COMPRESSED TRIMEBUTIN MALEATE WITH LAMINATE COATING
DESCRIPTIVE MEMORY Sector of the art to the crue belongs the invention The present invention refers to an improved trimebutine maleate tablet and provided with laminar coating, intended for oral administration, and also refers to its preparation procedure. In particular, the present invention relates to a new tablet that allows administering a therapeutically effective amount of trimebutine maleate for rapid or prolonged biological disposal but, in any case, without causing a persistent bitter effect which, in the long term, hinders the good observance of the treatment by the patient. Technological basis of the invention Trimebutine, or 3, 4, 5-trimethoxybenzoate of 2-dimethylamino-2-phenyl-n-butyl, is the first drug known to act on peripheral enkephalinergic receptors, especially digestive receptors. It is a regulator of digestive motility. In its own state, or in salt form by maleic acid, trimebutine has been proposed in the form of a tablet, an injectable solution, a suppository or a powder preparation for the preparation of a drinkable suspension. Internationally marketed, these various pharmaceutical forms are indicated in the treatment of pain related to functional problems of the digestive tract and bile ducts and in the treatment of pain and discomfort related to intestinal functional problems. Orally administrable forms are more particularly adapted to outpatient treatments. They are essentially the tablets and also the granulates or powder preparations that can be used for the preparation of drinkable suspensions. Trimebutine maleate is the active principle currently used for the preparation of these oral forms with a daily indicative dosage of 300 to 600 mg for adults. This product, obtained by crystallization in water, has a melting temperature of 105-106 ° C. Its solubility in water at 25 ° C is approximately 1% (w / v) while trimebutin base is insoluble in it. Trimebutine is, from the chemical point of view, an ester of the benzoate type sensitive to agents that favor hydrolysis reactions or the like. These agents especially comprise water and reactive solvents such as lower alcohols, temperature, light and various catalysts, in particular metallic, both alkaline and alkaline earth metals. The hydrolysis of trimebutine leads, among other by-products, to the formation of 3,4,5-trimethoxybenzoic acid, whose quantitative determination allows its chemical stability to be assessed under various storage conditions. Likewise, maleic acid is thermosensitive due to its propensity to be isomerized in fumaric acid, whose acidity constant is lower than that of maleic acid. This acid, by salification with trimebutine leads to a trimebutine fumarate of reduced solubility in water. On the other hand, as in many compounds positively charged in aqueous solution at pH close to the neutral state, trimebutine maleate, administered orally, induces a strong bitter taste and a lasting astringent sensation in the cavity and buccal mucosae. In the long term, it can cause poor compliance with the treatments in which the product has been prescribed. This bitter taste is especially conditioning when it is necessary to obtain a rapid therapeutic effect, which means an almost immediate biological availability since the medicine has been swallowed. To illustrate the reality of this problem, one of the specialties in the form of a tablet, used in France, states that "the tablets must be swallowed without being crushed, with a glass of water" (dictionary of the pharmaceutical specialties "Vidal" - ed. 1996) Currently, the state of the art does not indicate more than imperfect attempts to overcome the problems sed, that is, simultaneously ensuring the stability of the trimebutine maleate when the preparation of the drugs takes place and in its preservation and to mask or eliminate, on a buccal level, the persistent bitter taste caused by the product, without delaying its therapeutic effect. With regard to the powder form, Patent FR 2 468 364 published in 8/5/1981 describes a process for preparing microcapsules containing a pharmaceutically active compound whose walls are ethylcellulose, a process carried out in cyclohexane and which makes a phase separation inducing agent, preferably from the class of phospholipids, is involved. As an example, microcapsules of trimebutine maleate have been prepared for which one of the elaborated quality criteria is the absence of bitter taste. According to this same procedure carried out in cyclohexane, the following patents refer to improving the quality of the microcapsules. The document FR 2 506 613 published in 3/12/1982 discloses microcapsules whose walls are constituted by ethylcellulose and a water-insoluble polymer but soluble in an acidic medium which aim at a rapid release of the product in the gastric medium. The amount of trimebutine maleate incorporated does not exceed 15%, obtaining the release of 50% of the product in artificial gastric medium after 17 minutes. The patent EP 0 076 515 published on 13/4/1983 also refers to fast-release microcapsules in gastric medium, whose walls are constituted by ethylcellulose and a water-soluble polymer and / or acid medium. The amount of product included is, at most, 12% of which 50% is released in a period of time of 10 to 20 minutes. Patent EP 0 076 428 also published in
