DE3942131C2 - Pharmaceutical preparation containing trimebutin with prolonged release of active ingredient and process for its preparation - Google Patents

Description

The invention relates to a pharmaceutical trimebutin hal term preparation according to the preamble of claim 1. Such a preparation is characterized by an extended Drug release from. The invention further relates to a process for the preparation of this preparation.

"Trimebutin" is a 3,4,5-trimethoxy benzoic acid (2-dimethylamino, 2-phenyl-butyl) ester with the following structural formula

Trimebutin regulates the organization of ver duration function. In 1970 trimebutin was used as a substance or as a maleic acid salt in the form of the usual galenic Preparations of the pharmaceutical industry in gastro-enterology for the treatment of spasmodic conditions, painful over gait and colonic disease suggested. Consequently the preparation was indicated in cases of esophagitis, Gastritis, gastroduodenitis, dyspepsia, biliary dyski nesia, as well as in cases of reflux in the stomach area and esophagus (RGO) and duodenum and stomach.

Orally administrable trimebutin preparations were also available been beaten up about the galenic design affect the rate of drug release and thus the drug release rate and / or influence and / or adjust the duration of action.

Document EP 00 76 515 A1 discloses trimebutine maleate hal term microcapsules, which release the active ingredient quickly. These microcapsules consist of an active ingredient holding core and from an envelope. The quick one This ensures that the active ingredient is released obtained that the core at 80 ° C in cyclohexane with Ethylcel lulose and with a water-soluble compound such as hydroxy propylmethyl cellulose has been coated.

The document US 44 86 471 A describes microcapsules that contain a pharmaceutically active mixture and their Coating consisting essentially of ethyl cellulose and an in Water-insoluble, but acid-soluble polymer stands. Will the teaching of this publication on the manufacturer trimebutin maleate-containing microcapsules so first be a granulate containing the active ingredient  provided, which then at 70 ° C in cyclohexane Ethyl cellulose and coated with a polymer or copolymer which, among other things, can be a cellulose derivative.

The document EP 01 69 821 A2 describes pharmaceutical preparations which are intended to ensure a controlled and programmed release of the various active substances according to zero order kinetics, that is to say at a constant rate, until the active substance present in these preparations has been released. In the general embodiment described, this dosage form contains:

• - a central core from an insoluble, not gelling polymer matrix, in the pores next to it other the active ingredient, a dissolution additive with nega tive solution heat, such as a polyalcohol or also citric acid, and also optionally Buffer means are present, which the dissolution of the Promotes active ingredient in the fluid under consideration;  
• - A first coating of the core, which is to regulate the diffusion of the active substance dissolved in the fluid outside the system. This coating is formed by a homogeneous and uninterrupted polymer film which is at the same time insoluble and permeable to the fluid under consideration. The regulating effect can be influenced by the film thickness, which in turn can be calculated according to the desired drug release rate using physico-chemical parameters which depend on the drug, the polymer coating and the dimensions of the preparation;
  a second protective coating, which is soluble and also consists of a polymer film, which in turn can contain part of the active ingredient in order to ensure a quick effect.

This coating technique is especially for drug Active ingredients provided. Without the calculation mentioned above Examples 5 and 6 attempt this structure for to use a trimebutin preparation, citric acid as Main solvent is used in the central container.

The effectiveness of the preparations obtained is determined by "in vitro "dissolution tests, the released Trimebutin amount at various times during egg ner total duration of approximately 6 hours determined becomes.

The finished preparation according to Example 5 sets the trimebutin irregularly free in quantities ranging from simple to Double ranges (12 mg between the first and the two tenth hour, 23 mg between the fourth and fifth Hour), whereas the finished product according to Example 6 in Trimebutine release rate over the course of the experiment shows speed that quickly and after the first hour  noticeably decreases.

These results clearly show that no con trolled or extended, even trimebutin-free Settling speed is guaranteed, in particular no such release rate with kinetics of approximately zero order.

