OA10968A - Trimébutine maleate film-coated tablet - Google Patents

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

Maleat tablet? PCIÜCUE. g, g 9 g pomaine of the invemiPh

The present invention relates to an improved trimebutine maleate tablet and film for oral administration and its method of preparation.

In particular, the invention relates to a novel tablet which makes it possible to administer a therapeutically effective amount of trimebutine raeaeate for rapid or prolonged biological delivery, but in any case without causing a bitter-finish effect which, in the long run , harms the good observance of the treatment by the patient. 10

BACKGROUND OF THE INVENTION [0002] Trimebutine, or 3,4,5-trimethyl-2-dimethylamino-2-phenyl-zircyl trifluorobenzonate. is the first drug known to act on the peripheral, digestive, peripheral kephainergic receptors. It is a regulator of the digestive tract. As it is, or saluted by maleic acid, trimebutine is proposed in the form of tablet, this injectable solution, suppository and powder for preparation of an oral suspension. Internally commercialized, these various pharmaceutical forms are indicated in the treatment of pain related to the functional furniture of the digestive tract and vasculitis, and in the treatment of pain and discomfort related to intestinal functional disorders.

Orally administrable forms are more particularly adapted to ambulatory treatments. These are essentially tablets and also granules or powders or, may be intended for the preparation of oral suspensions. Trimebutine maleate is the active ingredient commonly used for the preparation of oral forms with an indicative daily dosage of 300 to 600 mg for adults.

This product, obtained by crystallization from water, melts at 105-106 ° C. Its solubility in water 25-C is about 1 "(w / v) while trimebutine base is insoluble. Ufimébutine is. from the chemical point of view, a benroate type ester which is sensitive to agents promoting hydrolysis or related reactions. These agents include, in particular, water and reactive solvents such as lower alcohols, temperature and the light of a variety of catalysts, in particular metal, whether alkaline or aortic. The hydrolysis of trimebutine leads, among other by-products, to the formation of 3,4,5-trimethoxybenzoic acid, the quantitative determination of which makes it possible to assess its chemical stability under various storage conditions.

Also maleic acid is thermosensitive by its propensity to beomerize fumaric acid whose acidity constant is lower than that of maleic acid. This acid, by salification with rimebetin, leads to a fumigant of trimebutine of low solubility in water.

Furthermore, as many positively charged compounds in aqueous solution near neutral, trimebutine maleate. administered orally, induced in the cavity and on the oral mucosa a strong bitterness and astringentecurable sensation that may ultimately cause poor compliance with the treatments in which the product is prescribed. This bitterness is particularly disadvantageous when it is necessary to obtain a rapid therapeutic effect which supposes an almost immediate biological availability as soon as the drug has been swallowed. For the sake of illustration of this problem, one of the two specialties in compressed form marketed in French indicates that the tablets should be swallowed without being crimped with a glass of water. (Dictionary of Pharmaceutical Specialties Vidal, 1996) ) To date, the state of the art reports only imperfect attempts to overcome the problems presented, namely to both ensure the stability of trimebutine maleate during the preparation and storage of drugs and to mask or eliminate, at level 23 buccal, persistent bitterness caused by the product without delaying 1 therapeutic effect.

Regarding the powder form, patent FR 2 468 364 published on 8/5/1981 discloses a process for the preparation of microcapsules containing a pharmaceutically active compound whose walls are ethylcellulose, a process carried out in cyclohexane and which makes it easy to .piT an inducing agent for phase separation, preferably of the class these phospholipids. For example, microcapsules of trunehutin maleate are prepared for which one of the quality criteria evaluated is the absence of bitter taste.

According to the same process carried out in cyclohexane, the following patents are intended to improve the quality of microcapsules: FR 2,506,613 published on December 3, 1982, describes microcapsules whose walls consist of ethylcellulose and an insoluble polymer in water but soluble in acidic medium which aim at a rapid release of the product in gastric medium. The amount of trimebutine maleate incorporated does not exceed 15%, the release of 50% of the product in artificial gastric medium being obtained after 17 minutes. EP 0 076 515 published on 13/4/1983 also relates to rapid release microcapsules in a gastric medium whose walls consist of ethylcellulose and a polymer solubled in water and / or in acidic medium. The quantity of product included is at best 12% so 50% are released in 10 to 20 minutes. EP 0 076 428 also published on 13/4/1983 has the same purpose as the previous patents, the walls consist of ethylcellulose and a polymer 'inflatable * in water. They contain about 10% of active ingredient of which 50% are released in 4 to 25 minutes in artificial gastric medium. EP 0 099 109 published on 25/1/1984 discloses an advantageous advertised process for the preparation of microcapsules in which a particular phase separation inducing agent is involved.