4/13/1983 aims at the same objective as the previous Patents, the walls being constituted by ethylcellulose and a polymer "inflatable" in water. They contain approximately 10% of active principle of which 50% is released in a time of 4 to 25 minutes in an artificial gastric medium. EP 0 099 109 published on 1/25/1984 discloses a process disclosed as advantageous for the preparation of microcapsules in which a specific phase separation inducer intervenes. It is evident that through this sequence of patents the applicant pursues the preparation of a powder preparation containing trimebutin maleate in the state of coating with the purpose of masking its bitter taste, simultaneously trying to obtain a rapid release of the active principle from the proposed microcapsules. It is observed that this objective is obtained imperfectly since, on the one hand, this procedure, complex and economically unsatisfactory, uses cyclohexane, which is a flammable solvent, difficult to eliminate and submitted as a residual solvent to rigorous standards by the health authorities. and that, on the other hand, leads to microcapsules that contain only an amount of trimebutine maleate of less than 20%, which requires patients to absorb an excessively large amount of medication, taking into account the recommended daily dose of 300 to 600 mg of trimebutine maleate, since it contains more than four times the amount of excipients than of active principle. In the patent application JP 80 40 885 published on 2/13/1996, a formulation composed of a mixture of granules is described in which, for those containing trimebutine maleate, the bitter taste is practically eliminated by granulation of the active principle with a polymer insoluble in water and a hydrophobic salt. For example, granules comprising trimebutine maleate contain 20% of the active ingredient, 3% of insoluble polymer and 5% of a hydrophobic salt, ie, magnesium stearate or calcium stearate. No results are mentioned regarding the rate of release and / or stability of trimebutine maleate in these granules. As regards the tablets intended for the oral administration of trimebutine maleate, in the patent FR 2 640 876 published on 06/29/1990, a pharmaceutical composition is described in the form of a tablet without coating and comprising, as Trimethoxy-3,4,5-dimethylamino-2-phenyl-2-butanol-1-trimethoxy maleate active ingredient, characterized in that this active principle representing 35 to 45% by weight of the composition is dispersed homogeneously in a matrix hydrophilic porous hydroxypropylmethylcellulose which represents from 15 to 20% by weight of the composition further comprising from 20 to 25% by weight of a water-soluble diluent and from 10 to 20% by weight of tartaric acid. According to this invention, the dissolution kinetics of the active principle is between thirty minutes and 8 hours close to zero, about 50% of the product being released after 8 hours. It should be noted that these tablets, especially those with high doses, can hardly be swallowed by a hundred patients -
and that, under these conditions, the duration of involuntarily prolonged contact in the oral cavity inevitably causes an unpleasant and persistent bitter taste. The application JP Na 73574/1990 published in
12/6/1991, refers to a solid preparation very similar to that of Patent FR 2 640 876 and tablets of trimebutine maleate intended for oral administration, in which, an organic acid at a ratio of 0.1 to 20 mg per 100 mg of maleate, significantly inhibits the decomposition of the product, decomposition in which magnesium stearate is partially involved. It has been specified that the suitable acids are tartaric acid or citric acid and that the formulation comprises a metal stearate (magnesium or calcium) as a lubricating agent for compression. Description of the invention Overcoming the problems that have not been solved such as those indicated in the state of the art, the present invention is a technically simple, economically advantageous and beneficial solution for the patient, which aims at a new improved trimebutine maleate tablet