHOD AND THEIR
UTILISATIONUSE
La présente invention est relative à des compositions pharmaceutiques à base de céphalosporines, notamment sous forme de comprimés dispersibles, ainsi qu'à leur utilisation pour améliorer la perception sensorielle des patients à l'administration orale de telles compositions.The present invention relates to pharmaceutical compositions based on cephalosporins, in particular in the form of dispersible tablets, as well as to their use for improving the sensory perception of patients with the oral administration of such compositions.
Dans l'industrie pharmaceutique, les céphalosporines sont très largement utilisées à titre d'agents anti-bactériens et sont, par conséquent, proposées par un très grand nombre de fournisseurs de produits chimiques. Parmi ces céphalosporines, on peut citer, à titre d'exemple, les principes actifs connus sous les dénominations communes internationales (DCI) céfadroxil, céphadrine ou bien encore céfalexine. A ce jour, le principe actif céfadroxil est, à lui seul, proposé par 28 fournisseurs de produits chimiques. Les céphalosporines et leurs dérivés peuvent être fabriqués selon différents procédés de synthèse.In the pharmaceutical industry, cephalosporins are very widely used as anti-bacterial agents and are therefore offered by a very large number of chemical suppliers. Among these cephalosporins, there may be mentioned, by way of example, the active ingredients known under the international nonproprietary names (INNs) cefadroxil, cephadrine or even cefalexin. To date, the active ingredient cefadroxil has been offered by 28 chemical suppliers alone. Cephalosporins and their derivatives can be produced according to various synthetic processes.
C'est ainsi que dans la demande de brevet FR 1 603 618, il est décrit un procédé de préparation de dérivés de céphalosporines consistant à faire réagir un dérivé de l'acide 7-aminodésacétoxycéphalosporanique (7-ADCA) avec un agent d'acylation comportant une fonction aminé protégée par un groupement protecteur pouvant être notamment un groupement t-butyloxycarbonyle (t-BOC), le dérivé de céphalosporine attendu étant ensuite obtenu par hydrolyse du groupement protecteur dans un solvant inerte. Ces dérivés de céphalosporines sont obtenus sous forme anhydre avec un très faible rendement. De plus l'utilisation d'agent d'acylation comportant un groupement protecteur comme le t-BOC est très coûteuse.Thus, in patent application FR 1 603 618, a process for the preparation of cephalosporin derivatives is described which consists in reacting a derivative of 7-aminodeacetoxycephalosporanic acid (7-ADCA) with an acylating agent. comprising an amino function protected by a protective group which may in particular be a t-butyloxycarbonyl group (t-BOC), the expected cephalosporin derivative then being obtained by hydrolysis of the protective group in an inert solvent. These cephalosporin derivatives are obtained in anhydrous form with a very low yield. In addition, the use of acylating agent comprising a protective group such as t-BOC is very expensive.
Le brevet US 3,985,741 décrit un autre procédé de préparation de céphalosporines dans lequel l'agent d'acylation utilisé est choisi parmi des composés dans lesquels le groupe alpha-amino est protégé par un groupe β-céto tel que par exemple l'acétylate de méthyle. Cet agent d'acétylation est un acide anhydre mixte obtenu par réaction entre un sel d'acide carboxylique (sel de Dane) et un chloroformate d'éthyle en présence d'un catalyseur, laN-méthylmorpholine. Un autre procédé de synthèse, tel que décrit par exemple dans la demande de brevet FR 2 365 570, consiste schématiquement a) à silyler le 7-ADCA, puis b) à acyler le 7-ADCA silylé à l'étape a) par du chlorhydrate de chlorure de D-(-)-α-amino-α-(p-hydroxyphényl)acétyle en présence d'un accepteur d'acide tel que la triéthylamine, la diméthylamine, la diméthylaniline, la quinoléine, la lutidine ou la pyridine, puis c) à cliver tous les groupes silyle du produit d'acylation de l'étape b) pour obtenir l'acide céphalosporanique désiré.US Patent 3,985,741 describes another process for preparing cephalosporins in which the acylating agent used is chosen from compounds in which the alpha-amino group is protected by a β-keto group such as for example methyl acetylate . This acetylating agent is a mixed anhydrous acid obtained by reaction between a carboxylic acid salt (Dane salt) and an ethyl chloroformate in the presence of a catalyst, N-methylmorpholine. Another synthetic process, as described for example in patent application FR 2 365 570, schematically consists of a) silylating the 7-ADCA, then b) acylating the silylated 7-ADCA in step a) with D - (-) - α-amino-α- (p-hydroxyphenyl) acetyl chloride hydrochloride in the presence of an acid acceptor such as triethylamine, dimethylamine, dimethylaniline, quinoline, lutidine or pyridine , then c) cleaving all the silyl groups from the acylation product of step b) to obtain the desired cephalosporanic acid.
Les céphalosporines pouvant être obtenues selon ces différents procédés doivent ensuite subir une ou plusieurs étapes de cristallisation et de purification avant de pouvoir être incorporées dans des compositions pharmaceutiques.The cephalosporins obtainable by these different processes must then undergo one or more stages of crystallization and purification before they can be incorporated into pharmaceutical compositions.
