CA2256751C

CA2256751C - Coated trimebutine maleate tablet

Info

Publication number: CA2256751C
Application number: CA002256751A
Authority: CA
Inventors: Loutfy Benkerrour; Bernard Doat
Original assignee: PARKE-DAVIS
Current assignee: PARKE-DAVIS
Priority date: 1996-08-07
Filing date: 1997-07-11
Publication date: 2008-09-23
Anticipated expiration: 2017-07-11
Also published as: CA2256751A1; UA52682C2; EA199900102A1; EP0942718B1; AU3697097A; CN1206986C; CZ294195B6; FR2752162B1; JP2000515535A; GR1002907B; PT942718E; MXPA98010007A; FR2752162A1; ES2130081B1; ITGE970067A1; DZ2272A1; KR20000029866A; CO4900042A1; BR9711032B1; IT1294671B1

Abstract

A coated trimebutine maleate tablet for oral delivery, including a core containing 30-60 % of trimebutine maleate, carriers suitable for preparing said core and carriers enhancing the stability and release of the active principle, as well as a water-soluble coating temporarily but sufficiently effective to prevent disintegration of the core and premature release of the active principle in the mouth.

Description

Coated Trimebutine Maleate Tablet Field of the invention The present invention relates to an improved and film-coated trimebutine maleate tablet intended for oral administration, and to a process for preparing it.
In particular, the invention relates to a new tablet which makes it possible to administer a therapeutically effective amount of trimebutine maleate for a rapid or sustained bioavailability, but, in any case, without causing a persisting bitter effect which is eventually prejudicial to the patient's proper compliance with the treatment.
Technological background of the invention Trimebutine, or 2-dimethylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate, is the first medicament known to act on the peripheral encephalinergic receptors, in particular those associated with digestion. It is a regulator of digestive motor function. As it is, or salified with maleic acid, trimebutine is offered in tablet, injectable solution and suppository form and in powder form for the preparation of a suspension for oral administration.
Marketed internationally, these various pharmaceutical dosage forms are indicated in the treatment of pain associated with functional disorders of the alimen-tary tract and the biliary tract, and in the treatment of pain and discomfort associated with functional intestinal disorders.
The orally administrable dosage forms are more especially suited to ambulatory treatments. Tablets and also granules or powders are essentially the forms which can be intended for the preparation of suspensions for oral administration.
Trimebutine maleate is the active principle commonly used for the preparation of these oral dosage forms, with a daily indicative dosage of 300 to 600 mg for an adult. This product, obtained by crystallization in water, melts at 105-106 C. Its solubility in water at 25 C is approximately I% (w/v), whereas trimebutine base is insoluble in water.
Trimebutine is, from a chemical standpoint, a benzoate type ester which is sensitive to agents that promote hydrolysis reactions or related reactions.
These agents comprise, in particular, water and reactive solvents such as lower alcohols, temperature, light and various catalysts, especially both alkali metal-containing and alkaline-earth metal-containing catalysts. The hydrolysis of trimebutine leads, among other by-products, to the formation of 3,4,5-trimethoxybenzoic acid, the quantitative determination of which enables its chemical stability to be assessed under various storage conditions.
In addition, maleic acid is temperature sensitive as a result of its propensity to isomerize to fumaric acid, the acidity constant of which is lower than that of maleic acid. This acid, on salification with trimebutine, leads to a trimebutine fumarate of low water-solubility.
Moreover, like many compounds which are positively charged in aqueous solution at pH values close to neutrality, trimebutine maleate administered orally induces, in the cavity and on the buccal mucosae, a strong bitterness and a lasting astringent sensation which can eventually cause poor compliance with the treatments in which the product is prescribed. This bitterness is especially disadvantageous when it is necessary to obtain a rapid therapeutic effect, which implies an almost immediate bioavailability as soon as the medicament has been swallowed. As an illustration of the truth of this problem, one of the two specialities in tablet form marketed in France states that "the tablets must be swallowed without being crunched, with a glass of water" ("Vidal" Dictionary of Pharmaceutical Specialities - 1996 ed.).
To date, the prior art reports only some imperfect attempts at overcoming the problems described, namely both to provide for the stability of the trimebutine maleate during preparation and storage of the medicaments, and to mask or eliminate the persisting bitterness in the mouth caused by the product without retarding its therapeutic effect.
As regards the powder form, Patent FR 2,468,364 published on 8/5/1981 describes a process for preparing microcapsules containing a pharmaceutically active compound, the walls of which are ethylcellulose, a process carried out in cyclohexane and which involves a phase separation-inducing agent, preferably of the phospholipid class. As an example, microcapsules of trimebutine maleate are prepared, for which one of the quality criteria evaluated is the absence of bitter taste.
According to this same process carried out in cyclohexane, the patents which follow are directed towards improving the quality of the microcapsules:
- FR 2,506,613 published on 3/12/1982 describes microcapsules, the walls of which consist of ethylcellulose and a polymer which is insoluble in water but soluble in an acid medium, which aim at a rapid release of the product in the gastric medium. The amount of trimebutine maleate incorporated does not exceed 15%, the release of 50%