It is clear that through this succession of patents their plaintiffs are aiming at the preparation of a powder containing, in the coated state, trimebutine maleate in order to mask the impurity while attempting to obtain a rapid release of the active principle from proposed microcapses. It appears that this goal is imperfectly achieved since, on the one hand, this process, which is complex and economically unsatisfactory, uses cyclohexane, which is a flammable solvent that is difficult to remove and subjected to the use of residual solvent to rigorous standards by the health authorities, and whereas, on the other hand, it leads to microcapsules which contain only a quantity of trimebutine maleate less than 20%. This requires the patients to absorb an excessively large amount of the drug, given the recommended daily dosage of 300 to 600 mg of trimebutine maleate, since it contains more than four times more excipients than the active ingredient. JP 80 40 885 published on 13/2/1996 discloses a compound formulation of a mixture of granules, in which, for those containing trimebutine maleate, the bitter taste is practically eliminated by granulation of the active ingredient with a polymer insoluble in water and a hydrophobic salt. For example, granules comprising trimebutine emaleate contain 20% of the active ingredient, 3% of insoluble polymer and 5% of a hydrophobic salt, namely magnesium stearate or calcium stearate. No mention is made of the rate of release and / or stability of trimebutinealeate in these granules. - ♦ - Π f: 9 6 8

As regards the tablets for the oral administration of trimebutine maleate, FR 2,640,876 published on 29/06/1990, there is disclosed a pharmaceutical composition in the form of a coating-free tablet and comprising as the active principle of trimethoxy-3,4,5-benzoate dimethylamino-2-phenyl-2-butanol-1 maleate, characterized in that this active ingredient, which represents from 35 to 45% by weight of the composition is dispersed from a homogeneous manner in a poroushydrophilic hydroxypropyl-ethylcellulose marrimrepresenting from 15 to 20% by weight of the composition which further comprises from 20 to 25% by weight of a water-soluble diluent and from 10 to 20% by weight of tanic acid. According to this invention the kinetics of dissolution of the active ingredient is, between thirty minutes and 8 hours related to zero order, about 50% of the product being released after 8 hours. It should be noted that these tablets, especially those with high dosages, can be easily swallowed by some patients, and that under these conditions the prolonged contact time prolonged in the oral cavity inevitably causes an unpleasant and persistent bitterness.

JP 73574/1990, published on 6/12/1991, relates to a solid preparation very similar to that of patent FR 2,640,876 and tablets of trimethylbuteate maleate intended for oral administration, in which an organic acid, on the basis of 0.1 to 20 mg per 100 mg of maleate significantly inhibits the decomposition of the product, in which magnesium stearate is partially involved. Suitable acids are stated to be tanic acid or citric acid and the formulation comprises a metal stearate (magnesium or calcium) as a lubricant for compression. 25 PsscDBtigiLds Γ invention

Overcoming the unsolved problems as set forth in the state of the art, the present invention is a technically simple, economically advantageous and patient-friendly solution for a new improved trimebutine maleate tablet for oral administration, characterized in that it comprises: - a nucleus comprising 30 to 60% trimebutine maleate, and excipients suitable for the preparation of said nucleus and those suitable for the stability and release of the active ingredient. a hydrosoluble petliculage, of transient efficiency but sufficient to preserve a disintegration of the nucleus and a premature release of the active principle in the oral environment. 'f f Ί · -

As described in this specification, in its main aspect, the invention relates to a novel tablet for the oral administration of a therapeutically effective amount of trimebutine maleate, the biological delivery of which can be rapid or prolonged, but in any event, causing no persistent bitterness in the oral cavity, which in use causes a repulsive attitude of the patient. These tabletshave a remarkable resistance and physical stability that makes them suitable for the most diverse conditions (blister, loose in ways ...) under demanding conditions of conservation (temperature, humidity ...)