Dans ce but, de nombreuses techniques de cristallisation mettant en œuvre différents types de solvants peuvent être utilisées.For this purpose, many crystallization techniques using different types of solvents can be used.
C'est ainsi qu'il a par exemple été proposé, notamment dans le brevet US 3,985,741 ou dans la demande de brevet FR 2 365 570, d'utiliser un solvant choisi parmi l'acétonitrile, le méthanol, le toluène, le diméthylformamide (DMF), le diméthylacétamide (DMAC) et leurs mélanges.Thus it has for example been proposed, in particular in US patent 3,985,741 or in patent application FR 2 365 570, to use a solvent chosen from acetonitrile, methanol, toluene, dimethylformamide ( DMF), dimethylacetamide (DMAC) and mixtures thereof.
Compte tenu de la diversité des procédés permettant la synthèse, la cristallisation et la purification des céphalosporines, les composés obtenus présentent des variations notables tant du point de vue de leurs caractéristiques structurales notamment cristallographiques que du degré de pureté qu'ils présentent (présence de traces de solvants résiduels).Taking into account the diversity of the processes allowing the synthesis, the crystallization and the purification of cephalosporins, the obtained compounds present notable variations as well from the point of view of their structural characteristics in particular crystallographic as of the degree of purity which they present (presence of traces residual solvents).
Les médicaments à base de céphalosporines sont généralement administrés par voie orale et peuvent se présenter sous des formes galéniques variées telles que gélules, granulés ou poudres pour suspension buvable, comprimés dispersibles ou non dispersibles.Medicines based on cephalosporins are generally administered orally and can be presented in various galenical forms such as capsules, granules or powders for oral suspension, dispersible or non-dispersible tablets.
L'administration de céphalosporines sous la forme de gélules ou de comprimés non dispersibles ne peut pas toujours être envisagée, notamment chez les enfants et chez les personnes souffrant des voies supérieures du tractus digestif et ayant des difficultés à déglutir. Les gélules et les comprimés non dispersibles présentent également une biodisponibilité qui peut être moindre que celle des poudres et comprimés dispersibles. D'autre part, l'administration de céphalosporines sous la forme de poudres ou de granulés pour suspension buvable nécessite avant emploi la reconstitution de la suspension par ajout d'eau, l'agitation de cette suspension avant chaque utilisation et la mesure de la dose appropriée avant chaque administration. L'ensemble de ces différentes opérations est une source d'erreurs quant à la dose de céphalosporine administrée.The administration of cephalosporins in the form of capsules or non-dispersible tablets cannot always be envisaged, especially in children and in people suffering from the upper tract of the digestive tract and having difficulty swallowing. Non-dispersible capsules and tablets also have a bioavailability which may be less than that of dispersible powders and tablets. On the other hand, the administration of cephalosporins in the form of powders or granules for oral suspension requires before use the reconstitution of the suspension by addition of water, the agitation of this suspension before each use and the measurement of the dose. appropriate before each administration. All of these different operations are a source of errors regarding the dose of cephalosporin administered.
La présentation sous forme de comprimés dispersibles présente par contre plusieurs avantages :However, the presentation in the form of dispersible tablets has several advantages:
- le comprimé dispersible, qui doit être dispersé dans l'eau avant * ingestion, correspond toujours à une dose unique et précise du principe actif à administrer ;- the dispersible tablet, which must be dispersed in water before * ingestion, always corresponds to a single and precise dose of the active ingredient to be administered;
- ce type de formulation permet également une administration facilitée du médicament chez les personnes ayant des problèmes de déglutition, en particulier les personnes âgées et les enfants. Cependant, la formulation de principes actifs sous forme de comprimés dispersibles nécessite l'addition d'excipients tels que des arômes et des agents édulcorants de façon à masquer l'odeur et le goût, éventuellement désagréables du principe actif en lui-même, et ainsi améliorer la perception olfactive et gustative du médicament lors de l'ingestion A ce jour, l'ORACEFAL ® est le seul médicament disponible à base de céphalosporine pouvant se présenter sous la forme de comprimés dispersibles. Ces comprimés dispersibles renferment 1 g de principe actif (céfadroxil) en association avec différents excipients nécessaires à ce genre de formulation parmi lesquels on peut notamment citer la polyvinylpyrrolidone réticulée (connue sous la dénomination commerciale crospovidone ®) et qui est un agent désintégrant, la cellulose microcristalline (agent liant), du stéarate de magnésium (agent lubrifiant), des édulcorants tels que du gluconate ou du cyclamate de sodium ou de la saccharine sodique et des arômes tels que des arômes d'orange et de pamplemousse.- This type of formulation also allows easier administration of the drug in people with swallowing problems, in particular the elderly and children. However, the formulation of active principles in the form of dispersible tablets requires the addition of excipients such as flavors and sweetening agents so as to mask the odor and the taste, possibly unpleasant of the active principle in itself, and thus improve the olfactory and gustatory perception of the drug during ingestion To date, ORACEFAL ® is the only available cephalosporin-based drug which can be in the form of dispersible tablets. These dispersible tablets contain 1 g of active ingredient (cefadroxil) in combination with various excipients necessary for this type of formulation, among which we can notably cite crosslinked polyvinylpyrrolidone (known under the trade name crospovidone ®) and which is a disintegrating agent, cellulose. microcrystalline (binding agent), magnesium stearate (lubricating agent), sweeteners such as gluconate or sodium cyclamate or sodium saccharin and flavors such as orange and grapefruit flavors.