of the product in an artificial gastric medium being obtained after 17 minutes.
- EP 0 076 515 published on 13/4/1983 also relates to microcapsules affording rapid release in the gastric medium, the walls of which consist of ethylcellulose and a polymer which is soluble in water and/or in an acid medium. The amount of product included is at best 12%, 50% of which is released in 10 to 20 minutes.
- EP 0 076 428 also published on 13/4/1983 is directed towards the same objective as the preceding patents; the walls consist of ethylcellulose and a polymer which is "expandable" in water. They contain approximately 10% of active principle, 50%
of which is released in 4 to 25 minutes in an artificial gastric medium.
- EP 0 099 109 published on 25/1/1984 describes a process for preparing microcapsules which is declared to be advantageous, in which a particular phase separation-inducing agent participates.
It is clear that, through this succession of patents, their applicant is aiming at the preparation of a powder containing trimebutine maleate in the coated state in order to mask its bitterness while attempting to obtain a rapid release of the active principle from the microcapsules proposed. It is apparent that this objective is imperfectly achieved since, on the one hand this complex and economically unsatisfactory process employs cyclohexane, which is an inflammable solvent, difficult to remove and subjected as a residual solvent to strict specification limits by the health authorities, and on the other hand it results in microcapsules which only contain an amount of trimebutine maleate of less than 20%, making it necessary for the patients to take an excessively large amount of medicament, bearing in mind the recommended daily dosage of 300 to 600 mg of trimebutine maleate, since it contains more than four times as much excipients as active principle.
In Application JP 80 40 885 published on 13/2/1996, a formulation composed of a mixture of granules is described, in which, in the case of the granules containing trimebutine maleate, the bitter taste is practically eliminated by granulation of the active principle with a water-insoluble polymer and a hydrophobic salt.
As an example, granules comprising trimebutine maleate contain 20% of the active principle, 3% of insoluble polymer and 5% of a hydrophobic salt, namely magnesium stearate or calcium stearate. No result is mentioned regarding the rate of release and/or the stability of the trimebutine maleate in these granules.

