DD272797A5 - METHOD FOR PRODUCING SOLID MEDICAMENT PREPARATIONS WITH LONG-LASTING EFFECT ON DIHYDROPYRIDINE - Google Patents

Abstract

The invention relates to a process for the preparation of solid pharmaceutical preparations having a long-lasting effect for dihydropyridines consisting of a rapidly releasing core with a coat delaying the release beginning thereon. The sustained-release preparations produced according to the invention achieve a high bioavailability.

Description

For this 1 page drawing

Field of application of the invention

The invention relates to a process for the preparation of solid pharmaceutical preparations having a long-lasting effect for dihydropyridines consisting of a rapidly releasing core with a coating which delays the initiation of the release around it.

Characteristic of the known state of the art

Active substances from the class of dihydropyridines and their use as circulatory agents are already known (cf., Brit. Pat., 1173862, Brit. Pat., 1358951, US Pat.No.4256749, DE-OS 3311003, and US Pat.No.4264611). In the galenic preparation of these potent drugs, difficulties often arise because the substances have only a very low solubility, are often photosensitive and their absorbability in biological systems often leads to problems.

Some. Dihydropyridines also have a special pharmacokinetics: their metabolism occurs predominantly in the first passage of the liver (so-called first pass effect), which takes place directly after the absorption of the active substance. The metabolisation rate of these active substances depends on the rate of infeed of the active substance into the liver: with increasing amount per unit of time, less active substance is degraded (so-called "saturable first pass effect") .The bioavailability of the active substance then depends on the in vivo release rate of the active ingredient.

In the case of the abovementioned dihydropyridines, which have a bioavailability which depends on the in vivo release rate, the sustained release formulations mentioned hitherto also lead to comparatively low bioavailabilities.

It is also known from the prior art to coat pharmaceutical preparations with an enteric coating. For these medicines, part or all of the active ingredient is released from the drug after it has left the stomach. Diose discontinuous releasing sustained-release forms are unreliable, simply because of their pH dependency of the active substance liberation, since the gastric residence times spread from patient to patient and also depend substantially on food intake (residence times about 0.2 to 12 h). However, with such a dosage form, part of the active ingredient may be released at a later time, but the reproducibility of this prolonging phase (lag time) is not given for the reasons given above, so that e.g. B. a safe adaptation to daily rhythm-dependent biological processes hereby can not be achieved.

Object of the invention

The sustained-release preparations produced according to the invention contain the active ingredient in the core in rapidly releasing form. The coat contains no active ingredient.

The drug release takes place staggered, in predeterminable time intervals and is pH-independent. High bioavailability is achieved.

Explanation of the essence of the invention

The present invention has for its object to provide a method for producing solid pharmaceutical preparations with long-lasting action for dihydropyridines available.

It has now been found that solid pharmaceutical preparations with a long-lasting effect for 1 to a maximum of 2 times daily application, consisting of a fast-setting nucleus and the start of the release delaying delay coat for Dihydropyridinwirkstoffe are particularly suitable and surprisingly ensure a loo effectiveness and safe timing of absorption ,

The invention relates to the process for the preparation of solid pharmaceutical preparations having a long-lasting effect for 1 to a maximum of 2 times daily administration consisting of a rapidly releasing core and a coat delaying the start of release at least

a Üihydropyridin the general formula I.

R ³ OOC

in which

R ^{1 is} a phenyl radical which carries one or two identical or different substituents from the group nitro, halogen or trifluoromethyl or the radical

or

stands,

R ^{2 is} a nitro group or is the radical COOR ₆ , where

Re λ Ikylmit 1 to 10 carbon atoms, which is optionally substituted by alkoxy having 1 to 4 carbon atoms or

by one or more halogens or

R ² together with R ^{5 represents} the lactone group -CO-O-CH ₂ -, R ^{3 represents} alkyl having 1 to 10 C atoms, which is optionally substituted by alkoxy / with 1 to -1 C atoms by

one or more fluoro and R ⁴ and R ^{5 are the} same or different and are each alkyl of 1 to 4 carbon atoms, which is optionally substituted by hydroxy

Subs''tuiert are, where the core-coat-Darreichungsfoim

a) consists of a core containing at least one of the above-mentioned dihydropyridines in rapidly releasing form, and

b) consists of a lying around the core coat which contains no active ingredient and which dissolves only slowly in an aqueous environment, and

c) optionally on the coat additionally contains a fast-releasing initial dose of Dihydropyridinwerkstoffs, wherein the diameter of the preparation form is between 0.5 and 15mm.

Preference is given to those preparations which contain 20-100 wt .-%, preferably 40-100 wt .-%, in particular 50-100Gew .-% of the total Dihydropyridinwirkstoffs of the dosage form in the core.

If a fast-release initial dose is applied to the shell, it preferably contains 10% by weight, in particular 15% by weight, of the total amount of dihydropyridine.

Depending on the nature of the active ingredient, the preparations according to the invention contain a total of preferably 1 to 200mc, more preferably 10 to 150 mg of at least one active compound from the class of dihydropyridines.

The rapidly releasing core of the preparation preferably contains the active substance in amorphous form or in finely ground or micronized crystalline form.

Preferred nuclease nuclei are nuclei which contain the dihydropyridine drug in non-retarded form and release it at least 75% in a maximum of 1 hour under the following release conditions:

USP paddle method using sink conditions, that is to say those conditions in which the aqueous release medium is chosen such that it can dissolve at least three times the amount of active ingredient used.