Or malgré la présence d'agents édulcorants et d'arômes, la présentation d'ORACEFAL ® sous la forme de comprimés dispersibles est mal tolérée d'un point de vue sensoriel (odeur et goût) lors de son ingestion. C'est afin de remédier à ces problèmes que les Inventeurs ont mis au point ce qui fait l'objet de l'invention.However, despite the presence of sweetening agents and flavors, the presentation of ORACEFAL ® in the form of dispersible tablets is poorly tolerated from a sensory point of view (odor and taste) when ingested. It is in order to remedy these problems that the inventors have developed what is the subject of the invention.
Les Inventeurs se sont donc fixés pour objectif de pourvoir à une composition pharmaceutique dispersible à base de céphalosporine présentant tous les avantages de ce type de formulation galénique ainsi qu'une odeur et un goût améliorés.The inventors therefore set themselves the objective of providing a dispersible pharmaceutical composition based on cephalosporin having all the advantages of this type of galenical formulation as well as an improved odor and taste.
La présente invention a donc pour objet une composition pharmaceutique dispersible dans un liquide comprenant au moins une céphalosporine à titre de principe actif, seule ou en association avec un autre principe actif, et au moins un agent désintégrant, caractérisée par le fait que ladite céphalosporine présente un taux d'impureté en N,N-diméthylacétamide (DMAC) inférieur à 21,4 ppm et que ledit agent désintégrant est de la carboxyméthylcellulose de sodium réticulée (croscarmellose ® sodique).The present invention therefore relates to a pharmaceutical composition dispersible in a liquid comprising at least one cephalosporin as active ingredient, alone or in combination with another active ingredient, and at least one disintegrating agent, characterized in that said cephalosporin has an N, N-dimethylacetamide (DMAC) impurity level of less than 21.4 ppm and that said disintegrating agent is crosslinked sodium carboxymethylcellulose (croscarmellose® sodium).
Les Inventeurs ont en effet démontré que l'association spécifique de ces deux composés, permet d'obtenir une composition pharmaceutique dispersible présentant des propriétés olfactive et gustative nettement améliorées par rapport à celles des compositions pharmaceutiques de l'art antérieur à base de céphalosporines, sans qu'il soit nécessaire d'agir principalement sur l'aromatisation de celle-ci.The inventors have in fact demonstrated that the specific association of these two compounds makes it possible to obtain a dispersible pharmaceutical composition having olfactory and gustatory properties markedly improved compared to those of pharmaceutical compositions of the prior art based on cephalosporins, without that it is necessary to act mainly on the flavoring thereof.
Les compositions pharmaceutiques conformes à l'invention présentent l'avantage supplémentaire de se désintégrer complètement en moins de 3 minutes lorsqu'elles sont mises en contact avec un liquide tel que l'eau et de conduire ainsi à une suspension buvable dont l'homogénéité peut être aisément obtenue par agitation.The pharmaceutical compositions in accordance with the invention have the additional advantage of disintegrating completely in less than 3 minutes when they are brought into contact with a liquid such as water and thus leading to an oral suspension whose homogeneity can be easily obtained by stirring.
La composition pharmaceutique conforme à l'invention peut se présenter sous la forme de comprimés dispersibles ou de granulés dispersibles.The pharmaceutical composition according to the invention can be in the form of dispersible tablets or dispersible granules.
Selon une forme de réalisation particulièrement avantageuse de l'invention, le taux d'impureté en DMAC des céphalosporines est inférieur à 5 ppm.According to a particularly advantageous embodiment of the invention, the DMAC impurity level of the cephalosporins is less than 5 ppm.
Les céphalosporines pouvant être utilisées à titre de principe actif dans la composition pharmaceutique conforme à l'invention sont de préférence choisies parmi le céfadroxil, la céphadrine, la céfalexine, la céfatrizine et le céfixime.The cephalosporins which can be used as active principle in the pharmaceutical composition in accordance with the invention are preferably chosen from cefadroxil, cephadrine, cefalexin, cefatrizin and cefixime.
Ces céphalosporines doivent être préparées selon un procédé de synthèse ne nécessitant pas l'emploi de diméthylaniline. Elles sont par contre de préférence préparées selon un procédé de synthèse mettant en œuvre un sel de Dane, tel que décrit par exemple dans le brevet US 3,985,741.These cephalosporins must be prepared according to a synthetic process which does not require the use of dimethylaniline. However, they are preferably prepared according to a synthetic process using a Dane salt, as described for example in US patent 3,985,741.
Selon l'invention, la croscarmellose ® sodique représente de préférence de 1 à 25 % en poids environ du poids total de la composition pharmaceutique et encore plus particulièrement de 2 à 10 % en poids.According to the invention, croscarmellose ® sodium preferably represents from 1 to 25% by weight approximately of the total weight of the pharmaceutical composition and even more particularly from 2 to 10% by weight.