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

With the present invention is now a pharmaceutical cal composition has been provided that is simple and is economical to manufacture, as an active ingredient Trimebutin or one of its addition salts with a pharmaceutically acceptable acid, especially the trime contains butyne maleate which is an extended active ingredient-free Settlement allows, the active ingredient with a kinetics zero order is released and the biocompatible guaranteed like a conventional tablet.

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

Starting from a pharmaceutical preparation in the form of a coating-free tablet, the active ingredient 3,4,5-tri-methoxy-benzoic acid (2-dimethylamino, 2-phenyl-butyl) ester with the following structural formula or one of its addition salts with a pharmaceutical compatible acid contains:

is the inventive solution to this problem ge indicates that the active ingredient 35 to 45 wt .-% of the prep rates and in a porous, hydrophilic matrix dispersed from hydroxypropylmethylcellulose, the 15th makes up to 20 wt .-% of the preparation, and the preparation further 20 to 25% by weight of water-soluble diluent from the group Contains lactose or mannitol and 10 to 20 wt .-% tartaric acid.

The in vitro experiments show that according to the invention composite tablets with a hardness of have at least 7.5 kg, not on the punch of one Tablet-making machine stick, whereas Tablets with the same composition, but without Stick tartaric acid on the punch of a tablet machine stay. Unless the tartaric acid is replaced by citric acid which are at least traditionally used for tablets det, tablets with insufficient hardness hold. The experiments have also shown that the wine acid causes it to be introduced into an aqueous fluid Tablet maintains its integrity and does not disintegrate. In the case of tablet disintegration, the fluid with the fluid in coming areas changed significantly, which is an regulated and uncontrollable drug release Consequence. The in vitro tests also show astonishingly that the compositions tested in vitro have an unacceptable biocompatibility. Just  those compositions which, apart from tartaric acid, contain the Lö contain agents, and their constituent ratios correspond to the conditions prescribed by the invention Chen, have a good, conventional tablets Active bioavailability or biocompatibility on.

As hydroxypropylmethyl cellulose (HPMC) ver various, commercially available, especially under the Trademark names "Metholose" (Shin Etsu Chemical) and "Methocels" (Dow Chemical Co.) varieties offered be det. These HPMC differ from one another by the degree of etherification (which is in percentages of me thoxy group and in percentages hydroxypropoxy ) and also by their molecular weights. she are usually determined by the nominal viscosity of their characterized aqueous solutions, which are defined under Conditions is determined. According to the invention especially such hydroxypropylmethyl celluloses are preferred used, whose viscosity is between 3000 and 5000 mPa.s lies.

Water-soluble carbohydrates can be used as diluents can be used, for example sugars such as mannitol and Sucrose, especially lactose preferably used becomes. A dispersant can be added to the diluent are set, the proportion of the diluent in in this case also the amount of dispersant added contains.

In small quantities, water-insoluble ones can also be used Fillers are used, such as cellulose or calcium phosphates, here preferably in particular dikalziumphos phat, as well as small amounts of tablets commonly used drug carriers such as magnesium stearate, silica gel, polyvinyl pyrrolidone, etc.  

Each tablet preferably contains between 275 and 325 g Active ingredient. In an in vitro dissolution attempt, 200 tablets containing up to 300 mg trimebutine maleate 45 to 65%, in particular 50 to 60% of the active ingredient within 8 hours with approximately zero order kinetics free, between 30 minutes and 8 Hours. Ensure when administered to humans these tablets have an extended drug release between 9 and 15 hours with a bioavailability that is comparable to that of the active substance in the form is administered by conventional tablets.

Aside from those benefits that the drug farms with prolonged release of active ingredient usually increases come, the tablet of the invention meets the requirement certain diseases treated with trimebutin. In particular, advantages in the case of reflux are in the range of Stomach and esophagus (RGO), which is often achieved by chronic painful symptoms that is characterized occur especially after meals and at night.

The invention further relates to a method for Production of a preparation according to the invention. This The method is characterized in that the active ingredient Hydroxypropylmethylcellulose, the diluent and Tartaric acid are mixed together and the obtained Mixture is compressed into tablets.

Below are those for the determination of the Invention according to the composition of significant experiments described. In general and unless otherwise specified have been used to carry out the tests necessary steps familiar to a specialist. This Steps are briefly described in the examples, which explain the preparations made.