intended for oral administration, characterized by comprising: a core comprising from 30 to 60 % of trimebutine maleate, and excipients adapted to the preparation of said nucleus and those suitable for the stability and release of the active principle. a water-soluble laminar coating, of transient efficacy but sufficient to preserve with respect to a disintegration of the core and premature release of the active principle in the buccal medium. As described herein, in its main aspect, the invention relates to a new tablet for the oral administration of a therapeutically effective amount of trimebutine maleate which can be rapidly or prolonged biologically available, but in all case, which does not cause any persistent bitter taste in the oral cavity that causes an attitude of repulsion on the part of the patient. These tablets have a remarkable strength and physical stability that makes them suitable for the most diverse packaging (blisters, bulk in jars, etc.) under proven storage conditions (temperature, humidity ...) Also an important aspect refers to the remarkable chemical stability of trimebutine maleate presented in this form of tablets, even preserved under stringent conditions, which ensures patients a certain safety and therapeutic advantages. According to another aspect, the invention relates to the process for manufacturing the tablets. Another aspect of the invention relates to a composition suitable for the preparation of tablet cores which is characterized in that the quantitative and qualitative adaptation of its main constituents makes it possible to obtain a rapid or prolonged release of the active principle. In general, the laminar coating of the tablets provides advantages both for their industrial manufacture and for their use by the patient. Thus, in regard to manufacturing, the forms provided with laminar coating are recognized less sensitive to mechanical erosions and therefore, generate less dust and therefore eliminate within the premises the contaminations between medicines; it is also recognized that the laminar coating favors the placement in primary packaging, mainly blister, of the tablets. As regards the use by patients, the glossy or satin texture provided by the smoke mixture of the laminar coating prevents adhesion of the naked tablet to the buccal mucosa and makes swallowing easier. Improvements made by the tablets of the invention are developed in this description below and are shown by assays for the release of the active principle and physical and chemical stability in comparison with commercial specialties In the broadest sense of the invention, the tablets are characterized because their cores comprise in weight of 30 to 60%, and, as excipients, of 15 to 45% of one or more diluting agents, of 2.5 to 25% of one or more binding agents, of 0.5 to 25% of one or more acidifying agents, optionally from 1 to 5% of one or more disaggregating agents and agents of technical utility, that is, from 0.5 to 5% of a fluidifying agent and of 0.25 to 2.5% of a lubricating agent characterized in that said cores are coated with a film representing from 1 to 5% by weight of said tablet, so that the composition of the film comprises one or more water-soluble smoke-forming agents, one or more opacifying agents and, optionally, one or more plasticizing agents. More precisely, the composition of a core comprises: - from 20 to 40%, one or more diluting agents selected from cellulose in microcrystalline form or powder material, mannitol, starch and more particularly, lactose, especially hydrated, which is the Preferred dilution agent, - at a ratio of 2.5 to 25%, one or more binder agents chosen from microcrystalline cellulose, pharmaceutically acceptable grade gelatin, methylcellulose or pregelatinized starch. Preference is given to povidone, pregelatinized maize starch and hydroxypropyl methylcellulose having a viscosity of between 2.5 and 15,000 mPa.s. Particularly, for the nuclei in which a rapid disaggregation is desired, a mixture representing 5 to 10% of the tablet is used and composed of 5 to 10 parts of corn starch and 0.5 to 2 parts of hydroxypropylmethyl cellulose whose viscosity remains between 2.5 and 17.5 mPa.s while for the nuclei for which a prolonged release of the active ingredient is desired, a mixture composed of 5 to 15 parts of hydroxypropylmethyl cellulose is used at the rate of 15 to 20% of the tablet. whose viscosity is between 1,500 and 15,000 mPa.s and from 0.5 to 1 parts of povidone. Particular preference is given to hydroxypropylmethyl cellulose with a viscosity of 5.2 to 7.0 mPa.s for nuclei with rapid disaggregation and hydroxypropylmethylcellulose with a viscosity of 4000 mPa.s for prolonged release nuclei. - The acidifying agent is chosen from the pharmaceutically acceptable organic acids known for their sequestering properties of metals and / or which have a stabilizing effect on the active principle and / or which allow the creation of an acid medium favorable to the release of the active principle of the hydrophilic nuclei directed to a prolonged release. These acids are citric acid and tartaric acid, which are used in the nuclei for which rapid desaggregation is desired at a rate of 0.5 to 2% and in nuclei where a prolonged release of trimebutine maleate is desired. , they are preferably used at a ratio of 10 to 20%, especially with the tartaric acid which is preferred.WAT