Also an important aspect is the remarkable chemical stability of trimebutine maleate presented in this form of tablets, even preserved under severe conditions, which provides the patients with a certain safety and therapeutic benefit. In another aspect, the invention is directed to the method of manufacturing tablets.

Another aspect of the invention relates to a composition suitable for the preparation of nuclei of tablets, characterized in that the quantitative adaptation and gna lira rfy? qe 15 main consumables allows to obtain a fast or prolonged release of the principal.

In general, laminating tablets provides advantages both for their industrial manufacture and for their use by the patient. Thus, with regard to the aspect of manufacture, the film-coated forms are recognized to be less sensitive to mechanical erosions, thus to generate less dust and, as a result, to reduce inter-drug contamination in the premises; It is also recognized that film coating favors lamise in primary packaging, especially in blistering tablets. Regarding the use by patients, the saunty or lustrous texture provided by the film-forming mixture of film coating avoids the adhesion of the naked tablet to the oral mucosa and makes swallowing easier.

In addition to these known advantages, the improvements made by the tablets of the invention have been developed later in this thesis and have been produced by tests of the liberation of the principle and physical and chemical stability, compared with two commercial specialties. 30

In the broadest sense of the invention, the tablets are characterized in that their cores comprise, by weight of 30 to 60% of trimebutine maleate, and, as excipients, 45% of one or more agents. diluents, from 2.5 to 25% of one or more binding agents, from 0.5 to 25% of one or more acidifying agents, optionally from 1 to 5% of one or more disintegrating agents, and from agents of technical utility, namely from 0.5 to 5% of a flow agent and from 0.25 to 2.5% of a lubricating agent and characterized in that said nuclei are coated with a film representing at 5% by weight of said tablet, a film whose composition comprises one or more water-soluble fogogenic agents, one or more opacifying agents, and, optionally, one or more plasticizing agents.

More specifically, the composition of a core comprises: at the rate of 20 to 40%, one or more diluents chosen from microcrystalline cellulose or powder, mannitol, starch, and more particularly lactose, in particular hydrated, which is the preferred diluting agent. at the rate of 2.5 to 25%, one or more binding agents chosen from microcrystalline cellulose, gelatin of pharmaceutically acceptable quality, methylcellulose and pregelatinized starch. Povidone, pre-gelatinized maize starch and hydroxypropylmethylcellulose with a viscosity of between 2.5 and 15,000 mPa.s are preferred. In particular, for nuclei which are desired to be rapidly disintegrated, a mixture representing from 5 to 10% of the tablet and composed of 5 to 10 parts of starch and 0.5 to 2 parts of hydroxypropylmethyl cellulose whose viscosity is between 2.5 and 17.5 mPa.s while for nuclei for which extended release is desired 15 to 20% of the active compound is a mixture of 5 to 15 parts of hydroxypropylmethylcellulose with a viscosity of between 1,500 and 15,000 mPa.s and 0.5 to 1 part of povidone. Particularly preferred is the hydroxypropylmechyl cellulosic cellulose having a viscosity of 5.2 to 7.0 mPa.s and, for hydroxypropylmethylcellulose extended release nuclei with a viscosity of 4000 mPa.s. the acidifying agent is chosen from the pharmaceutically acceptable organic acids, known for their sequestering properties of metals and / or having a stabilizing effect on the active ingredient and / or allowing the creation of an acid environment favorable to the release of the active principle of the hydrophilic nuclei aimed at prolonged release These acids are citric acid and tartaric acid, which in nuclei of which a rapid aggregation is desired are used in the range of 0.5 to 2%. and in nuclei for which prolonged release of trimebutine maleate is desired, preferably from 10 to 20% is used, particularly with tannic acid, which is preferred. the flow agent is silica dioxide, anhydrous or hydrated, which is used in the 0.75 ± 2.5% range. i u '! The lubricating agent is chosen from the metal salts of stearic acid, to the exclusion of other agents usually provided for this purpose. The lubricating agent is thus chosen from calcium or magnesium stearates. The latter is preferred at concentrations of 0.5 to 1.5% and more preferably 1%, the optional disintegrating agent is selected from crospovidone (poiyvidone-terminated), sodium salt of crosslinked carboxymethyl cellulose. Also known as "croscarmellose sodium" and carboxymethyl starch which is preferred, the optional nature of this agent corresponds to the possible need to rapidly release the active ingredient which is obtained by the rapid disintegration of the nuclei after passage of the bucco-pharyngeal sphere. this effect for so-called immediate release tablets is used sodium tartrate methyl starch at 1 to 5% and preferably 2% to obtain the expected aggregation.

