DE3942131A1 - Uncoated tablets for slow, zero order release of trimebutin - for treating gastrointestinal disorders, contg. hydroxypropyl methylcellulose matrix, tartaric acid and diluent - Google Patents

Abstract

Uncoated tablets contain 35-45 wt.% 2-dimethylamino-2-phenylbutyl 3,45-trimethoxybenzoate (; trimebutin) or one of its pharmaceutically acceptable salts, homogeneously dispersed in a porous, hydrophilic matrix of hydroxypropylmethyl-cellulose (HPMC) at 15-20 wt.%. The tablets also include 20-25 wt.% water-soluble and 10-20 wt.% tartaric acid (II). The diluent is pref. lactose or mannitol and the HPMC has viscosity 3000-5000 mPa.s. USE/ADVANTAGE - (I) is known for treating a variety of gastro-enterological disorders, e.g. spasms, coloric disease, oesophagitis, gastritis, reflux, etc.. These compsns. provide, slow, zero-order release of (I) with bioavailablity equal to that of conventional tablets, and are simple to prepare. The tablets are hard and do not adhere to punch.

Description

Trimebutin is a 3,4,5-trimeth oxy-benzoic acid (2-dimethylamino, 2-phenyl-butyl) ester with following structural formula:

It has the property on the organization of the regulation tion mechanisms of the digestive function. in the In 1970, trimebutine became a substance or malein acid salt in the form of the usual galenic preparations the pharmaceutical industry in gastro-enterology for the treatment spasmodic conditions, painful transitional severe and colon diseases are suggested. Thus was the product indicated in cases of esophagitis, gastri tis, gastroduodenitis, dyspepsia, biliary dyskinesia, as well as in cases of reflux in the area of stomach and Esophagus (RGO) as well as the duodenum and stomach.  

In addition, orally administered dosage forms of the Drug has been suggested to be on the galenic Form to enter the drug release rate act and thus the drug release rate and / or to influence the duration of action and / or to fit.

Thus, in European Patent Nos. 76,515 and no. 99 109 microcapsules described in which the Wirk fabric is located inside the preparation and with a Membrane is coated, which Äthylzellulose in Zusam containing the outer shell of the Präpa is formed. The microcapsules thus obtained have good drug passage properties, the ver various galenic administration forms are advantageous and also enable a surprisingly fast free tion of the active substance in the organism.

On the other hand, in European Patent No. 1 69 821 described a dosage form that controlled a and programmed release of the different drugs according to zero order kinetics, the goal is to means with a constant speed, until released the active ingredient present in this preparation has been. In the described general embodiment form contains this dosage form:

• - a central core container made of a insoluble chen, non-gelling polymer matrix, which in at the same time the active substance, an up Additive with negative heat of solution, such as a polyalcohol or citric acid, and fer optionally, contains a buffering agent containing the Dissolution of the active substance in the considered fluid promotes;  
• a first coating of the core, which is the diffusion of the active ingredient dissolved in the fluid outside the system should regulate. This cover is covered by a ho formed by continuous and homogeneous polymer film, at the same time insoluble and for the considered one Fluid is permeable. The regulatory effect is influenced by the film thickness, which in turn ent speaking the desired drug release amount speed based on physico-chemical parameters can be calculated, which of the active ingredient, from Polymer coating and the dimensions of the preparation are dependent on it;
• a second protective coating which is soluble and also consists of a polymer film, his Part of the active ingredient may contain to ensure a fast effect.

This coating technique in particular is for medicinal Active ingredients provided. Without the above-mentioned calculation is tried in Examples 5 and 6, this structure for apply a Trimebutinpräparat, citric acid as Main solvent is used in the central container.

The effectiveness of the preparations obtained is indicated by "in In vitro dissolution tests, the released Trimebutin amount at different times during egg total test duration of about 6 hours becomes.

The finished preparation according to Example 5 sets the trimebutin irregularly free in quantities ranging from simple to Double rich (12 mg between the first and the two ten hours, 23 mg between the fourth and the fifth Hour), whereas the finished preparation according to Example 6 in During the experiment, a trimebutine release rate speed, and that after the first hour  noticeably decreases.

From these results it is clear that no kon trolled or prolonged, even trimebutin-free settlement speed is ensured, in particular no such rate of release with kinetics of approximately zero order.

Because this preparation has three, necessary for its function Containing ingredients, it is difficult to manufacture and requires a consistent costly to manufacture Equipment.