- the flow agent is silicon dioxide, anhydrous or hydrated, which is used at a rate of 0.75 to
2.5% - the lubricating agent is chosen from the metal salts of stearic acid to the exclusion of other agents usually proposed for this purpose. The lubricating agent is thus chosen among the calcium or magnesium stearates. The latter is preferred in concentrations of 0.5 to 1.5% and more particularly of 1%. the disaggregation agent, which is optional, is chosen from crospovidone (crosslinked polyvidone), the sodium salt of the crosslinked carboxymethylcellulose, also known as "croscarmellose sodium" and the carboxymethylstarch which is preferred. The optional nature of this agent corresponds to the eventual need to rapidly release the active principle, which is achieved by rapid disaggregation of the nuclei after the passage of the oropharyngeal sphere. For this purpose, for the "immediate release" tablets, the sodium carboxymethyl starch is used in a proportion of 1 to 5%, preferably 2%, in order to obtain the desired disaggregation. As regards the coating material, it is essentially constituted by a r-soluble smoke-like agent chosen from acrylic polymers or cellulosic polymers such as hydroxypropylmethyl cellulose with a viscosity between 2.5 and 17.5 mPa.s, methylcellulose, ethylcellulose, hydroxypropylcellulose; a filler that allows a better adhesion of the film to the core such as lactose or microcrystalline cellulose. The opacifying agents and / or additive dyes are chosen from iron oxides or titanium dioxide. The usable plasticizing agents are selected from among the macrogols with average molecular weight of 3000 to 6000, propylene glycol, glycerin or polyoxyl 40 stearate. For the preparation of the laminar coating of the cores, according to the invention, compounds mixed in solution or in suspension in r or in pharmaceutically acceptable solvents such as ethanol, acetone or their mixtures with r can be used. However, a mixture comprising an aqueous suspension of hydroxypropylmethyl cellulose having a viscosity of between 2.5 and 17.5 mPa.s and titanium dioxide or even a mixture comprising a hydroxypropylmethyl cellulose having a viscosity of 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. Particularly preferable are mixtures in which the hydroxypropylmethyl cellulose has a viscosity of 5.2 to 7.0 mPa.s; these mixtures, which are particularly suitable, are marketed by the company Colorcon under the trademark OPADRY * or by the company Seppic under the trademark SEPIFILM *, allowing to obtain at a ratio of 1.5 to 3% by weight with respect to the weight of the core and in particular to 2% ratio of a film of transient resistance in bucco-pharyngeal medium that allows the tablet to be administered without a bitter taste effect, thus preserving the biological availability of the active principle in the release conditions chosen for it. On the other hand, the laminar coating made by the film under the conditions of the invention perfectly respects the engravings, in hollow or in relief, of the cores, indicative of the active principle and its dosage and that during the course of the coating operation with inappropriate compositions they can be blinded, eroded or erased and in any case they can be illegible. The invention particularly preferably relates to tablets whose centesimal compositions are the following: Rapidly disaggregated tablets A in the form of an immediate release: "FLI" i) Composition for nuclei of 200 & 400 mg trimebutine maleate 50.00%
- lactose monohydrate 36.00%
- corn starch 7.00%
- hydroxypropylmethyl cellulose (6 mPa.s) 1.00% - carboxymethyl sodium starch 2.00%
- Tartaric acid 1.00% - silica gel 2.00%
- magnesium stearate 1.00% ii) coating with 2.00% of the weight of the core of a composition comprising hydroxypropylmethyl cellulose (6 mPa.s), lactose, polyethylene glycol 4000 and titanium dioxide, or alternatively hydroxypropylmethyl cellulose (6 mPa.s), microcrystalline cellulose, polyoxyl 40 stearate and titanium dioxide. B-tablets called prolonged release: "FLP" i) core composition of 747.00 & 508.00 ms - trimebutine maleate 39.37%