And, with regard to the coating film, this essentially consists of a water-soluble agent selected from acrylic polymers or cellulosic polymers such as hydroxypropylmethylcellulose with a viscosity of between 2.5 and 17.5 mPa.s. ethylcellulose, ethylcellulose, hydroxypropylcellulose; a filler substance which allows for better adhesion of the film to the core such as lactose or cellulose and microcrystalline. The opacifying agents and / or additive dyes are chosen from iron oxides or titanium dioxide. The plasticizing agents that can be used are chosen from the average molecular weight of 3000 to 6000, propylene glycol, glycerol or polyoxyl stearate. In carrying out the peeling of the cores, the invention may use the mixed compounds in solution or suspension in water or in pharmaceutically acceptable solvents such as ethanol, acetone or mixtures thereof with water. However, a mixture comprising an aqueous suspension of hydroxypropylmethylcellulose whose viscosity is between 2.5 and 17.5 mPa.s and titanium dioxide or a mixture comprising a hydroxypropylmethylcellulose with a viscosity of between 2.5 and 17.5 is preferred. mPa.s, lactose or microcrystalline cellulos, polyethylene glycol of molecular weight 4000 or polyoxyl 40 stearate and titanium dioxide in aqueous suspension. Mixtures in which the hydroxypropylmethylcellulose is of viscosity of 5.2 to 7.0 mPa.s are particularly preferred: such mixtures, which are particularly suitable, are marketed by the companyColorcon under the brand OPADRY · or by the company Seppic under the trademark SEPIFILM They make it possible to obtain from 1.5 to 3% by weight with respect to the weight of the core and, particularly with 2%, a film of transient resistance in the bucco-pharyngeal medium. allows the tablet to be administered without any bitterness effect while preserving a biological provision of the active ingredient under the chosen release conditions for the latter. Moreover, the film-coating carried out by the film under the conditions of the invention perfectly respects the engravings, hollow or in relief, of the nuclei, indicative etchings of the active ingredient and of its dosage and which can, during the coating operation with inappropriate compositions to be either filled, eroded or erased and in all cases become illegible. In a particularly preferred embodiment, the invention relates to tablets whose minimum compositions are as follows:

Fast disintegrating tablets A called immediate release forms: ΤΙ_Γ i) composition for novels of 2QQ & 4QQ trimebutine maleate 50.00% lactose monohydrate 36.00% corn starch 7.00% bydroxypropylmethyl cellulose (6 mPa.s) 1.00% carboxymethyl sodium starch 2.00% tartaric acid 1.00% silica gel 2.00% magnesium stearate 1.00% il) coating 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 hydroxypropylme ± cellulose (6 mPa.s), microcrystalline cellulose, polyoxyl 40 stearate and titanium dioxide.

So-called prolonged-release tablets B: 'FLP * i) Novel composition of 747.00 & 508.0Q trimebutine ma - maleate 39.37% - lactose monohydrate 23.6% - hydroxypropylmethyl cellulose (4000mPa.s) 15.75% - tartaric acid 15.75% --povidone 1.57% - silica gel 1.00 %

WF ο 1 Ο 9 6 8 - 9 - - magnesium stearate 1.00% ii) coating 2.00% of the weight of the core of a composition comprising hydroxypropylmethylcellulose (6 mPa.s) and titanium dioxide or alternatively hydroxypropylmethylcellulose (6 mPa.s), lactose, polyethylene glycol 4000 and titanium dioxide,