The following determinations and measurements were carried out on the tablets produced from different compositions:

• - The hardness is measured in the "Schleuniger" apparatus. she must be greater than 7.5 kg. For the measurement with Using a mechanical device to apply pressure exerted a tablet until it breaks. This Pressure is measured and expressed in Kgf; he must be sufficiently large so that the Ta the various conditioning measures can be subjected to without being physically change;
• - The attempts to dissolve the active ingredient are included With the help of a device as it is in the Me Method 2 of USP XXI. As a solution tel 1 l demineralized water is used, which at Kept 37 ° C and during the test at 50 rpm is stirred. The solution liquid is kon with a squeeze pump taken, and the released active ingredient becomes 15, 30, 60 minutes and then every hour up to 8 hours after Ver Start of search analyzed. The determination is made spec trophotometric at a wavelength of 290 nm, where the Lambert-Beer law for Trimebu tin solutions with concentrations between 0 and 350 mg per liter applies. The ord resolution kinetics between t = 30 minutes and t = 8 hours, and if these are 0 then the slope coefficient of the straight line becomes r calculated for this period. The hydration and corresponding to the gel formation phase of the preparation Period between t = 0 and t = 30 minutes remains this kinetic evaluation is not taken into account.

During the trials and regardless of the resolution of the Active ingredient will look and integrity of the gelled Matrix observed. According to the principle of the preparation must  the matrix remains practically unchanged after gel formation ben; a real decay is significant for an inappropriate nete composition to be discarded. Erosions or Changes in appearance must be recorded and have a big caveat in the quality assessment of the examined formulation.

More specifically, the appearance of the liquid and the Tablet carefully during dissolution attempt guards who like with a tablet in a liter of solution is performed as described above. In the event of decay an irregular crushing of the tablet represents that may be more insoluble from the appearance of fine Particles in the liquid is accompanied. With an Ero sion retains the tablet examined as a whole original form, but the tablet form erodes in Course of the experiment, which gradually insoluble loading Components appear in the liquid. At one suitable The tablet preserves its appearance and the recipe Liquid remains transparent during the experiment.

TRIES Test series A

Those components are to be determined which are necessary to achieve the desired prolonged release of active ingredient. These tests are identified by the code A-1 to A-4. Each formulation contains an identical amount of hydroxypropylmethyl cellulose with the viscosity mentioned of 4000 mPa.s and, also in a constant amount, manufacturing additives such as polyvinyl pyrrolidane, magnesium stearate and silica gel. The manufacturing process comprises the following steps:

• - A mixture of trimebutin maleate, lactose, poly vinylpyrrolidone and possibly the acid agent  moistened with an alcoholic solution. On it The mixture is then granulated, the grains obtained dried and the resulting dry grain sorted;
• - Hydroxypropylmethylcellulo become the dry grain se and then add silica gel and magnesium stearate adds;
• - The mixture produced in this way is rounded Runner tablet machine pressed with flat Die cutters with a diameter of 14 mm is.

In the Versu the following effects on a base group composition (A-1) examined.

• - over-saturation of the composition with lactose (A-2), causing the in vitro dissolution of the drug should be favored;
• - An addition of citric acid (A-3) or tartaric acid (A-4), which should also favor this resolution compared to each ner that has been observed in experiment (A-1).

  Trials A-1 through A-4 and results

  Trials A-1 through A-4 and results

These attempts enable:

• - from the outset, the composition of the Trial (A-2), since those with this composition tablets produced the active ingredient in the dissolution try a kinetics not equal to the zero order release, namely from a matrix gel that decomposes significantly in the course of the experiment.
• - The finding that the compositions (A-1) to (A-3) tablets produced during the Trial about 50% of the active ingredient with the ge wanted to release zero order kinetics that these compositions, however, are a poor compression have availability. This is how the granules cause the Composition (A-1) a sticking on the punches, resulting in frequent interruptions in the work process forces. The granules of composition (A-3) yield in turn tablets with insufficient hardness, regardless of the setting options of the used machine.
• - the selection of the composition (A-4) from this ver search series as the preferred composition since they behaves satisfactorily in every test step holds and a matrix can be made from it, that behaves correctly in the attempt to dissolve them adds about 50% of the active ingredient after 8 hours zero order kinetics.