- lactose monohydrate 23.6%
- 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% by weight of the core of a composition comprising hydroxypropylmethyl cellulose (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, it consists initially of preparing an appropriate compound and then subjecting it to compression in order to obtain the cores which are then provided with a laminar shell. Thus, carrying out the process for preparing the tablets called "FLI" whose preferred components have been described above for the tablets A consists of: i) preparation of the composition - mixing in a powder mixer or in a fluidized bed apparatus trimebutine maleate, lactose monohydrate, pregelatinized maize starch, hydroxypropylmethyl cellulose and half of the carboxymethyl starch and then granulate the homogeneous mixture with tartaric acid in aqueous solution and calibrate the wet granules. - dry the granules in a fluidized bed or in a ventilated oven at 60 ° C, then calibrate them on a sieve with an opening of 1 to 1.5 mm and then mix them in a mixer of powder material with the second half of the carboxymethylstarch. silica and magnesium stearate. ii) prepare the cores by compression of the granulates on rotary tablet preparation machine with punches of appropriate dimensions to obtain cores of mass equivalent to 200 or 400 mg, dosed respectively in 100 and 200 mg of trimebutine maleate and whose hardness is 50 to 70 N. iii) apply a laminar coating to the turbine cores with the film forming suspension at a temperature between 35 ° and 45 ° C and under such conditions that this laminar layer uniformly coats the cores with an amount of 4 mg for the nuclei of 200 mg and 8 mg for the nuclei of 400 mg. The preparation process of the tablets B called "FLP", which is not very different from that indicated above, consists in: i) preparation of the composition - in a powder mixer or a fluidized bed apparatus, mix the trimebutine maleate, the lactose monohydrate, and tartaric acid and then granulate the homogeneous mixture with an aqueous solution or in ethanol of povidone and calibrate the wet granules, dry in a fluidized bed or in a ventilated oven at a temperature of 45 to 60 ° C granules, calibrate them on sieve with an opening of 1 to 1.5 mm, and then mix them in a powder mixer with hydroxypropylmethyl cellulose, silica gel and magnesium stearate. ii) prepare the cores by compression of the granules on a rotary tablet preparation machine with punches of appropriate dimensions to obtain cores of mass equivalent to 747 or 508 mg, dosed respectively in 300 and 200 mg of trimebutine maleate and whose hardness is from 80 to 200 N. iii) apply laminar coating to the cores in turbine with the laminar coating formation suspension at a temperature comprised between 35 and 45 ° C and under conditions such that this laminar coating uniformly coats the cores at a rate of amount of 15 mg for the cores of 747 mg and 10 mg for the cores of 508 mg. Once prepared, the tablets provided with laminar coating are immediately packaged in blister packs, in polypropylene or high density polyethylene bottles, etc. The invention has been shown in a non-limiting manner by the following examples. Example 1: tablets with a fast-disintegrating laminar coating dosed with 100 ma of trimebutine maleate-form called "FLI" In a projection and turbulence powder mixer are introduced: - 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 hydroxypropylmethyl cellulose (6 mPa.s) The homogeneous mixture of the components is carried out by stirring for 3 minutes, and then, in the same apparatus using the useful adapted to the granulation, the mixture is wetted by a solution of 0.208 kg of tartaric acid in solution in 2.7 1 of water.
The granulates are wet calibrated on a rotary calibrator and then dried on the fluidized bed at 50 ° C until the residual moisture is less than 1%. The granules are then calibrated on a quick screen mesh opening of 1.5 mm and then they are introduced in a powder mixer, container type. It is then added: - 0.208 kg of carboxymethylstarch, - 0.416 kg of silica gel, - 0.208 kg of magnesium stearate. The assembly is mixed for 20 minutes at a slow speed (5 to 10 revolutions / minute) and then subjected to compression in a rotary press equipped with punches with a diameter of 8 mm. The obtained cores have the following characteristics: average mass 200 mg ± 15 mg average hardness 60 N ± 10 N - friability <1% unbundling time in water at 37 ° C: maximum 8 minutes. The cores are provided with turbine laminar coating (for example, in an "ultra coater aeromatic Sz" type apparatus) by spraying an aqueous suspension containing methylhydroxypropyl cellulose (6 mPa.s), hydrated