With regard to the process for producing the tablets according to the invention, it is first necessary to prepare an appropriate composition and then to compress it to obtain the cores which are subsequently film-coated. of the process for the preparation of the so-called FLI tablets, the preferred constituents of which have been described previously for tablets A consists of: i) in the preparation of the composition - in a powder mixer or a fluidized-bed apparatus mixing the maleate of rimebutin, lactose monohydrate, pregelatinized maize starch, hydroxypropylmethylcellulose and half carboxymethyl starch, and then granulate the homogeneous mixture with tartaric acid in aqueous solution and calibrate the wet granules, dry in a fluidized bed or in a ventilated oven at 60.degree. granules, then calibrate on sieves 1 to 1.5 mm aperture, then mix them in a mixer po with the second half carboxymethyl starch, silica gel and magnesium stearate. Ii) preparing the cores by compressing the pellets on a rotary pelletizer with punches of appropriate size to obtain cores of mass equivalent to 200 or 400 mg, respectively dosed at 100 and 200 mg of trtmebutine maleate and having a hardness of 50 to 70 N, iii) laminating the turbine cores with the drying suspension at a temperature between 35 and 45 ° C and under conditions such that this peeling uniformly covers the cores at a rate of 4 mg for the nuclei. 200 mg and 8 mg for the 400 mg nuclei.

The process for the preparation of the so-called 'FLP' tablets B, which is slightly different from that previously described, consists in: i) preparing the composition * in a powder mixer or a fluidized bed apparatus mixing the maleate digrybutine, lactose monohydrate, and tartaric acid, and then granulate the homogenous mixture with an aqueous or ethanolic solution of povidone and calibrate the wet granules.

rw -Y - V - 10 - 9 - 8 - drying in fluidized Ht or in a ventilated oven at a temperature of 45 to 60 ° C the granulesles to calibrate on sieves 1 to 1.5 mm aperture, then mix them in a powder blender with bydroxypropyimethyl cellulose, silica gel and magnesium stearate. ii) preparing the cores by compressing the pellets on a rotary pelletizer with punches of appropriate size to obtain cores with a mass equivalent to 747 or 508 mg, dosed respectively at 300 and 200 mg of trimebutine maleate and having a hardness of 80 to 200 N, iii) compounding the turbine cores with the film-coating slurry at a temperature between 35 ° and 45 ° C and under such conditions that such lamination uniformly covers the cores at a rate of 15 mg for the cores of 747 mg and 10 mg for the nuclei of 508 mg.

As prepared the pellicuîés tablets are then packaged in blisters, enflacons polypropylene or high density polyethylene, etc. The invention is illustrated in a nonlimiting manner by the examples which follow. EXAMPLE 1 Rapid Disintegration Film Films Assayed at 100 mg Trimebutine Maleate - NFLI Form

In a blender of powder for spraying and swirling, 10.400 kg of trimebutine maleate, 7.488 kg of lactose monohydrate, 20 - 1.450 kg of pregelatinized maize starch, 0.208 kg of sodium carboxymethyl starch, 0.208 kg are introduced. hydroxypropylmethyl cellulose (6 mPa.s).

The homogeneous mixture of the constituents is made by stirring for 3 minutes, 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% of water. water.

The granules are calibrated wet on a rotary sizer and then dried on a fluidized bed at 50 ° C. until the residual moisture content is less than 1%.

The granules are then calibrated on a 1.5 mesh quick opening sieve and then introduced into a powder mixer, container type. Then added are: 0.308 kg of carboxymethyl diamide, 0.416 kg of silica gel, 0.208 kg of magnesium stearate. The mixture is mixed for 20 minutes at a slow speed (5 to 10 revolutions / minute) and then subjected to compression on a rotary press equipped with punches with a diameter of 8 mm. - Il - 91 09 68 - medium hardness - friability ίο 15

The cores obtained have the following characteristics: - average mass 200 mg ± 15 mg60 N ± 10 N <I% - disintegration time in water at 37 ° C: maximum 8 minutes.

The cores are then film-coated in a turbine (for example in an ultracater aeromatic SJ apparatus by spraying an aqueous suspension containing lamethylhydroxypropyl cellulose (6 mPa.s), hydrated lactose, titanium dioxide and polyethylene glycol 4000. In the aforementioned type of apparatus, the conditions of the operation are as follows: - air temperature of the air: 50 ° C., - rate of introduction of the shrinkage suspension: 30 g / minute, - spray pressure: 2 bar, to obtain, at a temperature of 35 to 45 ° C., a homogenous 4 mg membrane with a mean final mass of 204 mg ± 15.3 mg and the unit composition of which is as follows: trimebutine maleate 100, 0 mg - lactose mooobydrate 72.0 mg - pregelatinized maize starch 14.0 mg 20 - hydroxypropylmethylbetyl cellulose 2.0 mg - sodium carboxymethyl diamid 4.0 mg - tartaric acid 2.0 mg - silica gel 4.0 mg - stearate magnesium 2.0 mg Mixture of laminating agents 4.0 mg of which 6mPa.s is hydroxypropylmethylcellulose 0.93 mg, hydrated lactose 1.4 mg, titanium dioxide 0.87 mg and polyethylene glycol 4000 0.80 mg.