With the present invention is now a pharmaceuti The composition has been provided simply and to produce economically, as the active ingredient Trimebutine or one of its addition salts with a pharmaceutically acceptable acid, namely the trime Butin maleate contains an extended drug-free permitting the active ingredient with a kinetics zeroth order is released and the biocompatible ensured equality of a conventional tablet.

The object of the present invention is a pharmaceutical preparation in the form of a coating-free Ta to provide the active ingredient 3,4,5-trimeth oxy-benzoic acid (2-dimethylamino, 2-phenyl-butyl) ester with the following structural formula or one of its additions salts with a pharmaceutically acceptable acid ent that is easy and economical to produce, the prolonged drug release, especially one such release with zero order kinetics Ensures and the one, with conventional tablets ver has comparable, good biocompatibility.

Starting from a pharmaceutical preparation in the form of egg ner coated tablet, the active ingredient as 3,4,5-tri  methoxy-benzoic acid (2-dimethylamino, 2-phenyl-butyl) ester with the following structural formula or one of its Addi tion salts with a pharmaceutically acceptable acid includes:

the solution according to the invention is characterized ge task indicates that the active ingredient 35 to 45 wt .-% of Präpa rates and in a porous, hydrophilic matrix is dispersed from hydroxypropyl methylcellulose, the 15 to 20% by weight of the preparation, and the preparation further 20 to 25% by weight of water-soluble diluent and 10 to 20 wt .-% tartaric acid.

The in vitro experiments show that according to the invention composite / built-up tablets having a hardness of at least 7.5 Kgf, not at the punch one Tablet manufacturing machine stick, whereas Tablets of the same composition, but without Add tartaric acid to the punch of a tablet machine stay. If the tartaric acid replaced by citric acid which, after all, is classically used for tablets he is so tablets with insufficient hardness he hold. The experiments have also shown that the wine acid causes the introduced into an aqueous fluid Tablet maintains its integrity and does not disintegrate. When tablet disintegration are the with the fluid in Berüh significantly changed in the coming years, resulting in an regulated and non-controllable drug release to Episode has. The in vitro experiments also show astonishing cherweise that the in vitro tested compositions have an unacceptable biocompatibility. Just  those compositions which except the tartaric acid the Lö containing and their constituent ratios the conditions prescribed according to the invention chen, have a good, conventional tablets entspre active bioavailability or biocompatibility on.

As hydroxypropylmethylcellulose (HPMC) ver various, commercially available, namely among the Trademark "Metholose" (Shin Etsu Chemical) and Use "Methocels" (Dow Chemical Co.) be. These HPMC differ among themselves by the degree of etherification (expressed in percentages of Me thoxy group and in percentages hydroxypropoxy and also by their molecular weights. you are usually determined by the nominal viscosity of their aqueous solutions characterized under defined Conditions is determined. According to the invention are inbe especially those Hydroxypropylmethylcellulosen preferably used, whose viscosity is between 3000 and 5000 mPa · s lies.

Diluents may be water-soluble carbohydrates used, for example, sugars such as mannitol and Sucrose, with particular preference to lactose becomes. The diluent may be a dispersant be set, wherein the proportion of the diluent in This case also includes the added amount of dispersant enthällt.

In small amounts can also not water-soluble inert Fillers are used, such as cellulose or calcium phosphate, here preferably in particular Dikalziumphos phat, as well as small amounts of in the tablet production commonly used excipients such as magnesium stearate, silica gel, polyvinylpyrrolidone, etc.  

Preferably, each tablet contains between 275 and 325 g Active ingredient. For an in vitro dissolution test set 200 Tablets 45 to 300 mg containing trimebutine maleate 65%, in particular 50 to 60% of the active ingredient within 8 hours with a kinetics of approximately zero order free, in a period between 30 minutes and 8 Hours. When administered to humans ensure these tablets prolonged drug release between 9 and 15 hours with bioavailability, the comparable to that of the active ingredient in the form is administered by conventional tablets.

Apart from those benefits that the drug forms with prolonged drug release usually too come, the tablet of the invention meets the requirements of certain diseases treated with trimebutine. In particular, advantages at reflux in the range of Stomach and esophagus (RGO) scores, often through chronic painful symptoms that is especially after meals and at night.

Furthermore, an object of the invention is a method for Preparation of a preparation according to the invention. This Process is characterized in that the active ingredient, Hydroxypropylmethylcellulose, the diluent and Tartaric acid are mixed together and the resulting Mixture is compressed into tablets.