As regards tablets intended for the oral administration of trimebutine maleate, in Patent FR 2,640,876 published on 29/06/1990, a pharmaceutical composition in the form of a coating-free tablet comprising as active principle 2-dimethylamino-2-phenyl-l-butyl 3,4,5-trimethoxybenzoate maleate is described, characterized in that this active principle, which represents 35 to 45% by weight of the composition, is dispersed homogeneously in a hydrophilic porous matrix of hydroxypropylmethylcellulose representing 15 to 20% by weight of the composition, which comprises, in addition, 20 to 25% by weight of a water-soluble diluent and 10 to 20% by weight of tartaric acid.
According to this invention, the kinetics of dissolution of the active principle are, between thirty minutes and 8 hours, close to zero order, approximately 50% of the product being released after 8 hours. It should be noted that these tablets, in particular those containing a high dose, can be swallowed only with difficulty by some patients, and that, under these conditions, the unintentionally prolonged contact time in the buccal cavity inevitably causes an unpleasant and persisting bitterness.
Application JP No. 73574/1990 published on 6/12/1991 relates to a solid preparation very similar to that of Patent FR 2 640 876 and to trimebutine maleate tablets intended for oral administration, in which an organic acid in the proportion of 0.1 to 20 mg per 100 mg of maleate significantly inhibits the decomposition of the product, in which decomposition magnesium stearate is partially involved. It is specified that appropriate acids are tartaric acid or citric acid, and that the formulation comprises a metal (magnesium or calcium) stearate as lubricant for the compression.
Description of the invention Overcoming the unresolved problems as described in the prior art, the present invention is a technically simple and economically advantageous approach which is beneficial to the patient, the subject of which is a new improved trimebutine maleate tablet intended for oral administration, characterized in that it comprises:
- a core comprising 30 to 60% of trimebutine maleate, and excipients suitable for the preparation of the said core and those appropriate to the stability and to the release of the active principle, - a water-soluble film coating, of transient but sufficient efficacy to protect from a disintegration of the core and from a premature release of the active principle in the buccal medium.
As described in this specification, in its main aspect, the invention relates to a new tablet for the oral administration of a therapeutically effective amount of trimebutine maleate, the bioavailability of which can be rapid or sustained but which, in any case, does not cause in the buccal cavity any persisting bitterness which, on use, gives rise to an attitude of revulsion in the patient. These tablets display resistance and an exceptional physical stability which makes them amenable to the most diverse kinds of packaging (blister packs, in bulk in bottles, etc.) under adverse storage conditions (temperature, humidity, etc.).
In addition, an important aspect relates to the exceptional chemical stability of the trimebutine maleate presented in this tablet form, even with the tablets stored under harsh conditions, thereby providing patients with a product which is safe and of definite therapeutic benefit.
In another aspect, the invention relates to the process for manufacturing the tablets.
Another aspect of the invention relates to a composition which is suitable for the preparation of the cores of the tablets, characterized in that quantitative and qualitative adaptation of its main constituents enables a rapid or sustained release of the active principle to be obtained.
Generally speaking, the film-coating of tablets brings about advantages both for their industrial manufacture and for their use by the patient. Thus, as regards the manufacturing aspect, film-coated dosage forms are acknowledged to be less sensitive to mechanical erosion, hence to generate less dust and, as a result, to decrease inter-drug contamination in the premises; in addition, it is acknowledged that film-coating favours the immediate packaging, in particular in blister packs, of the tablets.
As regards the use by patients, the satiny or shiny texture provided by the film-forming mixture of the film coating prevents the naked tablet from adhering to the buccal mucosa and makes swallowing easier.
Besides these known advantages, the improvements provided by the tablets of the invention are elaborated upon in the subsequent part of this specification and illustrated by tests of release of the active principle and of physical and chemical stabilities in comparison with two commercially available specialities.
For the purposes of the invention in its broadest aspect, the tablets are characterized in that their cores comprise, by weight, 30 to 60% of trimebutine maleate and, as excipients, 15 to 45% of one or more diluents, 2.5 to 25% of one or more binding agents, 0.5 to 25% of one or more acidifying agents, optionally 1 to 5%
of one or more disintegrating agents, and technical adjuvant agents, namely 0.5 to 5%
of a glidant and 0.25 to 2.5% of a lubricant, and characterized in that the said cores are coated with a film representing 1 to 5% by weight of the said tablet, the composition of which film comprises one or more water-soluble film-forming agents, one or more opacifying agents and, optionally, one or more plasticizers.
More specifically, the composition of a core comprises:
- in the proportion of 20 to 40%, one or more diluents chosen from cellulose in microcrystalline or powder form, mannitol, starch and, more especially, lactose, in particular hydrated, which is the preferred dilution agent;
- in the proportion of 2.5 to 25%, one or more binding agents chosen from microcrystalline cellulose, gelatin of pharmaceutically acceptable quality, methylcellulose and pregelatinized starch. Povidone, pregelatinized maize starch and hydroxypropylmethylcellulose of viscosity between 2.5 and 15,000 mPa.s are preferred.
In particular, for cores for which a rapid disintegration is desired, a mixture is used representing 5 to 10% of the tablet and composed of 5 to 10 parts of maize starch and 0.5 to 2 parts of hydroxypropylmethylcellulose whose viscosity is between 2.5 and 17.5 mPa.s, whereas for cores for which a sustained release of the active principle is desired, a mixture composed of 5 to 15 parts of hydroxypropylmethylcellulose whose viscosity is between 1,500 and 15,000 mPa.s and 0.5 to 1 part of povidone is used in the proportion of 15 to 20% of the tablet. It is especially preferable to use hydroxypropylmethylcellulose of viscosity 5.2 to 7.0 mPa.s for the cores affording rapid disintegration, and hydroxypropylmethylcellulose of viscosity 4,000 mPa.s for the cores affording sustained release;
- the acidifying agent is chosen from pharmaceutically acceptable organic acids known for their properties of sequestering metals and/or possessing a stabilizing effect on the active principle and/or enabling an acid environment, favourable to the release of the active principle from hydrophilic cores aimed at a sustained release, to be created.