La composition pharmaceutique conforme à l'invention peut en outre renfermer un ou plusieurs excipients pouvant être choisis parmi les agents d'écoulement, les agents lubrifiants, les agents liants, les édulcorants, les agents de sapidité, les arômes, etc ... Parmi les agents d'écoulement pouvant être utilisés dans la composition pharmaceutique conforme .à l'invention, on peut notamment citer le dioxyde de silice précipitée, la silice colloïdale, le talc, l'acide stéarique, le stéarate de magnésium et leurs mélanges, le dioxyde de silice précipitée étant particulièrement préféré. Ces agents d'écoulement sont utilisés pour empêcher les composants des comprimés ou des granulés de former des agrégats au cours de la préparation de ces comprimés ou granulés et pour réduire également les frictions pendant les opérations de compression. Ils sont généralement présents dans des proportions comprises entre 0,1 et 3 % du poids total de la composition pharmaceutique.The pharmaceutical composition in accordance with the invention may also contain one or more excipients which can be chosen from flow agents, lubricating agents, binding agents, sweeteners, flavoring agents, flavorings, etc. flow agents which can be used in the pharmaceutical composition in accordance with the invention, mention may in particular be made of precipitated silica dioxide, colloidal silica, talc, stearic acid, magnesium stearate and their mixtures, particularly preferred precipitated silica dioxide. These flow agents are used to prevent the components of the tablets or granules from forming aggregates during the preparation of these tablets or granules and also to reduce friction during compression operations. They are generally present in proportions of between 0.1 and 3% of the total weight of the pharmaceutical composition.
Parmi les agents lubrifiants pouvant être utilisés dans la composition pharmaceutique conforme à l'invention, on peut notamment citer le stéarate de magnésium, le stéarate de calcium et leurs mélanges. Ces agents lubrifiants, dont le rôle est de réduire les opérations de frictions pendant les opérations de compression, sont avantageusement présents dans des proportions comprises entre 0,1% et 3% du poids total de la composition pharmaceutique. Parmi les agents liants pouvant être utilisés dans la composition pharmaceutique conforme à l'invention, on peut notamment citer la cellulose microcristalline, le lactose, l'hydroxypropylméthylcellulose (HPC), l'amidon prégélatinisé et leurs mélanges, la cellulose microcristalline étant particulièrement préférée. Les agents liants facilitent les opérations de compressions nécessaires à l'obtention de comprimés et confèrent une dureté adéquate à ces derniers. Lorsqu'ils sont utilisés, ces agents liants représentent de préférence de 5 à 60% du poids total de la composition pharmaceutique. Les édulcorants peuvent notamment être choisis parmi l'aspartame, la saccharine sodique, le cyclamate de sodium, l'acésulfame de potassium, le glycérinate d'ammonium et leurs mélanges. Ces édulcorants représentent de préférence de 1 à 20% du poids total de la composition pharmaceutique. Bien que la composition pharmaceutique conforme à l'invention présente une odeur et un goût améliorés par rapport aux compositions de l'art antérieur à base de céphalosporine, elle peut néanmoins renfermer un ou plusieurs arômes, ceux-ci pouvant notamment être choisis parmi les arômes de fruits tels que fraise, citron, framboise, pamplemousse, orange, etc et les arômes menthe, chocolat, vanille fraise, réglisse et leurs mélangesAmong the lubricating agents which can be used in the pharmaceutical composition in accordance with the invention, mention may in particular be made of magnesium stearate, calcium stearate and their mixtures. These lubricating agents, the role of which is to reduce friction operations during compression operations, are advantageously present in proportions of between 0.1% and 3% of the total weight of the pharmaceutical composition. Among the binding agents which can be used in the pharmaceutical composition in accordance with the invention, mention may in particular be made of microcrystalline cellulose, lactose, hydroxypropylmethylcellulose (HPC), pregelatinized starch and their mixtures, microcrystalline cellulose being particularly preferred. Binding agents facilitate the compression operations necessary to obtain tablets and give adequate hardness to them. When used, these binding agents preferably represent from 5 to 60% of the total weight of the pharmaceutical composition. The sweeteners can in particular be chosen from aspartame, sodium saccharin, sodium cyclamate, potassium acesulfame, ammonium glycerinate and their mixtures. These sweeteners preferably represent from 1 to 20% of the total weight of the pharmaceutical composition. Although the pharmaceutical composition in accordance with the invention has an improved odor and taste compared to the compositions of the prior art based on cephalosporin, it may nevertheless contain one or more aromas, these being in particular able to be chosen from the aromas fruits such as strawberry, lemon, raspberry, grapefruit, orange, etc. and the aromas of mint, chocolate, vanilla, strawberry, licorice and their mixtures
Bien entendu, l'homme de l'art veillera à cette occasion à ce que le ou les excipients éventuellement utilisés soient compatibles avec les propriétés intrinsèques attachées à la présente composition pharmaceutique.Of course, those skilled in the art will take care on this occasion that the excipient (s) possibly used are compatible with the intrinsic properties attached to the present pharmaceutical composition.