The following are the for the determination of the invention According to the composition significant experiments described. In general and unless specified have been to carry out the experiments required steps familiar to a person skilled in the art. These Steps are briefly described in the examples which explain the preparations prepared.

On those made of various compositions  Tablets were following determinations and measurements carried out:

• - The hardness is measured in the "Schleuniger" -Apparat. you must be greater than 7.5 Kgf. For the measurement is with Help a mechanical device on a pressure a tablet is exercised until it breaks. This Pressure is measured and expressed in Kgf; he must be sufficiently large for the produced Ta blot the various conditioning measures can be subjected without being physically too change;
• - The attempts to dissolve the drug are carried out with the aid of a device, as described in the Me method 2 of USP XXI. As Lösungsmit tel 1 l of deionized water is used, which is maintained at 37 ° C and stirred during the experiment at 50 rpm. The dissolving liquid is taken continuously with the aid of a pinch pump and the released active substance is analyzed for 15, 30, 60 minutes and then every hour until 8 hours after the beginning of the test. The determination is made spek trophotometrically at a wavelength of 290 nm, in which the Lambert-Beer law for Trimebu tin solutions with concentrations between 0 and 350 mg per liter applies. From the results, the order of the dissolution kinetics between t = 30 minutes and t = 8 hours is determined, and if this is 0, then the slope coefficient of the line r is calculated for this period. The period of time between t = 0 and t = 30 minutes corresponding to the hydration and gelation phases of the preparation is disregarded in this kinetic evaluation.

During the experiments and regardless of the resolution of the Active ingredients will look and integrity of the gelled Matrix observed. According to the Prizip of the drug must  the matrix remains virtually unchanged after gelation ben; a true decay is significant for a disreputable nete composition, which is to be singled out. Erosions or Appearance changes must be detected and have a great reservation in the quality assessment of examined recipe.

More specifically, the appearance of the liquid and the Pay attention to the tablet during the dissolution test wakes up with a tablet in a liter of solution like described above. At a decay is an irregular comminution of the tablet festge which may be more susceptible to the appearance of finer ones Particles in the liquid is accompanied. At an Ero sion keeps the examined tablet in its entirety but does erode the tablet shape in the During the experiment, which gradually insoluble Be constituents in the liquid occur. In a suitable The tablet preserves its appearance, and the formula Liquid remains transparent during the experiment.

tries Batch A

It should be determined those components that required Lich are the desired prolonged drug-free to achieve. These experiments are with the code A-1 to A-4. Each formulation contains an identi amount of hydroxypropylmethylcellulose with the ge called viscosity of 4000 mPa · s and, also in kon constant amount, manufacturing additives such as polyvinyl pyrrolidone, magnesium stearate and silica gel. The manufacturer includes the following steps:

• - A mixture of trimebutine maleate, lactose, poly vinylpyrrolidone and possibly the acidulant  moistened with an alcoholic solution. thereon towards the mixture is gekornt, the grains obtained dried and the resulting dry grain sorted;
• to the dry grain are hydroxypropylmethylcellulose and then adding silica gel and magnesium stearate adds;
• - The mixture thus prepared is on a round Runner tablet machine pressed with flat Punching equipped with a diameter of 14 mm is.

In the Versu listed in Table 1 below the following effects on a basis composition composition (A-1):

• a supersaturation of the composition with lactose (A-2), reducing the in vitro dissolution of the drug should be favored;
• an addition of citric acid (A-3) or tartaric acid (A-4), which also has this resolution compared to each which would have to be observed in comparison (A-1) been tet.

Table 1

Experiments A-1 to A-4 and Results

These experiments allow:

• - a departure from the composition of the Experiment (A-2), since those with this composition tablets prepared the drug in the dissolution try with a kinetics not equal to the zeroth ord release from a matrix gel, the significantly decomposes in the course of the experiment.
• - the statement that those from the compositions (A-1) to (A-3) produced tablets during the Try about 50% of the active ingredient with the ge Wanted to release 0th order kinetics but these compounds are a bad compress have availability. So causes the granules of Composition (A-1) adhering to the punches, resulting in frequent interruptions of the work process forces. The granules of the composition (A-3) result in turn tablets of insufficient hardness, regardless of the setting options of used machine.
• - the selection of the composition (A-4) from this Ver As a preferred composition, as they Satisfactory ver with each test step ver holds and from it a matrix can be made, which behaves in the attempt to dissolve correctly: she puts about 50% of the active ingredient after 8 hours a zero-order kinetics free.