These acids are citric acid and tartaric acid which are used in the proportion 0.5 to 2%
in the cores for which a rapid disintegration is desired, and are preferably used in the proportion of 10 to 20%, in particular with tartaric acid which is preferred, in the cores for which a sustained release of trimebutine maleate is desired;
- the glidant is silica, anhydrous or hydrated, which is used in the proportion of 0.75 to 2.5%;
- the lubricant is chosen from the metal salts of stearic acid, to the exclusion of the other agents customarily proposed for this purpose. The lubricant is thus chosen from calcium and magnesium stearates. The latter is preferred, at concentrations of 0.5 to 1.5%, and more especially 1%;
- the disintegrating agent, which is optional, is chosen from crospovidone (crosslinked povidone), the sodium salt of crosslinked carboxymethylcellulose, also known as "croscarmellose sodium", and carboxymethyl starch which is preferred. The optional character of this agent corresponds to the need, where appropriate, to release the active principle rapidly, which is obtained by rapid disintegration of the cores after passage through the buccopharyngeal region. To this end, for the so-called "immediate-release" tablets, sodium carboxymethyl starch is used in the proportion of 1 to 5%, and preferably 2%, to obtain the requisite disintegration.
And as regards the coating film, the latter consists essentially of a water-soluble film-forming agent chosen from acrylic polymers and cellulose polymers such as hydroxypropylmethylcellulose of viscosity between 2.5 and 17.5 mPa.s, methylcellulose, ethylcellulose and hydroxypropylcellulose; and of a filler substance permitting better adhesion of the film to the core, such as lactose or microcrystalline cellulose. The opacifying agents and/or additive colorants are chosen from iron oxides and titanium dioxide. The plasticizers which can be used are chosen from macrogols of average molecular weight 3000 to 6000, propylene glycol, glycerol and polyoxyl stearate. To carry out the film-coating of the cores, according to the invention, the compounds may be used mixed in solution or in suspension in water or in pharmaceutically acceptable solvents such as ethanol, acetone or mixtures thereof with water. Preference is nevertheless given to a mixture comprising an aqueous suspension of hydroxypropylmethylcellulose whose viscosity is between 2.5 and 17.5 mPa.s and titanium dioxide, or alternatively a mixture comprising a hydroxypropyl-methylcellulose whose viscosity is between 2.5 and 17.5 mPa.s, lactose or microcrystalline cellulose, polyethylene glycol of molecular weight 4000 or polyoxyl 40 stearate and titanium dioxide in aqueous suspension. Special preference is given to mixtures in which the hydroxypropylmethylcellulose is of viscosity 5.2 to 7.0 mPa.s;
such especially suitable mixtures are marketed by the company Colorcon under the brand name OPADRY or by the company Seppic under the brand name SEPIFILM ; they make it possible to obtain, in the proportion of 1.5 to 3% by weight relative to the weight of the core, and especially in the proportion of 2%, a film of transient resistance in the buccopharyngeal medium which enables the tablet to be administered without an effect of bitterness while preserving a bioavailability of the active principle under the conditions of release chosen for the latter.
Moreover, the film coating produced by the film under the conditions of the invention is fully compatible with the imprinting, engraved or embossed, on the cores, such imprinting being indicative of the active principle and the dosage thereof and it being possible, during the coating operation with unsuitable compounds, for it to be filled in or eroded or erased, in any case, to become illegible.
As a special preference, the invention relates to the tablets whose percentage compositions are as follows:
Tablets A for rapid disintegration, termed immediate-release forms: "IRF"
i) composition for cores weighing 200 & 400 mg - trimebutine maleate 50.00%
- lactose monohydrate 36.00%
- maize starch 7.00%
- hydroxypropylmethylcellulose (6 mPa.s) 1.00%
- sodium carboxymethyl starch 2.00%
- tartaric acid 1.000/, - silica gel 2.00%
- magnesium stearate 1.00%
ii) coatin 2.00% of the weight of the core of a composition comprising hydroxypropylmethylcellulose (6 mPa.s), lactose, polyethylene glycol 4000 and titanium dioxide, or alternatively hydroxypropylmethylcellulose (6 mPa.s), microcrystalline cellulose, polyoxyl 40 stearate and titanium dioxide.