So this last one is unexpectedly different, Composition containing tartaric acid positive from the beginning their. Because in contrast to the discussed status of Technology, according to which the acids, thus also tartaric acid, come from expressly have the property of releasing those To favor active ingredients in a milieu with pleasant neutral pH are not very soluble, so confirm  the in vitro experiments that tartaric acid in this case not the expected property, but that a Tartaric acid addition rather the manufacture of a pressable Composition for tablets allows the sufficient Hardness and also good cohesiveness of the matrix gel in the Have attempted dissolution. This role of tartaric acid in this composition is surprising.

Test series B

The compositions of the experiments (B-1) to (B-4) are derived from the composition (A-4), which had emerged as preferred from the experiments of the A series of experiments which had started before. The changes concern:

• - quantitatively the hydroxypropylmethyl cellulose, in order to Extent of their impact on prolonged action to determine substance release, which in the dissolution ver has also been observed;
• - qualitatively the type of solvent, namely by Adding dicalcium asphate, which is insoluble.

Furthermore, the composition identical to (A-4) enables (B-2) a review of the previous experiments identified properties.

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

Trials B-1 through B-4 and results

Trials B-1 through B-4 and results

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

A quantitative change in hydroxypropylmethylcellu loose content causes a change in the resolution speed, the greater in 8 hours, the lower the total amount of hydroxypropylmethylcellulose in the total setting is.

From the tests and results of the in vitro tests of test series A and 3 it follows:

• - The amount of hydroxypropylmethylcellulose is decisive for influencing drug release the matrix out; and
• - The tartaric acid is unexpected - and for this together measures also exceptionally necessary, to assemble pressable under suitable conditions to produce tongues, which in turn then a matrix can be produced, which is based on the gel education behaves stably.

Thus the compositions of experiments B-1 bis B-4 the requirements both with regard to their Production as well as with regard to the experiments with the tablets made therefrom. The tablets of trials B-1, B-2, B-4 and A-1 have been used in a pharmacokinetic Study used in humans and their effects with the Effects of a standard tablet compared to the commercial is commonly available and ent per unit 100 mg of active ingredient holds.

This study serves to determine the pharmacokinetic Parameters after ingestion by volunteers of either one tablet with 300 mg of the different manufactured forms or of three standard tablets in  the dose of 100 mg, in cross and random ver drive.

The subjects were given this experiment after Prescription of tablets on an empty stomach too fixed times and over a total period of 48 hours taken from the blood samples. After his separation that was Plasma of blood samples up to analysis at -20 ° C maintains. The analysis is not the quick resor determined and immediately implemented trimebutin, son rather the immediate Metaboli representative of it ten, the N-monodesmethyltrimebutin.

The analysis method used is the samples extracted in a suitable manner and on the Ex tracts the metabolite content with the help of the high-performance Determine liquid chromatography (HPLC). Worked comes with a silica gel column for the reverse phase and egg An eluate mixture of methanol and 0.05M acetate buffer. The separated phases are determined by means of absorption spectrophotometry at 265 nm analyzed for their type and amount.

The pharmacokinetic parameters are determined using the PHARM programs determined. (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 values of the metabolite were made after a One or two chamber model with absorption analyzes where for the model depending on the one included in the program Statistics method was selected.

The following were determined:

• - t ½ form. (h), the half-life of the metabolite bil which in turn function as the half life of the Precursor absorption is: trimebutin;  
• - C max (ng / ml), the maximum reached at T max (h) Plasma concentration;
• - t ½ elim, the half-life of the metabolite excretion; - AUC _° → ∞ (ng.h / ml), the area under the curve of the metabolite values analyzed in plasma as a function of time; this area is calculated according to the trapezoid rule with an extrapolation of the time from 0 to infinity using the following formula:
  AUC _° → ∞ = AUC _° → t + Ct / β,
  where Ct is the last concentration in plasma measured at time t and β is the slope during the elimination phase. This value actually corresponds to the relative bioavailability of the active ingredient in the pharmaceutical form concerned.
• - F. rel, the relative bioavailability of the active ingredient from the controlled release (FLC) preparation form in comparison to the relative bioavailability from the standard tablet assumed as the reference value. This coefficient is calculated using the following formula:
  
• - MRI, the mean residence time of the metabolite in the organism. This parameter takes into account on the one hand the duration of the release of the active ingredient from the tablet and on the other hand the active ingredient absorption and excretion. The results of this investigation are summarized in Table 3.