So, unexpectedly, this last one differs Tartaric acid composition positive from the their. Because in contrast to the discussed state of Technique, according to which the acids, thus also tartaric acid expressly have the property, the release of those To favor active substances, which in a milieu with nahä hert netralem pH are slightly soluble, so confirm  the in vitro experiments that the tartaric acid in this case not the expected property, but that one Tartaric acid addition rather the production of a pressable Composition for tablets allows adequate Hardness and also good cohesiveness of the matrix gel in the Have dissolution attempt. This role of tartaric acid in This composition is surprising.

Batch B

The compositions of Experiments (B-1) to (B-4) are derived from the composition (A-4) consisting of the above outgoing experiments of the test series A as preferred had emerged. The changes concern:

• quantitatively the hydroxypropylmethylcellulose to the Extent of their effect on the prolonged action substance release, which in the dissolution Ver has been observed;
• - quality of the solvent, by Adding dicalcium phosphate that is insoluble.

Further, the composition identical to (A-4) enables (B-2) a check of those in the previous experiments established characteristics.

The procedure corresponds to that of the test series A. The respective compositions and test results  (B-1) to (B-4) are shown in Table 2 below focus:  

Table 2

Try B-1 through B-4 and see results

These results show that the modified parameters neither on the pressing process nor on the properties of the tablets or matrix after gel formation to have.

A quantitative change of hydroxypropylmethylcellu Loose content causes a change in the Auflösungsge speed, which is greater in 8 hours, the lower the amount of hydroxypropylmethylcellulose in the co composition is.

From the experiments and results of in vitro experiments The test series A and B thus follows:

• - The Hydroxypropylmethylcellulose amount is relevant for influencing drug release out of the matrix; and
• - the tartaric acid is unexpected - and for this together composition is also extraordinarily necessary, to be compressed under suitable conditions make tongues, from which then turn make a matrix that follows the gel formation behaves stably.

Thus, the compositions of Experiments B-1 to meet B-4 made the requirements both in terms of their Production as well as with respect to the experiments with the tablets made therefrom. Tablets of trials B-1, B-2, B-4 and A-1 were in a pharmacokinetic Used in humans and their effect with the Compared the effects of a standard tablet, the trade is usually available and per unit 100 mg of active ingredient ent holds.

This study is intended for the determination of pharmacokinetic Parameters after ingestion by volunteers of either one tablet containing 300 mg of the different ones or three standard tablets in  the dose of 100 mg, in the cross and Randversver drive.

Subjects were screened for this trial after administration The tablets are fixed on an empty stomach ten times and over a total period of 48 hours taken from the blood samples. After its separation became the Plasma the blood sample until analysis at -20 ° C aufbe preserves. The analysis is not the quick resor brewed and immediately reacted trimebutine, son rather, the representative immediate metaboli N-monodesmethyltrimebutin.

The method of analysis used is to sample to extract in a suitable manner and on the Ex obtained extracts the metabolite content with the help of high performance To determine liquid chromatography (HPLC). worked is filled with a silica gel column for the reverse phase and egg ner eluate mixture of methanol and 0.05 M acetate buffer. The separated phases are determined by absorption spectrophotometry analyzed at 265 nm in terms of their type and quantity.

The pharmacokinetic parameters are determined with the help of PHARM program. (R. Gomeni: An interactive gra phic program for individual and population pharmacokinetic parameter estimations. In Medinfo 83-Ed. by J.H. van Bemmel - Elsevier - Amsterdam; 1983 p. 1022-1025). The Curves of the plasma levels of the metabolite were after a One- or two-chamber model with absorption analyzes where in the model depending on the one included in the program Statistics method was selected.

It was determined:

• - t ½ form. (h), the half-life of metabolite formation, which in turn is a function of the half-life of precursor absorption: trimebutine;
• - C max. (ng / ml), the maximum, at T max. (h) reached plasma concentration;
• - t ½ elim, the half-life of the metabolite excretion;
• - AUC ° → ∞ (ng · h / ml), the area under the curve of the analyzed plasma metabolite values as a function of time; This area is calculated according to the trapezoid rule with an extrapolation of the time from 0 to infinity according to the following formula: AUC ° → ∞ = AUC ° → t + Ct / β , where Ct is the last concentration measured in plasma at the time t and β is the Slope in the course of the excretion phase is. This value actually corresponds to the relative bioavailability of the active substance in the galenic form in question.
• - F. rel., The relative bioavailability of the drug from the controlled release formulation (FLC) compared to the relative bioavailability from the standard tablet adopted as a benchmark. This coefficient is calculated using the formula below:
• - MRI, the mean residence time of the metabolite in the Or organism. On the one hand, these parameters are considered the duration of release of the drug from the Ta Blake out and on the other hand, the drug-Resorp tion and excretion. The results of this sub Chung are summarized in Table 3.