lactose, titanium dioxide and polyethylene glycol 4000. In the type of apparatus indicated above, the operating conditions are as follows: - air inlet temperature: 50 ° C, introduction flow of the laminar coating formation suspension: 30 g / minute, spray pressure: 2 bars, to obtain a temperature of 35 to 45 ° C, a homogenous laminar coating formation of 4 mg per tablet whose average final mass is 204 mg ± 15.3 mg and whose unit composition is as follows: trimebutine maleate 100, 0 mg lactose monohydrate 72.0 mg - pregelatinized corn starch 14.0 mg hydroxypropylmethyl cellulose 2.0 mg sodium carboxymethylstarch 4.0 mg tartaric acid 2.0 mg silica gel 4.0 mg - stearate of magnesium 2.0 mg mixture of laminar forming agents 4.0 mg of which hydroxypropylmethyl cellulose 6 mPa.s 0.93 mg, lactose hydrate 1.4 mg, titanium dioxide 0.87 mg and polyethylene glycol 4000 0, 80 mg. The primary packaging of these tablets is made in thermoformed plates (aluminum-polyvinyl chloride). An identical operating mode is used to prepare the "FLI" tablets dosed with 200 mg of trimebutine maleate. The modification provided consists of equipping the rotary compression press of appropriate punches to obtain cores with an average 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 provided with laminar coating by the mixture of coating film forming agents, at a rate of 8 mg per core in order to obtain finished tablets with an average mass of 408 mg. Example 2: prolonged-release laminar-coated tablets dosed with 300 mg of trimebutine maleate-form called "FLP" In an "Aéromatic" fluidized-bed apparatus, 10,500 kg of trimebutine maleate, 2,100 kg of lactose monohydrate are introduced , 4,200 kg of tartaric acid, after homogenization, 2,000 kg of an aqueous solution are added progressively to 21% (w / v) of povidone and mixing is continued for 16 minutes. The grains obtained are dried at 60 ° C until the residual solvation, determined by thermal balance, is less than 0.6%. The granulate is then calibrated on a rapid screen with a mesh opening of 1.5 mm and then it is introduced by a powder mixer with projection and turbulence. 4,200 kg of lactose spray, 4,200 kg of hydroxypropylmethyl cellulose 400 mPa.s, 262.5 g of silica gel and 262.5 g of magnesium stearate are then introduced. The assembly is then mixed for 2 minutes and then subjected to compression in a rotary press. The obtained cores have the following characteristics: - average mass 747 mg ± 30 mg average hardness 180 N ± 20 N friability < 1% The cores are coated with turbine film as described in Example 1 with an aqueous suspension containing hydroxypropylmethyl cellulose (6 mPa.s), and titanium dioxide to obtain a homogeneous laminar coating of 15 mg per tablet whose average final mass is 762 mg ± 30 mg and whose composition is as follows: - trimebutine maleate 300.0 mg
- lactose monohydrate 180.0 mg
- tartaric acid 120.0 mg
- polyvidone 12.0 mg
- hydroxypropylmethyl cellulose 120.0 mg - silica gel 7.5 mg
- magnesium stearate 7.5 mg - mixture of coating sheet forming agents 15.0 mg in which hydroxypropylmethylcellulose 6 mPa.s 11.5 mg and titanium dioxide 3.5 mg. The tablets are packaged in thermoformed plates or in bottles according to their use and storage conditions. A variant of this operating mode consists in equipping the rotary pressing press with punches adapted to obtain cores whose average mass is 508.0 mg dosed in 200.0 mg of trimebutine maleate. These cores are provided with laminar coating with the mixture of laminar coating forming agents at a rate of 10.0 mg per core to obtain finished tablets whose average mass is 518.0 mg. Assays The tests carried out comprise: - study of the physical and chemical stability of the tablets equipped with laminar coating of rapid or prolonged release of the invention, - comparative study of the tablets equipped with laminar coating with fast release of the invention with commercialized tablets. Except for the evaluation of the aspect, the tests referring to the physical criteria have been carried out according to protocols adapted from the European Pharmacopoeia, which are the tests: - unbundling (Ph. Eur. V.5.1.1), - for dissolution (Ph. Eur. V.5.4.1), - of friability (Ph. Eur. V.5.8.2.-1), - of hardness (Ph. Eur. V.5.8.3.-1). As regards the chemical stability studies of trimebutine maleate, these have been determined by the dosage of 3,4,5-trimethoxybenzoic acid which is representative of the hydrolysis of the active principle. This dosage is made by high pressure liquid chromatography (CLHP - Ph. Eur. V.6.20.4) with a 125 mm column of a Lichrospher 60 RP select B Merck type support and by elution with a pH 3 phosphate buffer. , 6-acetonitrile, spectrophotometric detection at 220 nm.