The primary conditioning of these tablets is carried out in blister packs (aluminum-polyvinylchloride). 30

An identical procedure is used to prepare FLI * tablets dosed with 200 mg trimebutine maleate. The modification consists in equipping the rotary compression press with appropriate punches to obtain cores with an average mass of 400 mg, which, under the conditions of the example, is achieved with punches of which the diameter is is 11 mm. The cores are then coated with the film-coating mixture at a rate of 8 mg per core in order to obtain finished tablets with an average mass of 408 mg. Example 2: Extended Release Dandruff Tablets Assayed at 300 mg Maleatetriipébutine - "FLP" Form

In a fluidized bed apparatus of the type "Aeromatic" are introduced: - 10,500 kg of trimebutine maleate, 2,100 kg of lactose monobydrate 10 - 4,200 kg of tartaric acid, after homogenization is added gradually 2,000 kg of a 21% aqueous solution (w / v) povidone and mixing is continued for 16 minutes. The grain obtained is dried at 60 ° C. until the residual solvation, determined by the thermobalance, is less than 0.6%. The granule is then calibrated on a 1.5 mm mesh open sieve and then introduced into a powder blast and swirl mixer. 4,200 kg of lactose atomisai, 4,200 kg of hydroxypropylmethyl cellulose 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 then subjected to compression on a rotary press. The cores obtained have the following characteristics: - average mass 747 mg ± 30 mg

- average hardness 180 N ± 20 N - friability <1%

The cores are then rolled into a turbine 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 final average 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 - poiyvidone 12.0 mg - hydroxypropylmethyl cellulose 120.0 mg * gel silica 7.5 mg magnesium stearate 7.5 mg - 15.0 mg pelleting agent mixture of which hydroxypropylmethylcellulose 6 mPa.si, 5 mg and titanium dioxide 3.5 mg.

The tablets are packaged in blister packs or vials depending on their use and storage conditions. 5

An alternative to this procedure is to equip the rotary press with suitable stitches to obtain cores with an average mass of 508.0 mg at 200.0 mg Trimebutine Mate. These cores were pelleted with the pelleting agent mixture at 10.0 mg per core to obtain finished tablets with an average weight of 518.0 mg.

testing

The tests carried out include: - the study of the physical and chemical stability of the fast-release or prolonged-release film-coated tablets of the invention, - the comparative study of the fast-release film-coated tablets of the invention with commercially available tablets.

Except for the assessment of the aspect, the tests concerning the physical criteria were carried out according to adapted protocols of the European Pharmacopoeia which are the tests: - of disintegration (Pb.Eut.V.5.1.1), 20 - of dissolution ( Pb. Eur.V.5.4.1), - friability (Ph.Eur.V.5.8.2.-1), - hardness (Ph.Eut.V.5.8.3.-1).

As regards the chemical stability studies of trimebutine maleate, these have been determined by the determination of 3,4,5-uimethoxy benzoic acid which is representative of the hydrolysis of the active ingredient. This assay is carried out by high pressure liquid chromatography (HPLC - Ph.Eur.6.6.4.4) with a 125 mm column of a type Lichrospber 60 RP select B Merck support and by * practicing the unit with a pH 3 buffer phosphate mixture. , 6 - acetonitrile, the spectrophotometric detection being carried out at 220 nm. 30 - episodes of sabilirt

In blister packs (PVC-aluminum) or polypropylene bottles, the film-coated tablets 'FLI' and 'FLP' studied were kept for 6 months in 40 ° C ± 4 ° C incubators, in an anhydrous atmosphere or relative humidity ( HR) 75% ± 5% The results of these tests are reported in the following tables.

1) Stability of FLI tablets

The studies were carried out after 6 mob of storage of the tablets at 40 ° C. ± 4 ° C. relative humidity of 75% ± 5%.