Table 3

Results of pharmacokinetic examinations (preparations with 300 mg active substance)

These results confirm:

• The tablets in compositions B-1, B-2 and A-1 have an average residence time of analyzed Metabolites of about 12 hours, what the ge desired value, in what this time at the composition B-4 is considerably shorter.
• - The areas under the extrapolier to infinity th curve (AUC ° → ∞) of the tablet in the together B-2 and B-4 are the same size as those of the standard tablet.

These in essential parameters unexpected findings lead to the preference of the composition B-2, the both because of their duration of action and because of the suitable relative bioavailability of the invention underlying task solves both the prak requirements of the pharmaceutical industry crowded.

This selection is confirmed by a similar study, which is summarized in Table 4. Here was the us kung of a tablet of composition C-2 with 200 mg Trimebutine maleate with the effect of 2 standard tablets compared with 100 mg of active ingredient per tablet.  

Table 4

Results of pharmacokinetic examinations (preparation with 200 mg active substance)

For explanation, be in the following examples be preferred compositions of Präpa invention rate, their production, and their formation into tablets specified. In Examples 1 to 3, the tablet is done production by "wet granulation", in Example 4 by direct compression. It will be the characteristics of the tablet with prolonged drug release as well as the results from the dissolution attempts carried out ben.

Example 1 (the preferred composition B-2)

In a drum mixer are filled:

• - 1500.0 g of trimebutine maleate
  - 900.0 g of lactose
  - 600,0 g of tartaric acid,

While stirring, to the powder mixture 200.0 ml of a Add 30 vol.% Polyvinylpyrrolidone solution in ethanol mixed and then mixed for 5 minutes.

The granules produced are prepared by means of an "Aeroma tic "-Apparatur in a fluidized bed at 50 ° C dried until the with the help of a thermobalance determined residual moisture of the Granules is 0.6%. The granules will then be using an oscillating, with a sieve with 1 mm mesh size sorted granulator and sorted into a Double cone mixer filled. Then 600.0 g of hydro xypropylmethylcellulose 4000 mPa.s added, 5 minutes mixed, then 37.5 g of silica gel and 37.5 mg of stearate added and mixed again for 10 minutes.

The powder produced is then on a rotary Ma with flat, beveled punches with one Diameter of 14 mm pressed. This process is ongoing without special occurrences, in particular, neither occurs Gluing still seizing up.

Characteristics of the tablet - Average weight: | 749.8 mg Setpoint: 747.0 mg - hardness: 9.2 Kgf

Dissolution test (USP XXI method # 2; 1 liter of deionized water, v = 50 rpm, t = 37 ° C) - dissolved active substance after 8 hours: | 55.0% - apparent dissolution kinetics, @ t 30 min / 8h: zeroth order r = 0.990 - appearance of the matrix after 8 h: coherent and unchanged

analysis - Trimebutine maleate per target weight of the tablet: 294.1 mg Setpoint: 300.0 mg

Example 2 (the preferred composition C-2)

According to the method of Example 1 under Ver use of:

- 2600.0 g of trimebutine maleate
- 1560.0 g of lactose
- 1040.0 g of tartaric acid
- 104.0 g of polyvinylpyrrolidone 25
1170.0 g of hydroxypropylmethylcellulose 4000 mPa.s.
- 65.0 g of silica gel
- 65.0 g magnesium stearate

will get a mix on an alternative Machine with beveled punches with a diameter from 12 mm to tablets with a target weight of 508.0 mg is pressed.  

Each tablet contains:

The pressing of the powder takes place without special Vorkomm nisse.

Characteristics of the tablet - Average weight: | 506.1 mg Setpoint: 508.0 mg - hardness: 9.1 Kgf

Dissolution test (USP XXI method # 2; 1 liter of deionized water, v = 50 rpm, t = 37 ° C) - dissolved drug after 8 hours: | 51.9% - apparent dissolution kinetics, @ t 30 min / 8 h: zeroth order r = 0.9968 - appearance of the matrix after 8 h: Coherent and unchanged

analysis - Trimebutine maleate per target weight of the tablet: 193.7 mg Setpoint: 200.0 mg

Example 3 (Composition B-3)

Intensive mixing for 10 minutes:

- 500.0 g of trimebutine maleate
- 270.0 g lactose
30.0 g of dicalcium phosphate
200.0 g of hydroxypropylmethylcellulose 4000 mPa.s.