L'invention a également pour objet un procédé de préparation d'une composition pharmaceutique dispersible telle que précédemment définie, ledit procédé étant caractérisé en ce qu'il comprend : a) une étape de pré-mélange d'au moins une céphalosporine présentant un taux d'impureté en N,N-diméthylacétamide inférieur à 21,4 ppm avec de la carboxyméthylcellulose de sodium réticulée en présence éventuellement d'un agent liant et/ou d'un agent d'écoulement, pour obtenir un prémélange (A), b) une étape de mélange des excipients additionnels éventuels tels qu'agents liants, agents lubrifiants, agents édulcorants, arômes, pour obtenir un mélange d'excipients (B), c) une étape de mélange final du prémélange (A) et du mélange d'excipients (B), pour obtenir un mélange final (C), d) une étape de granulation et/ou de compression du mélange final (C) résultant.The invention also relates to a process for the preparation of a dispersible pharmaceutical composition as defined above, said process being characterized in that it comprises: a) a step of premixing at least one cephalosporin having a impurity of N, N-dimethylacetamide less than 21.4 ppm with crosslinked sodium carboxymethylcellulose in the presence, optionally, of a binding agent and / or a flow agent, to obtain a premix (A), b ) a step of mixing any additional excipients such as binding agents, lubricating agents, sweetening agents, flavorings, to obtain a mixture of excipients (B), c) a step of final mixing of the premix (A) and of the mixture of excipients (B), to obtain a final mixture (C), d) a granulation and / or compression step of the final mixture (C) resulting.
Selon l'invention, les étapes a) à c) du procédé décrit ci-dessus sont de préférence effectuées sous agitation et peuvent comporter des sous-opérations de tamisage des différents ingrédients utilisés et/ou mélanges obtenus.According to the invention, steps a) to c) of the process described above are preferably carried out with stirring and can include sub-sieving operations of the various ingredients used and / or mixtures obtained.
L'étape d) de granulation ou de compression peut être réalisée de façon classique selon les méthodes connues de granulation ou de compression. Enfin l'invention a pour objet l'utilisation d'au moins une composition pharmaceutique dispersible telle que définie précédemment pour améliorer la perception sensorielle (olfactive et gustative) d'un patient lors de l'administration orale d'une telle composition. Outre les dispositions qui précèdent, l'invention comprend encore d'autres dispositions qui ressortiront de la description qui va suivre, qui se réfère à un exemple de démonstration de l'amélioration de la perception sensorielle lors de l'administration orale d'une composition pharmaceutique conforme à l'invention comparativement à l'administration de compositions pharmaceutiques ne faisant pas partie de l'invention.Step d) of granulation or compression can be carried out conventionally according to known methods of granulation or compression. Finally, the subject of the invention is the use of at least one dispersible pharmaceutical composition as defined above to improve the sensory perception (olfactory and gustatory) of a patient during the oral administration of such a composition. In addition to the foregoing arrangements, the invention also comprises other arrangements which will emerge from the description which follows, which refers to an example of demonstration of the improvement of sensory perception during the oral administration of a composition. pharmaceutical according to the invention compared to the administration of pharmaceutical compositions not forming part of the invention.
Il doit être bien entendu toutefois que cet exemple est donné uniquement à titre d'illustration de l'objet de l'invention, dont il ne constitue en aucune manière une limitation.It should be understood, however, that this example is given only by way of illustration of the subject of the invention, of which it in no way constitutes a limitation.
EXEMPLE : DÉMONSTRATION DE L'AMÉLIORATION DE LA PERCEPTION SENSORIELLE LORS DE L'ADMINISTRATION D'UNE COMPOSITION PHARMACEUTIQUE DISPERSIBLE A BASE DE CÉPHALOSPORINEEXAMPLE: DEMONSTRATION OF THE IMPROVEMENT OF SENSORY PERCEPTION DURING THE ADMINISTRATION OF A DISPERSIBLE PHARMACEUTICAL COMPOSITION BASED ON CEPHALOSPORIN
1) Préparation de comprimés dispersibles à base de céfadroxil1) Preparation of dispersible tablets based on cefadroxil
Des comprimés dispersibles ayant les compositions figurant dans le Tableau I ci-après ont été préparés (les quantités sont données en mg) : Dispersible tablets having the compositions listed in Table I below were prepared (the quantities are given in mg):
Tableau ITable I
Figure imgf000009_0001
Figure imgf000009_0001
' : Composition comparative ne faisant pas partie de l'invention : Composition selon la présente invention': Comparative composition not forming part of the invention: Composition according to the present invention
Un comprimé dispersible CD 1, qui sert de référence et qui correspond à la formulation des comprimés dispersibles d'ORACEFAL ® 1000 de l'édition 1996 du dictionnaire VIDAL ® contenant 1000 mg de céfadroxil monohydrate, a également été étudié.A CD 1 dispersible tablet, which serves as a reference and which corresponds to the formulation of the ORACEFAL® 1000 dispersible tablets of the 1996 edition of the VIDAL® dictionary containing 1000 mg of cefadroxil monohydrate, was also studied.
Les différents excipients mentionnés pour le comprimé dispersible CD 4 correspondent à ceux présents dans le comprimé dispersible CD 1 d'ORACEFAL ® 1000.The different excipients mentioned for the CD 4 dispersible tablet correspond to those present in the CD 1 dispersible tablet of ORACEFAL ® 1000.