  Results of the pharmacokinetic studies (preparations with 300 mg active ingredient)

  Results of the pharmacokinetic studies (preparations with 300 mg active ingredient)

These results confirm:

• - The tablets in compositions B-1, B-2 and A-1 have an average residence time of the analyzed Metabolites of about 12 hours, which is the ge corresponds to the desired value, whereas this time at composition B-4 is significantly shorter.
• - The areas under the infinitely extrapolated curve (AUC _° → ∞) of the tablet in the compositions B-2 and B-4 have the same size as those of the standard tablet.

This unexpected finding in essential parameters gene led to preference for composition B-2, which both because of their duration of action and because of the suitable relative bioavailability of the invention underlying task solves, as well as the prak requirements of the pharmaceutical industry fills.

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

Results of the pharmacokinetic studies (Preparation with 200 mg active ingredient)

Results of the pharmacokinetic studies (Preparation with 200 mg active ingredient)

For explanation, be in the following examples preferred compositions of the preparation according to the invention te, their manufacture and their formation into tablets specified. In examples 1 to 3, the tablet is used production by "wet granulation", in Example 4 by direct pressing. It shows the characteristics of the tablet te with prolonged release of active ingredient and the results nisse from the attempted dissolution ben.

Example 1: (the preferred composition B-2)

The following are filled into a drum mixer:

• - 1500.0 g trimebutin maleate
• - 900.0 g lactose
• - 600.0 g tartaric acid

With stirring, 200.0 ml of a Add 30% by volume polyvinylpyrrolidone solution in ethanol added and then mixed for 5 minutes.

The granules produced are produced using an "Aeroma tic "apparatus dried in a fluid bed at 50 ° C until the residual moisture of the Granules is 0.6%. The granulate is then used with the help an oscillating one with a sieve with a 1 mm mesh size equipped pelletizer and sorted into one Double cone mixer filled. Then 600.0 g of Hydro xypropylmethylcellulose 4000 mPa.s added, 5 minutes mixed, then 37.5 g silica gel and 37.5 magnesium stearate added and mixed again for 10 minutes.

The powder produced is then pressed on a rotary machine with flat, beveled punches with a diameter of 14 mm. This process takes place without special occurrences, in particular there is neither sticking nor seizing.

• - Features of the tablet:
  • - Average weight: 749.8 mg
    Standard value: 747.0 mg
  • - Hardness: 9.2 kg
• - Dissolution test (USP XXI method No. 2; 1 l deionized water, v = 50 rpm, t = 37 ° C):
  • - dissolved active ingredient after 8 hours: 55.0%
  • - apparent kinetics of dissolution
    t 30 min / 8 h: zero order r = 0.990
  • - The appearance of the matrix after 8 h: coherent and unchanged
• - Analysis:
  • Trimebutin maleate
    per target weight of the tablet: 294.1 mg
    Standard value: 300.0 mg

Example 2: (the preferred composition C-2)

According to the procedure of Example 1 and using:

• - 2600.0 g trimebutin maleate
• - 1560.0 g lactose
• - 1040.0 g tartaric acid
• - 104.0 g of polyvinylpyrrolidone 25
• - 1170.0 g hydroxypropylmethyl cellulose 4000 mPa.s
• - 65.0 g silica gel
• - 65.0 g magnesium stearate

will get a mix based 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 powder is pressed without any special occurrence.