The powder is in a planetary mixer in the course from about 5 min. by adding 420.0 ml in portions (357 g) 10% polyvinylpyrrolidone 25 solution in ethyl water (80%) moistened.

The mixture is dried in a drying oven at 40 ° C., until the residual moisture measured with the aid of a thermobalance 2%. The mixture is then mixed with the help of an oscillating, equipped with a sieve with 1 mm mesh size sorted granulator continuously.

750 g of the resulting granules are ge in a mixer give and add one after the other:

- 150.0 g of tartaric acid
- 9.0 g magnesium stearate
- 27.0 g talcum
- 1.8 g of silica gel.

It is mixed for 5 minutes and then get the ne mix on an alternative machine with flat Stamped with a diameter of 12 mm. The Pressing takes place without any special occurrences.

Characteristics of the tablet - Average weight: | 769.0 mg Setpoint: 777.1 mg - hardness: 8,0 Kgf

Dissolution test (USP XXI method # 2; 1 liter of deionized water, v = 50 rpm, t = 37 ° C) - Dissolved drug after 8 hours: | 50.1% - apparent dissolution kinetics, @ t 30 min / 8 h: zeroth order r = 0.9997 - appearance of the matrix after 8 h: coherent and unchanged

analysis - Trimebutine maleate per target weight of the tablet: 289.9 mg Setpoint: 300.0 mg

example 4

In a free-fall mixer are filled:

150.0 g of trimebutine maleate
- 30.0 g lactose
- 50.0 g of tartaric acid
120.0 g of hydroxypropylmethylcellulose 4000 mPa.s.
- 3.5 g magnesium stearate
- 0.35 g of silicon.

The mixture is 20 min. long with a turn speed of 42 rpm and then on an old native machine with punches with a diameter of 12 mm pressed. Here the machine is set up that tablets with a target weight of 707.7 mg and be obtained with 300.0 mg of active ingredient per unit.

Characteristics of the tablet - Average weight: | 705.0 mg Setpoint: 707.7 mg - hardness: 8,0 Kgf

Dissolution test (USP XXI method # 2; 1 liter of deionized water, v = 50 rpm, t = 37 ° C) - dissolved active substance after 8 hours: | 45.5% - apparent dissolution kinetics, @ t 30 min / 8 h: zeroth order r = 0.9973 - appearance of the matrix after 8 h: coherent and very easily eroded

analysis - Trimebutine maleate per target weight of the tablet: 302.1 mg Setpoint: 300.0 mg

Claims (7)

1. Pharmaceutical preparation in the form of coating-free tablets, which as active ingredient 3,4,5-trimethoxy-ben zoesäure- (2-dimethylamino, 2-phenyl-butyl) ester having the following structural formula or one of its Addi tion salts with a pharmaceutically acceptable acid contain: characterized in that the active ingredient constitutes 35 to 45% by weight of the preparation and is homogeneously dispersed in a porous, hydrophilic matrix of hydroxypropylmethylcellulose constituting 15 to 20% by weight of the preparation; and the prepro advice further 20 to 25 wt .-% of water-soluble diluent and 10 to 20 wt .-% tartaric acid. 2. Preparation according to claim 1, characterized in that the water-soluble diluent lactose or Mannitol is. 3. A preparation according to claim 1 or 2, characterized in that the hydroxypropylmethylcellulose has a viscosity of 3000 to 5000 mPa · s. 4. Preparation according to one of the preceding claims, characterized in that the Active ingredient is a maleic acid addition salt. 5. Preparation according to one of the preceding claims, characterized in that each Tablet contains 275 to 325 mg of active ingredient. 6. A process for the preparation of a preparation according to a the aforementioned claims, characterized in that the active ingredient, hydroxypropylmethylcellulose, the Ver diluent and tartaric acid mixed together and the resulting mixture into tablets ver is pressed. 7. The method according to claim 6, characterized in that a mixture of active ingredient, diluent and tartaric acid is granulated in a wet state and wet granules are produced;
these wet granules are dried to obtain dry grains;
these dry grains are mixed with hydroxypropylmethylcellulose to obtain a hydroxypropylmethylcellulose-containing mixture; and
this hydroxypropylmethylcellulose-containing mixture is compressed into tablets.