The criteria used for the study are: 5 · the appearance, disintegration time, hardness, erosion and dissolution test of the active ingredient with regard to physical stability. - the determination of the ATMB with regard to the chemical stability of the active ingredient. Το T 6 mob 40 'C -r 75% RH Sakjhysiqug • off-white appearance - hardness 79 N 82 N - crumbling 1.27% 0.69% - disintegration time 7 to 9 min 10 to 12 min - dbsolution test 10 min 25% 20.7% - dissolution test 20 min 100.3% 96.9% • dissolution test 30 min 100.9% 101.8% SP.L. chemical -% ATMB 0.01% 0.10%

2) Stability of FLP tablets

The studies were carried out after 6 mob of storage of the tablets at 40 ° C. ± 4 ° under anhydrous medium and in a relative humidity of 75% ± 5%.

The criteria selected for the study are: - the appearance and dissolution test for physical stability, - the ATMB assay for the chemical stability of the active ingredient. 30 - 15 - U1 Ο 9 6 6

To T 6 months 40 * C 40 'C + 75% RH Stab. physical - appearance - dissolution 1 h 4 h 8 h white 7.6% 25.8% 49.0% off white 7.3% 27.7% 54.8% off-white S.tgb, -cAimiflMg -% ATMB 0.09% 0.10% 0.15 These tests, carried out under rigorous conditions of preservation, are evidence of the excellent stability of the tablets of the invention.

With regard to tablets' FLI *: - the physical stability proves to be remarkable especially considering the significant criterion of the aim of the invention which is to avoid the premature disintegration of the tablet and, consequently, the dissolution of the principle active. Indeed, there is observed on these points after 6 months a slight increase in disintegration time (about 3 minutes) which corresponds to a slight decrease in the dissolution rate of trirnébutine maleate, - the chemical stability is also considered satisfactory.

The formation of 0.09% ATMB corresponds to the molecular weight ratios at degradation of 0.09 x 503.5 = 0.21% trirnébutine maleate. 212.2 (ATMB - PM = 212.2, trirnébutine maleate - MW = 503.5)

With regard to 'FLP * tablets: - the physical stability is remarkable considering the dissolving criterion which is essential for the sustained-release forms, - the chemical stability is also good considering that the formation of 0.06% of ATMB corresponds to the degradation of 0.14% of trirnébutine maleate. For proof of the significant improvements made by the film-form according to the invention, comparative tests were carried out between the tablets obtained in Example 1 and commercial tablets dosed with 100.0 mg of maleate. trimebutine.

With regard to the latter, the qualitative information of the excipients of the two specialties can be found in the dictionary of pharmaceutical specialties "Vidal *: - tablets' D *: lactose, mannitol, sucrose, polyethylene glycol 6000. magnesium stearate, gelatin, wheat starch silica gel - "T" tablets: lactose, hypromellose, croscarmellose, magnesium stearate.

The tablets of Example 1 were compared with tablets D and / or tablets T on the one hand, the release of the active ingredient and on the other hand, their chemical stability after storage at 40.degree. C - 75% hygrometry for 6 months as regards the hydrolysis of trimebutine maleate determined by determination of 3,4,5-trimethoxy benzonic acid (ATMB).

The results are presented in the following tables:

Ex. 1 Cpmé 'D "Cpmé" T "% Dissolution - 10 mn 23.0% 26.0% 83.3% - 20 mn 101.2% 50.4% 98.7% - 30 mn 101.7% 69.2% 98.6% - 45 minutes - 92.9% - 60 minutes - 98.0%

Comparative dissolution study

Studies at 6 months 40 * C - 75% HR Ex. 1 Cpmé 'D * Cpmé "T" -% ATMB 0.10% 0.45% 0.70% -% degraded. active ingredient (') 0.23% 1.06% 1.66%.

Comparative Stability Study 30 (·)% relative degradation calculated at the ratio of PM of ΓΑΤΜΒ (212.2) to trimerbune maleate (503.5) and abstracting from ΓΑΤΜΒ present in To. J * Ü 9 6 6 - 17 -

These tests are convincing of the improvements made by the film-coated tablet according to the invention: the dissolution study proves the transient effectiveness of the thickening process, which makes it possible to release almost all of the active ingredient between 10 and 20 minutes while for the tablets * D * The whole of the release is obtained after 60 minutes and for the tablets this release is practically complete before 10 minutes.These results show that tablets * D ", to avoid bitterness, do not release the principle It is only slowly and excessively delayed that, unlike the tablets, release of trimebutine emaleate is excessively fast, resulting in the appearance of persistent bitterness. the chemical stability study shows that, overall, the degradation of the maleate of rimebutin is respectively 4 and 6 times greater in the tablets D * and T * than in the tablets of the invention according to Example 1.