Tablets B termed sustained-release: "SRF"
i) composition for cores wei2hin2 747.00 & 508.00 m2 - trimebutine maleate 40.16%
- lactose monohydrate 24.07%, - hydroxypropylmethylcellulose (4000 mPa.s) 16.06%
- tartaric acid 16.06%
- povidone 1.61%
- silica gel 1.02%
- magnesium stearate 1.02%
ii) coatin 2.00% of the weight of the core of a composition comprising hydroxypropylmethylcellose (6 mPa.s) and titanium dioxide, or alternatively hydroxypropylmethylcellulose (6 mPa.s), lactose, polyethylene glycol 4000 and titanium dioxide.
As regards the process for manufacturing the tablets according to the invention, this process consists, in a first stage, in preparing a suitable composition, and then in subjecting it to compression in order to obtain the cores which are thereafter film-coated.
Thus, the implementation of the process for preparing the tablets termed "IRF", the preferred constituents of which have been described above for the tablets A, consists in:
i) preparing the composition - in a powder mixer or a fluidized bed apparatus, mixing the trimebutine maleate, lactose monohydrate, pregelatinized maize starch, hydroxypropylmethylcellulose and half of the carboxymethyl starch, then granulating the homogeneous mixture with tartaric acid in aqueous solution and sizing the wet granules, - drying the granules in a fluidized bed or in a ventilated oven at 60 C, then sizing them on a screen of aperture 1 to 1.5 mm, then mixing them in a powder mixer with the second half of the carboxymethyl starch, the silica gel and the magnesium stearate, ii) preparing the cores by compression of the granules on a rotary pelleting machine with punches of suitable size for obtaining cores of mass equivalent to 200 or 400 mg, containing doses of 100 and 200 mg of trimebutine maleate, respectively, and the hardness of which is 50 to 70 N, iii) film-coating the cores in a coating pan with the film-coating suspension at a temperature of between 35 and 45 C and under conditions such that this film coating coats the cores uniformly in the proportion of an amount of 4 mg for the cores weighing 200 mg and 8 mg for the cores weighing 400 mg.
The implementation of the process for preparing the tablets B termed "SRF", differing little from the one described above, consists in:
i) preparing the composition - in a powder mixer or a fluidized bed apparatus, mixing the trimebutine maleate, lactose monohydrate and tartaric acid, then granulating the homogeneous mixture with an aqueous or ethanolic solution of povidone and sizing the wet granules, - drying the granules in a fluidized bed or in a ventilated oven at a temperature of 45 to 60 C, sizing them on a screen of aperture 1 to 1.5 mm, then mixing them in a powder mixer with the hydroxypropylmethylcellulose, the silica gel and the magnesium stearate, ii) preparing the cores by compression of the granules on a rotary pelleting machine with punches of suitable size for obtaining cores of mass equivalent to 747 or 508 mg, containing doses of 300 and 200 mg of trimebutine maleate, respectively, and the hardness of which is 80 to 200 N, iii) film-coating the cores in a coating pan with the film-coating suspension at a temperature of between 35 and 45 C and under conditions such that this film coating coats the cores uniformly in the proportion of an amount of 15 mg for the cores weighing 747 mg and 10 mg for the cores weighing 508 mg.
As prepared, the film-coated tablets are then packaged in blister packs, in polypropylene or high density polyethylene bottles and the like.
The invention is illustrated without implied limitation by the examples which follow.
Example 1: Film-coated tablets for rapid disintegration, containing a 100 mi!
dose of trimebutine maleate - so-called "IRF" form The following are introduced into a vortexing centrifugal powder mixer:
- 10.400 kg of trimebutine maleate, - 7.488 kg of lactose monohydrate, - 1.450 kg of pregelatinized maize starch, - 0.208 kg of sodium carboxymethyl starch, - 0.208 kg of hydroxypropylmethylcellulose (6 mPa.s).
Homogeneous mixing of the constituents is achieved by stirring for 3 minutes, and then, in the same apparatus, using the tool suitable for granulation, the mixture is wetted with a solution of 0.208 kg of tartaric acid dissolved in 2.7 1 of water.
The granules are sized wet on a rotary size grader, then dried in a fluidized bed at 50 C until the residual moisture content is less than 1%.
The granules are then sized on a rapid screen of mesh aperture 1.5 mm and thereafter introduced into a powder mixer of the container type. The following are then added:
- 0.208 kg of carboxymethyl starch, - 0.416 kg of silica gel, - 0.208 kg of magnesium stearate.
The whole is mixed for 20 minutes at slow speed (5 to 10 rpm), then subjected to compression on a rotary tableting press equipped with punches 8 mm in diameter.
The cores obtained have the following properties:
- mean mass 200 mg 15 mg - mean hardness 60 N f 10 N
- friability < 1%

- disintegration time in water at 37 C: not more than 8 minutes.
The cores are then film-coated in a coating pan (for example in an apparatus of the "Ultra Coater Aeromatic S2" type) by spraying with an aqueous suspension containing methylhydroxypropylcellulose (6 mPa.s), lactose hydrate, titanium dioxide and polyethylene glycol 4000. In the abovementioned type of apparatus, the working conditions are as follows:
- air inflow temperature: 50 C, - rate of introduction of the film-coating suspension: 30 g/minute, - spraying pressure: 2 bars, to obtain at a temperature of 35 to 45 C a homogeneous film coating of 4 mg per tablet, the mean final mass of which is 204 mg 15.3 mg and the unit composition of which is as follows:

- trimebutine maleate 100.0 mg lactose monohydrate 72.0 mg - pregelatinized maize starch 14.0 mg - hydroxypropylmethylcellulose 2.0 mg - sodium carboxymethyl starch 4.0 mg - tartaric acid 2.0 mg - silica gel 4.0 mg - magnesium stearate 2.0 mg - mixture of film-coating agents 4.0 mg including hydroxypropylmethylcellulose 6 mPa.s 0.93 mg, lactose hydrate 1.4 mg, titanium dioxide 0.87 mg and polyethylene glycol 4000 0.80 mg.
The immediate packaging of these tablets is performed in blister packs (aluminium/polyvinyl chloride).
An identical procedure is used to prepare "IRF" tablets containing a 200 mg dose of trimebutine maleate. The modification made consists in equipping the rotary tableting press with suitable punches for obtaining cores with a mean mass of 400 mg, which, under the conditions of the example, is carried out with punches whose diameter is 11 mm. These cores are then film-coated with the mixture of film-coating agents in the proportion of 8 mg per core so as to obtain finished tablets with a mean mass of 408 mg.
Example 2: Film-coated sustained-release tablets containin2 a 300 mg dose of trimebutine maleate - so-called "SRF" form The following are introduced into an "Aeromatic" type fluidized bed apparatus:
- 10.500 kg of trimebutine maleate, - 2.100 kg of lactose monohydrate, - 4.200 kg of tartaric acid, after homogenization, 2.000 kg of a 21% (w/v) aqueous solution of povidone are added gradually and mixing is continued for 16 minutes. The granule obtained is dried at 60 C until the residual solvation, determined with a thermobalance, is less than 0.6%.
The granule is then sized on a rapid screen of mesh aperture 1.5 mm and thereafter introduced into a vortexing centrifugal powder mixer. 4.200 kg of lactose atomisate, 4.200 kg of hydroxypropylmethylcellulose 4000 mPa.s, 262.5 g of silica gel and 262.5 g of magnesium stearate are then introduced.
The whole is then mixed for 2 minutes and thereafter subjected to compression on a rotary tableting press. The cores obtained have the following properties:
- mean mass 747 mg 30 mg - mean hardness 180 N t 20 N
- friability < 1 %
The cores are then film-coated in a coating pan as described in Example 1, with an aqueous suspension containing hydroxypropylmethylcellulose (6 mPa.s), and titanium dioxide, to obtain a homogeneous film coating of 15 mg per tablet, the mean final mass of which is 762 mg 30 mg and the composition of which is as follows:
- trimebutine maleate 300.0 mg - lactose monohydrate 180.0 mg - tartaric acid 120.0 mg - povidone 12.0 mg - hydroxypropylmethylcellulose 120.0 mg - silica gel 7.5 mg - magnesium stearate 7.5 mg - mixture of film-coating agents 15.0 mg including hydroxypropylmethylcellulose 6 mPa.s 11.5 mg and titanium dioxide 3.5 mg.
The tablets are packaged in blister packs or in bottles according to their use and the storage conditions.
A variant of this procedure consists in equipping the rotary tableting press with punches suitable for obtaining cores whose mean mass is 508.0 mg containing a 200.0 mg dose of trimebutine maleate. These cores are film-coated with the mixture of film-coating agents, in the proportion of 10.0 mg per core in order to obtain finished tablets whose mean mass is 518.0 mg.
Tests The tests carried out comprise:
- study of the physical and chemical stability of the film-coated rapid- or sustained-release tablets of the invention, - comparative study of the tilm-coated rapid-release tablets of the invention with commercially available tablets.
Except for the assessment of appearance, the tests relating to the physical criteria were carried out according to protocols adapted from the European Pharma-copoeia, which are:
- the disintegration test (Ph. Eur. V.5.1.1), - the dissolution test (Ph. Eur. V 5.4.1), - the friability test (Ph. Eur. V.5.8.2.-1), - the hardness test (Ph. Eur. V.5.8.3.-1).
As regards the studies of chemical stability of the trimebutine maleate, these were determined by assaying the 3,4,5-trimethoxybenzoic acid, which is repre-sentative of the hydrolysis of the active principle. This assay is carried out by high pressure liquid chromatography (HPLC - Ph. Eur. V.6.20.4) with a 125-mm column of a Merck Lichrospher 60 RP select B support and performing the elution with a pH 3.6 phosphate buffer/acetonitrile mixture, spectrophotometric detection being performed at 220 nm.
- stability studies In packagings in blister packs (PVC/aluminium) or in polypropylene bottles, the film-coated "IRF" and "SRF" tablets studied were stored for 6 months in ovens at 40 C 4 C, in an anhydrous atmosphere or an atmosphere of relative humidity (RH) 75% 5%. The results of these tests are recorded in the tables which follow.
1) Stability of IRF tablets The studies were carried out after 6 months of storage of the tablets at 40 C 4 C in an atmosphere of relative humidity 75% 5%.
The criteria adopted for the study are:
- appearance, disintegration time, hardness, crumbling and the test of dissolution of the active principle as regards physical stability, - the assay of TMBA as regards the chemical stability of the active principle.