Les comprimés CD 2 à CD 4 ci-dessus ont été préparés de la façon suivante : a) Préparation d'un prémélange AThe CD 2 to CD 4 tablets above were prepared as follows: a) Preparation of a premix A
Le céfadroxil, 80% de la quantité totale de cellulose microcristalline, la croscarmellose ® sodique ainsi que la moitié de la silice (comprimés CD 2 et CD 3), ont été tamisés sur un calibreur oscillant équipé d'une grille de 1 mm. Ces ingrédients tamisés ont ensuite été introduits dans un mélangeur à retournement à cuve mobile de type TUMBLER et mélangés pendant 30 minutes à une vitesse 19 tours/minute. b) Préparation d'un mélange d'excipients BCefadroxil, 80% of the total amount of microcrystalline cellulose, croscarmellose ® sodium and half of the silica (CD 2 and CD 3 tablets) were sieved on an oscillating calibrator equipped with a 1 mm grid. These sieved ingredients were then introduced into a TUMBLER type mobile bowl inversion mixer and mixed for 30 minutes at a speed of 19 revolutions / minute. b) Preparation of a mixture of excipients B
Les 20 % restants de cellulose microcristalline, les agents édulcorants, l'acide citrique anhydre ainsi que les arômes ont été tamisés sur un calibreur oscillant équipé d'une grille de 0,5 mm.The remaining 20% of microcrystalline cellulose, sweetening agents, anhydrous citric acid and the flavors were sieved on an oscillating calibrator equipped with a 0.5 mm grid.
Ces ingrédients tamisés ont ensuite été introduits dans un mélangeur granulateur de type Lodï'ge et mélangés pendant 2 minutes à une vitesse de 1450 tours/minute. c) Préparation d'un mélange final C cl) Préparation d'un prémélange finalThese sieved ingredients were then introduced into a granulator mixer type Lodi 'ge and mixed for 2 minutes at a speed of 1450 revolutions / minute. c) Preparation of a final mixture C cl) Preparation of a final premix
Les mélanges A et B obtenus aux étapes précédentes ont été calibrés séparément sur un calibreur oscillant équipé d'une grille de 1 mm fonctionnant à 110 oscillations/minute. Les mélanges A et B ainsi calibrés, ainsi que la deuxième moitié de la silice ont été introduits dans la cuve d'un mélangeur à cuve mobile de type TUMBLER et mélangés pendant 30 minutes à une vitesse de 19 tours/minute. c.2) Tamisage de l'agent d'écoulementThe mixtures A and B obtained in the preceding steps were calibrated separately on an oscillating calibrator equipped with a 1 mm grid operating at 110 oscillations / minute. The mixtures A and B thus calibrated, as well as the second half of the silica, were introduced into the tank of a mobile tank mixer of the TUMBLER type and mixed for 30 minutes at a speed of 19 revolutions / minute. c.2) Screening of the flow agent
L'agent d'écoulement, à savoir le stéarate de magnésium a été tamisé sur un calibreur oscillant équipé d'une grille de 0,25 mm. c.3) Etape de lubrificationThe flow agent, namely magnesium stearate, was sieved on an oscillating calibrator fitted with a 0.25 mm grid. c.3) Lubrication step
Le stéarate de magnésium ainsi tamisé a ensuite été ajouté au prémélange final obtenu ci-dessus à l'étape cl), au sein d'un mélangeur à cuve mobile de TUMBLER. L'ensemble a été mélangé pendant 5 minutes à 19 tours/minute. d) Compression du mélange final CThe magnesium stearate thus sieved was then added to the final premix obtained above in step c1), in a mobile tank mixer of TUMBLER. The whole was mixed for 5 minutes at 19 rpm. d) Compression of the final mixture C
Le mélange final obtenu ci-dessus à l'étape c a ensuite été comprimé dans une machine à comprimer rotative de type FETTE P2100 avec des poinçons de diamètre 23 mm, bi plan à facettes avec une barrette de sécabilité.The final mixture obtained above in step c was then compressed in a rotary tableting machine of the FETTE P2100 type with punches with a diameter of 23 mm, bi-plane faceted with a breakable bar.
La machine a été réglée de manière à obtenir une masse de comprimé égale à 2500 mg de dureté comprise entre 60 et 180 N, et présentant les caractéristiques suivantes :The machine was adjusted so as to obtain a tablet mass equal to 2500 mg of hardness between 60 and 180 N, and having the following characteristics:
- Épaisseur : 6 mm,- Thickness: 6 mm,
- Résistance à la rupture : 60 à 180 N,- Breaking strength: 60 to 180 N,
- Friabilité : < 1 %,- Friability: <1%,
- Vitesse de désagrégation : < 1 mn.- Disaggregation speed: <1 min.
2) Évaluation du temps de désintégration des comprimés2) Evaluation of the disintegration time of the tablets
Le temps de désintégration totale de chacun des comprimés CD 1 à CD 4 ci-dessus a été déterminé après immersion dans 100 ml d'eau par comprimé.The total disintegration time of each of the above CD 1 to CD 4 tablets was determined after immersion in 100 ml of water per tablet.