- stability studies In packaging in the form of thermoformed plates (PVC - aluminum) or in polypropylene bottles, the tablets with "FLI" and "FLP" laminar coating studied have been stored for 6 months in an oven at 40 ° C ± 4 ° C , in anhydrous atmosphere or relative humidity of (RH) of 75% ± 5%. The results of these tests have been indicated in the following tables. 1) Stability of the FLI tablets The studies have been carried out after 6 months of preservation of the tablets at 40 ° C + 4 ° C in an atmosphere with a relative humidity of 75% + 5%. The criteria used for the study are: - the appearance, the time of disaggregation, the hardness, the disintegration and the dissolution test of the active principle with regard to physical stability, - dosing of the ATMB with regard to stability chemistry of the active substance,
2) Stability of FLP tablets Studies have been carried out after 6 months of preservation of the tablets at 40 ° C + 4 ° C in anhydrous medium and in an atmosphere with a relative humidity of 75%
± 5%. The criteria considered for the study are: - the aspect and the dissolution test for physical stability, - the dosage of the ATMB for the chemical stability of the active principle.
These tests, carried out under rigorous preservation conditions, are demonstrative of the excellent stability of the tablets of the invention. As regards the "FLI" tablets: the physical stability is remarkable, especially considering the significant criterion of the objective pursued by the invention which is to avoid the premature disaggregation of the tablet and, as a consequence, the dissolution of the active principle. In effect, a slight increase in the time of disaggregation is observed in these points after 6 months.
(approximately 3 minutes) which corresponds to a slight decrease in the rate of dissolution of trimebutine maleate. - the chemical stability is considered equally satisfactory. The formation of 0.09% ATMB corresponds to the molecular weight ratios with a degradation of 0.09 x 503.5 = 0.21% of trimebutine maleate. 212.2 (ATMB - PM - 212.2; trimebutine maleate - MW = 503.5) With respect to "FLP" tablets: - physical stability is remarkable considering the dissolution criteria that are essential for prolonged release forms, chemical stability is equally good considering that the 0.06% formation of ATMB corresponds to the degradation of 0.14% of trimebutine maleate. - Comparative tests As proof of the remarkable improvements brought about by the laminar coating form according to the invention, comparative tests have been carried out between the tablets obtained in Example 1 and commercialized tablets dosed with 100.0 mg of trimebutine maleate. With regard to the latter, the qualitative information of the excipients of the two specialties is contained in the dictionary of the 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 have been compared with the "D" tablets and / or the "T" tablets with respect to, on the one hand, the release of the active principle and, on the other hand, their cpamic stability after storage at 40 ° C. - 75% hygrometry for 6 months with regard to the hydrolysis of trimebutine maleate determined by the dosage of 3, 4, 5 trimethoxy benzonic acid (ATMB). The results are indicated in the following tables.
Comparative study of dissolution
Comparative study of stability
(*) Relative% of degradation calculated with respect to the MW of the ATMB (212.2) and of the trimebutine maleate (503.5), in abstraction of the ATMB present in To.
These tests are demonstrative of the improvements provided by the tablets with laminar coating according to the invention: - the dissolution study proves the transient efficacy of the laminar coating that allows to release almost all of the active principle between 10 and 20 minutes while for the tablets " D "the totality of the release is obtained only after 60 minutes and for the tablets" T "this release is practically total before 10 minutes. These results show that the "D" tablets to avoid the bitter taste, do not release the active principle more than slowly and excessively delayed, while, contrarily, the "T" tablets release the trimebutine maleate excessively fast, taking as a result the appearance of a persistent bitter taste.
- the chemical stability study shows that globally, the degradation of trimebutine maleate is respectively 4 and 6 times more important in the "D" and "T" tablets than in the tablets of the invention according to example 1. Everything that does not affect , alter, change or modify the essence of the tablet described, will be variable for the purposes of this Patent.