To T 6 months 40 C + 75% RH

Physical stab.
- appearance white off-white - hardness 79 N 82 N
- crumbling 1.27% 0.69%
- disintegration time 7 to 9 min 10 to 12 min - dissolution test 10 min 25% 20.7%
- dissolution test 20 min 100.3% 96.9%
- dissolution test 30 min 100.9% 101.8%
Chemical stab.
- % TMBA 0.01% 0.10%
2) Stability of SRF tablets The studies were carried out after 6 months of storage of the tablets at 40 C 4 C in an anhydrous medium and in an atmosphere of relative humidity 75% f 5%.
The criteria adopted for the study are:
- appearance and dissolution test for physical stability, - the assay of TMBA for the chemical stability of the active principle.
To T 6 months 40 C 40 C + 75% RH
Physical stab.
- appearance white off-white off-white - dissolution 1 h 7.6% 7.3%
4 h 25.8% 27.7%
8 h 49.0% 54.8%

Chemical stab. 0.09% 0.10% 0.15%
- % TMBA

These tests, performed under harsh storage conditions, bear out the excellent stability of the tablets of the invention.
As regards the "IRF" tablets:
- the physical stability proves exceptional, in particular bearing in mind the significant criterion of the objective towards which the invention is directed, which is to avoid the premature disintegration of the tablet and consequently the dissolution of the active principle. In effect, regarding these points, a slight increase in the disintegration time (approximately 3 minutes) is observed after 6 months, which corresponds to a slight decline in the rate of dissolution of the trimebutine maleate, - the chemical stability is also considered satisfactory. The formation of 0.09% of TMBA corresponds, on the ratio of the molecular weights, to the 0. 09 x 503.5 degradation of 212.2 = 0. 21 % 1 of trimebutine maleate (TMBA - MW = 212.2; trimebutine maleate - MW = 503.5) As regards the "SRF" tablets:
- the physical stability is exceptional bearing in mind the criterion of dissolution which is essential for sustained-release forms, - the chemical stability is also good, considering that the formation of 0.06%
of TMBA
corresponds to the degradation of 0.14% of trimebutine maleate.

- comparative tests To demonstrate the noteworthy improvements provided by the film-coated dosage form according to the invention, comparative tests were carried out between the tablets obtained in Example 1 and commercially available tablets containing a 100.0 mg dose of trimebutine maleate.
As regards the latter, the qualitative information on the excipients of the two specialities appears in the "Vidal" Dictionary of Pharmaceutical Specialities:
- tablets "D": lactose, mannitol, sucrose, polyethylene glycol 6000, magnesium stearate, gelatin, wheat starch, silica gel.
- tablets "T": lactose, hypromellose, croscarmellose, magnesium stearate.
The tablets of Example 1 were compared with the tablets "D" and/or the tables "T" as regards, on the one hand the release of the active principle, and on the other hand their chemical stability after storage at 40 C - 75% relative humidity for 6 months as regards the hydrolysis of the trimebutine maleate, determined by assaying 3,4,5-trimethoxybenzoic acid (TMBA).
The results are presented in the tables which follow:

Ex. 1 Tab. "D" Tab. "T"
% dissolution - 10 min 23.0% 26.0% 83.3%
- 20 min 101.2% 50.4% 98.7%
- 30 min 101.7% 69.2% 98.6%
- 45 min - 92.9%
- 60 min - 98.0%
Comparative dissolution study Studies at 6 months 40 C - 75% RH