Les résultats obtenus figurent dans le Tableau II ci-après :The results obtained are shown in Table II below:
Tableau IITable II
Figure imgf000011_0001
Figure imgf000011_0001
Ces résultats montrent que les comprimés contenant un agent désintégrant conforme à l'invention, c'est-à-dire de la croscarmellose ® sodique ont un temps de désintégration environ deux fois plus court que les comprimés dispersibles contenant un agent désintégrant ne faisant pas partie de l'invention, à savoir la crospovidone ®.These results show that the tablets containing a disintegrating agent in accordance with the invention, that is to say croscarmellose® sodium have a disintegration time approximately twice as short as the dispersible tablets containing a disintegrating agent which are not part of the invention, namely crospovidone ®.
3) Évaluation de la perception sensorielle lors de l'administration par voie orale des comprimés CD 1 à CD 43) Evaluation of sensory perception during the oral administration of the tablets CD 1 to CD 4
Cette évaluation a été réalisée sur un panel de 12 . personnes volontaires.This evaluation was carried out on a panel of 12. volunteer people.
Chaque personne teste en aveugle les quatre comprimés CD1 à CD4 chacun dispersés dans un demi-verre d'eau, tant du point de vue olfactif de la suspension avant ingestion que du point de vue de l'appréciation globale de celle-ci (goût, finesse, présence ou absence d'arrière goût, etc..) lors de l'ingestion. Chaque personne attribue une note allant de 1 à 10 pour l'appréciation olfactive et une note allant de 1 à 10 pour l'appréciation globale.Each person blindly tests the four CD1 to CD4 tablets, each dispersed in half a glass of water, both from the olfactory point of view of the suspension before ingestion and from the point of view of its overall appreciation. (taste, finesse, presence or absence of aftertaste, etc.) during ingestion. Each person assigns a score ranging from 1 to 10 for the olfactory assessment and a score ranging from 1 to 10 for the overall assessment.
Ce test d'évaluation permet de prendre en compte l'odeur après désintégration du comprimé dans l'eau. Ce facteur est important car il reflète l'envie de porter le verre à la bouche et de s'administrer le produit.This evaluation test makes it possible to take into account the odor after disintegration of the tablet in water. This factor is important because it reflects the desire to bring the glass to the mouth and administer the product.
Les résultats obtenus sont regroupés sous forme de moyenne dans le Tableau III ci-après :The results obtained are collated as an average in Table III below:
Tableau IIITable III
Figure imgf000012_0001
Figure imgf000012_0001
Ces résultats mettent en évidence que le comprimé dispersible CD 2 conforme à l'invention, c'est-à-dire renfermant l'association d'une céphalosporine ayant un taux d'impureté en DMAC inférieur à 21,4 ppm à titre de principe actif et de la croscarmellose ® sodique à titre d'agent désintégrant, conduit à de meilleurs résultats, tant du point de vue de l'odeur que de l'appréciation globale après ingestion, que ceux obtenus avec les comprimés dispersibles CD 1, CD 3 ou CD 4 ne faisant pas partie de l'invention.These results demonstrate that the CD 2 dispersible tablet according to the invention, that is to say containing the combination of a cephalosporin having a DMAC impurity level of less than 21.4 ppm as a principle active and croscarmellose ® sodium as a disintegrating agent, leads to better results, both from the point of view of odor and of overall appreciation after ingestion, than those obtained with the dispersible tablets CD 1, CD 3 or CD 4 not forming part of the invention.
Ces résultats montrent également que l'utilisation d'un seul des deux éléments de cette association ne suffit pas à améliorer la perception sensorielle d'un patient lors de l'administration orale d'une telle composition.These results also show that the use of only one of the two elements of this association is not sufficient to improve the sensory perception of a patient during the oral administration of such a composition.
En effet, un comprimé contenant l'association d'une céphalosporine ayant un taux d'impureté en DMAC supérieur à 21,4 ppm, en association avec de la croscarmellose ® sodique à titre d'agent désintégrant (comprimé CD 3) donne des résultats globalement équivalents à la référence (comprimé CD 1). De la même manière, un comprimé contenant l'association d'une céphalosporine ayant un taux d'impureté en DMAC inférieur à 21,4 ppm, en association avec de la crospovidone ® à titre d'agent désintégrant (comprimé CD 4) donne également des résultats globalement équivalents à la référence (comprimé CD 1). Indeed, a tablet containing the combination of a cephalosporin having a DMAC impurity level greater than 21.4 ppm, in combination with croscarmellose ® sodium as a disintegrating agent (CD 3 tablet) gives results. generally equivalent to the reference (CD 1 tablet). Similarly, a tablet containing the combination of a cephalosporin having a DMAC impurity level of less than 21.4 ppm, in combination with crospovidone ® as a disintegrating agent (CD 4 tablet) also gives results generally equivalent to the reference (CD 1 tablet).

Claims

REVENDICATIONS
1. Composition pharmaceutique dispersible dans un liquide comprenant au moins une céphalosporine à titre de principe actif, seul ou en association avec un autre principe actif, et au moins un agent désintégrant, caractérisée par le fait que ladite céphalosporine présente un taux d'impureté en N,N-diméthylacétamide inférieur à 21,4 ppm et que ledit agent désintégrant est de la carboxyméthylcellulose de sodium réticulée.1. Pharmaceutical composition dispersible in a liquid comprising at least one cephalosporin as active principle, alone or in combination with another active principle, and at least one disintegrating agent, characterized in that the said cephalosporin has an impurity content of N, N-dimethylacetamide less than 21.4 ppm and that said disintegrating agent is crosslinked sodium carboxymethylcellulose.