• - Features of the tablet:
  • - Average weight: 506.1 mg
    Standard value: 508.0 mg
  • - Hardness: 9.1 kg
• - Dissolution test (USP XXI method No. 2; 1 l deionized water, v = 50 rpm, t = 37 ° C):
  • - dissolved active ingredient after 8 hours: 51.9%
  • - apparent kinetics of dissolution
    t 30 min / 8 h: zero order r = 0.9968
  • - The appearance of the matrix after 8 h: coherent and unchanged
• - Analysis:
  • Trimebutin maleate
    per target weight of the tablet: 193.7 mg
    Standard value: 200.0 mg

Example 3: (Composition B-3)

Mix intensively for 10 minutes:

• - 500.0 g trimebutin maleate
• - 270.0 g lactose
• - 30.0 g of dicalcium phosphate
• - 200.0 g hydroxypropylmethyl cellulose 4000 mPa.s.

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

The mixture is dried in a drying cabinet at 40 ° C. until the residual moisture measured using a thermal balance Is 2%. The mixture is then made using an oszil luring, equipped with a sieve with 1 mm mesh size sorted granulating device.

750 g of the granules obtained are placed in a mixer and added in succession:

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

Mix for 5 minutes and then get the ne mixture on an alternative machine with flat Stamped with a diameter of 12 mm pressed. The Pressing takes place without special occurrences.

• - Features of the tablet:
  • - Average weight: 769.0 mg
    Standard value: 777.1 mg
    Hardness: 8.0 kg
• - Dissolution test (USP XXI method No. 2; 1 l deionized water, v = 50 rpm, t = 37 ° C):
  • - dissolved active ingredient after 8 hours: 50.1%
  • - apparent kinetics of dissolution
    t 30 min / 8 h: zero order r = 0.9997
  • - The appearance of the matrix after 8 h: coherent and unchanged
• - Analysis:
  • Trimebutin maleate
    per target tablet weight: 289.9 mg
    Standard value: 300.0 mg

Example 4

The following are filled into a free-fall mixer:

• - 150.0 g trimebutin maleate
• - 30.0 g lactose
• - 50.0 g tartaric acid
• - 120.0 g hydroxypropylmethyl cellulose 4000 mPa.s
• - 3.5 g magnesium stearate
• - 0.35 g silicon.

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

• - Features of the tablet:
  • - Average weight: 705.0 mg
    Standard value: 707.7 mg
  • - Hardness: 8.0 kg
• - Dissolution test (USP XXI method No. 2; 1 l deionized water, v = 50 rpm, t = 37 ° C):
  • - dissolved active ingredient after 8 hours: 45.5%
  • - apparent kinetics of dissolution
    t 30 min / 8 h: zero order r = 0.9973
  • - The appearance of the matrix after 8 hours: coherent and very easily eroded
• - Analysis:
  • Trimebutin maleate
    per target weight of the tablet: 302.1 mg
    Standard value: 300.0 mg

Claims (3)

1. Pharmaceutical preparation in the form of coating-free tablets which contain 3,4,5-trimethoxybenzoic acid (2-dimethylamino-2-phenylbutyl) ester as the active ingredient with the following structural formula
or one of its addition salts with a pharmaceutically acceptable acid, in particular maleic acid addition salt, and also hydroxypropylmethyl cellulose as a matrix, characterized in that
the active ingredient makes up 35 to 45% by weight of the preparation and is homogeneously dispersed in a porous, hydrophilic matrix of hydroxypropylmethyl cellulose with a viscosity of 3 to 5 Pas, which makes up 15 to 20% by weight of the preparation; and
the preparation further contains 20 to 25% by weight of water-soluble diluent from the group of lactose or mannitol and 10 to 20% by weight of tartaric acid. 2. Preparation according to claim 1, characterized in that each tablet contains 275 to 325 mg of active ingredient. 3. A method for producing a preparation according to claim 1 or 2, characterized in that
a mixture of active ingredient, diluent and tartaric acid is granulated in the moist state and wet grains are produced;
these wet grains are dried; and
these dry grains are mixed with hydroxypropylmethylcellulose to obtain a hydroxypropylmethylcellulose-containing mixture, whereupon this hydroxypropylmethylcellulose-containing mixture is pressed into tablets.