Ex. 1 Tab. "D" Tab. "T"
- % TMBA 0.10% 0.45% 0.70%
- % degrad. active principle 0.23% 1.06% 1.66%
() Comparative stability study () Relative % of degradation, calculated on the ratio of the MWs of TMBA
(212.2) and of trimebutine maleate (503.5) and subtracting the TMBA present at To.
These tests bear out the improvements provided by the film-coated tablet according to the invention:
- the dissolution study proves the transient efficacy of the film coating, which enables virtually all of the active principle to be released in between 10 and 20 minutes, whereas, for the tablets "D", the whole of the release is obtained only after 60 minutes, and for the tablets "T", this release is almost complete before 10 minutes.
These results show that the tablets "D", in order to avoid buccal bitterness, release the active principle only slowly and in an excessively retarded manner whereas, on the contrary, the tablets "T" release the trimebutine maleate excessively rapidly with a consequent appearance of persisting buccal bitterness;

- the study of chemical stability shows that, overall, the degradation of trimebutine maleate is 4 and 6 times greater, respectively, in the tablets "D" and "T"
than in the tablets of the invention according to Example 1.

Claims

1. Film-coated trimebutine maleate tablet for oral administration, characterized in that it comprises a) a core comprising, by weight of the core, 30 to 60% of trimebutine maleate, and, as excipients, 15 to 45% of one or more diluents, 2.5 to 25% of one or more binding agents, 0.5 to 25% of one or more acidifying agents selected from citric acid and tartaric acid, optionally 1 to 5% of one or more disintegrating agents, 0.5 to 5% of a glidant and 0.25 to 2.5% of a lubricant;

and b) a water-soluble film coating representing 1 to 5% by weight of the tablet, the composition of said coating comprising one or more water-soluble film-forming agents, one or more opacifying agents and, optionally, one or more plasticizers.

2. Film-coated tablet according to Claim 1, characterized in that the acidifying agent is tartaric acid, in the proportion of 0.5 to 2% in the cores for rapid release of trimebutine maleate and in the proportion of 10 to 20% in the cores for sustained release.

3. Film-coated tablet according to Claim 1 or 2, characterized in that the film coating is chosen from a mixture of hydroxypropylmethylcellulose of viscosity between 2.5 and 17.5 mPa.s and titanium dioxide, and a mixture of hydroxypropylmethylcellulose of viscosity between 2.5 and 17.5 mPa.s, lactose or microcrystalline cellulose, polyethylene glycol of molecular weight 4000 or polyoxyl 40 stearate and titanium dioxide.

4. Film-coated tablet for rapid disintegration comprising a core and a coating, whose percentage composition by weight of the core for cores weighing 200 and 400 mg is:
i) cores - trimebutine maleate 50.00%
- lactose monohydrate 36.00%
- maize starch 7.00%
- hydroxypropylmethylcellulose 1.00%
- sodium carboxymethyl starch 2.00%
- tartaric acid 1.00%
- silica gel 2.00%

- magnesium stearate 1.00%
ii) coating 2.00% of the weight of the core of a composition comprising hydroxypropylmethylcellulose, lactose, polyethylene glycol 4000 and titanium dioxide, or alternatively hydroxypropylmethylcellulose, microcrystalline cellulose, polyoxyl 40 stearate and titanium dioxide.

5. Film-coated sustained-release tablet comprising a core and a coating, whose percentage composition by weight of the core for cores weighing 747.00 and 508.00 mg is:
i) cores - trimebuline maleate 40.16%
- lactose monohydrate 24.07%
- hydroxypropylmethylcellulose 16.06%
- tartaric acid 16.06%
- povidone 1.61%
- silica gel 1.02%
- magnesium stearate 1.02%
ii) coating 2.00% of the weight of the core of a composition comprising hydroxypropylmethylcellose and titanium dioxide, or alternatively hydroxypropylmethylcellulose, lactose, polyethylene glycol 4000 and titanium dioxide.

6. Process for preparing the film-coated tablet according to Claim 1, which consists of the steps of:
i) preparing a mixture of the components of the cores by - mixing the trimebutine maleate and the excipients in a powder mixer or a fluidized bed apparatus, followed by granulation of the homogeneous mixture with the acidifying agent in aqueous solution to prepare wet granules;
- sizing the wet granules; and - drying the wet granules in a fluidized bed or in a ventilated oven at 60°C, then sizing them and mixing them in a powder mixer with the glidant and the lubricant to prepare dried granules, ii) preparing the cores by compression of the dried granules on a rotary pelleting machine with punches of suitable size, iii) film-coating the cores in a coating pan with a film-coating suspension at a temperature of between 35 and 45°C and under conditions such that the film coating coats the cores uniformly in the proportion of an amount of 2% of the weight of the tablet.

7. The process of Claim 6 wherein the glidant is silica gel.

8. The process of Claim 6 or 7 wherein the lubricant is magnesium stearate.