2. Composition pharmaceutique selon la revendication 1, caractérisée par le fait qu'elle se présente sous la forme de comprimés ou de granulés. 2. Pharmaceutical composition according to claim 1, characterized in that it is in the form of tablets or granules.
3. Composition pharmaceutique selon la revendication 1 ou 2, caractérisée par le fait que ladite céphalosporine présente un taux d'impureté en N,N-diméthylacétamide inférieur à 5 ppm.3. Pharmaceutical composition according to claim 1 or 2, characterized in that said cephalosporin has an impurity level of N, N-dimethylacetamide less than 5 ppm.
4. Composition pharmaceutique selon l'une quelconque des revendications précédentes, caractérisée par le fait que ladite céphalosporine est choisie parmi le céfadroxil, la céphadrine, la céfalexine, la céfatrizine et le céfixime.4. Pharmaceutical composition according to any one of the preceding claims, characterized in that the said cephalosporin is chosen from cefadroxil, cephadrine, cefalexin, cefatrizine and cefixime.
5. Composition pharmaceutique selon l'une quelconque des revendications précédentes, caractérisée par le fait que la carboxyméthylcellulose de sodium réticulée représente de 1 à 25 %. en poids du poids total de ladite composition, et de préférence de 2 à 10%. 5. Pharmaceutical composition according to any one of the preceding claims, characterized in that the crosslinked sodium carboxymethylcellulose represents from 1 to 25% . by weight of the total weight of said composition, and preferably from 2 to 10%.
6. Composition pharmaceutique selon l'une quelconque des revendications précédentes, caractérisée par le fait qu'elle renferme un ou plusieurs excipients choisis parmi les agents d'écoulement, les agents lubrifiants, les agents liants, les édulcorants, les agents de sapidité, et les arômes.6. Pharmaceutical composition according to any one of the preceding claims, characterized in that it contains one or more excipients chosen from flow agents, lubricants, binding agents, sweeteners, flavoring agents, and the aromas.
7. Procédé de préparation d'une composition pharmaceutique dispersible telle que précédemment définie, ledit procédé étant caractérisé en ce qu'il comprend : a) une étape de pré-mélange d'au moins une céphalosporine présentant un taux d'impureté en N,N-diméthylacétamide inférieur à 21 ,4 ppm avec de la carboxyméthylcellulose de sodium réticulée en présence éventuellement d'un agent liant et/ou d'un agent d'écoulement, pour obtenir un prémélange (A), b) une étape de mélange des excipients additionnels éventuels tels qu'agents liants, agents lubrifiants, agents édulcorants, arômes, pour obtenir un mélange d'excipients (B), c) une étape de mélange final du prémélange (A) et du mélange d'excipients (B), pour obtenir un mélange final (C), d) une étape de granulation ou de compression du mélange final (C) résultant.7. A method of preparing a dispersible pharmaceutical composition as defined above, said method being characterized in that it comprises: a) a step of premixing at least one cephalosporin having an impurity content of N, N-dimethylacetamide less than 21.4 ppm with crosslinked sodium carboxymethylcellulose in the optional presence of a binding agent and / or a flow agent, to obtain a premix (A), b) a step of mixing any additional excipients such as binding agents, lubricating agents, sweetening agents, flavorings, to obtain a mixture of excipients (B), c) a step of final mixing of the premix (A) and of the mixture excipients (B), to obtain a final mixture (C), d) a granulation or compression step of the resulting final mixture (C).
8. Utilisation d'au moins une composition pharmaceutique dispersible telle que définie à l'une quelconque des revendications 1 à 6 pour améliorer la perception olfactive et gustative d'un patient lors de l'administration orale d'une telle composition. 8. Use of at least one dispersible pharmaceutical composition as defined in any one of claims 1 to 6 for improving the olfactory and gustatory perception of a patient during the oral administration of such a composition.
PCT/FR2001/002959 2000-09-29 2001-09-25 Dispersible pharmaceutical cephalosporin compositions, preparation and use thereof WO2002026235A1 (en)

Priority Applications (1)

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AU2001291980A AU2001291980A1 (en) 2000-09-29 2001-09-25 Dispersible pharmaceutical cephalosporin compositions, preparation and use thereof

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FR0012401A FR2814679B1 (en) 2000-09-29 2000-09-29 DISPERSIBLE PHARMACEUTICAL COMPOSITIONS BASED ON CEPHALOSPORINS, PROCESS FOR THEIR PREPARATION AND THEIR USE
FR00/12401 2000-09-29

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MXPA06012944A (en) 2004-05-10 2007-02-12 Lupin Ltd Novel pharmaceutical formulation of cefixime for enhanced bioavailability.

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EP0210540A1 (en) * 1985-07-19 1987-02-04 Fujisawa Pharmaceutical Co., Ltd. Time-controlled explosion systems and processes for preparing the same
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CN104447795B (en) * 2014-11-28 2016-08-17 珠海金鸿药业股份有限公司 A kind of cefadroxil benzyl compound and pharmaceutical composition thereof

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