Claims (1)

1. A film-coated tablet of trimebutine moneate for oral administration, characterized in that it comprises: a nucleus comprising 30 to 60% trimebutine maleate, and excipients suitable for the preparation of said nucleus and those suitable for the stability and release of the active ingredient, • a water-soluble pelletisation, of transient efficiency but sufficient to preserve a decay of the nucleus and a premature release of the active principle in the oral medium, 2.) Film-coated tablet according to the claim 1, characterized in that its nut comprises, by weight, 30 to 60% of nimebutine maleate, and, as excipients, from 15 to 45% of one or more diluents, from 2.5 to 25% of one or more binding agents, from 0.5 to 25% of one or more acidifying agents, optionally from 1 to 5% of one or more disintegrating agents, and agents of technical utility namely from 0.5 to 5%; % of a scouring agent and 0.25 to 2.5% of a lubricating agent, 3.) The film-coated tablet according to claims 1 and 2 characterized in that the acidifying agent is tartaric acid at a rate of 0 5 to 2% in the nuclei for rapid release of Maya '' '' from trimebutine and 10 to 20% in the nuclei for extended release, 4.) The film-coated tablet according to claim 1, characterized in that the peliiculagerepresents from 1 to 5 % by weight of the matrix and its composition comprises one or more water-soluble monomer agents, one or more opacifying agents, and, optionally, one or more plasticizers, 5.) The film-coated tablet according to claims 1 and 4 characterized in that the coating is chosen between a mixture of hydroxypropylmethyl cellulose viscositecomprise between 2.5 and 17.5 mPa.s and titanium dioxide and a mixture comprising hydroxypropylmethylcellulose 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. 6.) Fast disintegrating film-coated tablet whose centesimal composition for 200 &amp; cores. 400 mg is: i) Novel - Trimebutine Meate - Lactose Monohydrate - Corn Starch 50.00% 36.00% 7.00% - 19 - GC - Hydroxypropylmethylcellulose (6 mPa.s) - Carboxymethyl Sodium Starch - taruic acid - silica gel - magnesium stearate 1.00 * 2.00 * 1.00 * 2.00 * 1.00 * ii ii) coating 2.00 * of the weight of the core of a composition comprising hydroxyprcpylmethyl cellulose ( 6 mPa.s), lactose, polyethylene glycol 4000 and titanium dioxide, or alternatively hydroxypropylmethyl cellulose (6 mPa.s), microcrystalline cellulosic, polyoxyl 40 stearate and titanium dioxide. 7.) Extended release film tablet with a percentage composition of 747.00 kernels &amp; 508.00 mg is: i) nQYam - trimebutine maleate 39.37 * - lactose monobydrate 23.6 * 15 - hydroxypropylmethyl cellulose (4000mPa.s) 15.75 * - tartaric acid 15.75 * - povidone 1.57 * silica gel 1.00 * - magnesium stearate 1.00 * ii) coating 2.00% of the weight of the core of a composition comprising hydroxypropyl methylcellulose (6 nPa.s) and titanium dioxide or alternatively hydroxypropyl methylcellulose ( 6 mPa.s), lactose, polyethylene glycol 4000 and titanium dioxide, 8.) A process for the preparation of dandruff tablets which comprises: i) preparing the mixture of the components of the 25 * rings by mixing trimebutine maleate and excipients in a powder mixer or a fluidized bed apparatus mixing and then granulating the homogeneous mixture with the acidifying agent in aqueous solution and calibrating the wet granules, drying in a fluidized bed or in a ventilated oven at 60 ° C. the granules, then calibrating them and mix them in a mixture ur to powder with silica gel and magnesium stearate. (Ii) to prepare the cores by compressing the pellets on a rotary pelletizer with appropriately sized punches; (iii) to weigh the turbine cores with the film-coating slurry at a temperature between 35 and 45 ° C and under such conditions that such coating is uniformly coated the nuclei due to an amount of 2% of their weight. νύ! v, 1 ίό