The term "sink conditions" is explained in more detail as follows:

410.1 N hydrochloric acid + 0.1 to 0.5% wetting agent such as Tween 80 or Texapon K12 (sodium lauryl sulfate); 37 ⁰ C; lOOUpm. Of particular interest are the known dihydropyridines nifedipine, nitrendipine, nisoldipine and nimodipine. If the fast-release core contains amorphous dihydropyridine, it is preferably dissolved together with water-soluble polymers such as polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose in organic solvents such as acetone, methylene chloride, chloroform or lower aliphatic alcohols. It is expedient to use 1 to 1 part by weight of dihydropyridine 2 to 10 parts by weight, in particular 3 to 8 parts by weight, of the water-soluble polymers and to produce corresponding coprecipitates thereof.

If the rapidly releasing core contains dihydropyridines in crystalline form, it is preferable to use dihydropyridine crystals having a maximum mean particle size of 25 μm, in particular a maximum mean particle size of 15 μm. The particle size is determined by the Cilas method (Ref .: A.Buerkholz et al., Part. Charact., 1,1984,153-160, "Laser diffraction spectrometer / experience in particle size analysis").

When using crystalline .dihydropyridine in the core, the addition of slightly water-soluble excipients wi9 z. As lactose appropriate. Also, by the use of explosives, such. B. cross-linked polyvinylpyrrolidone (PVP) or by surface-active substances, such as. As sodium lauryl sulfate, the rate of dissolution are accelerated. The coat contains no active ingredient. In admixture with pharmaceutically customary excipients such. As lactose, starch, cellulose, citric acid u. a. and magnesium stearate as a lubricant, a hycrophilic gel forming polymer forms the shell material. This hydrophilic polymer controls the dissolution rate and erosion of the cladding, control factors for the cleavage / erosion rate of the cladding material are i.a. a. the layer thickness of the shell and the ratio polymer (s) / residual Kilfsstoffe.

As hydrophilic gel-forming polymers z. B. modified starches and cellulosic polymer * such. Methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and sodium carboxymethylcellulose, and optionally modulating hydrophobic excipients ₍ such as hydrogenated castor oil, calcium and magnesium stearate, stearic acid, cetyl palmitate and waxes such as beeswax.

The erosion and dissolution rate of the shell can also be controlled by the different degrees of viscosity of the polymer, the speed increasing as ni-viscous grades are used and slowing down when using high viscosity grades. Usually, the concentration of the polymer in the shell material is 5-100%, preferably 10-90%. The concentration used depends on the degree of viscosity of the polymer (s) and on the solubility / hydrophilicity of the auxiliaries used and their amount.

Suitable solid dosage forms for the core-shell principle according to the invention are e.g. Pellets and coated tablets. The size of the preparation may vary from 0.5 to 15 mm, the lower range being preferred for pellets and the range above 5 mm being preferred for tablets.

A particular advantage with the use of pellets lies in the division of the total active ingredient dose into several subunits (so-called multiple dose), which makes it possible to combine pellets with different thick or differently composed coatings so that the desired release profile of the dosage forms containing the total dose . {? B.-piece capsule! can be set, for. example, a linear drug delivery, a continuously faster expectant release of the drug or a vibrant role of the drug in time-shifted thrusting. the Initiaidosis can here introduced z. B. by non-coated drug cores In addition, by combining pellet populations with different lag phases, a dose minimization can be made such that the blood plasma concentrations do not leave the therapeutic area and the risk of side effects is diminished Placebomantel be applied so that here a discontinuous, bursty release is achieved.

The coat layer thickness and the proportions of the sequestering agents allow the desired delay times for the release of active ingredient from the core to be controlled. The set delay time until release of the active substance in the core by aberation of the jacket material causes ^a desired sustained release effect. The delay time due to aberration / detachment of the jacket is practically not influenced by the pH.

It should be expressly understood that the sustained-release preparation according to the invention differs from the hitherto known core-shell preparations in that the shell contains no active ingredient and the core contains the active ingredient in rapidly releasing form.

The coated tablet according to the invention is produced by customary methods, which are exemplified by the following methods:

First, the drug-containing chelell-releasing core is prepared by conventional tableting processes, e.g. B. from powder mixtures or granules, and then placed around this core with Hiife a coated tablet press (eg Kilian Pres'icoater) a drug-free placebo mantle, wherein the shell material from a free-flowing powder mixture or from uinem granules obtained by dry or wet granulation was, and where appropriate, on the se ei keepsn Manteltabletten still a lacquer layer using conventional painting, z. B. by spraying or by Au ressen another layer is applied, which optionally still contains an initial dose of the active ingredient. The preparation of shell pellets according to the invention is also carried out by conventional methods, for. B. in granulator or

Pelletizers that allow an up-building granulation z. B. in a pelletizer, a rotor granulator, a fluidized bed granulator or a coating pan, wherein the pellet cores either previously prepared separately or constructed directly continuously and then the jacket material is applied.

Particularly advantageous is the use of Roi granulators.

Conventionally known galenic measures ₍ such as, for example, the coating of the core, the use of flavorings and flavorings and customary auxiliaries which are familiar to the galenic expert, can of course also be used in the preparation according to the invention.

The prior art already describes multilayer tablets based on casein matrices which contain two or three layers, each of which in turn may contain active substances (cf US Pat. The tablets described therein, in contrast to the present invention in the outer jacket active ingredient.

Also in the US Pat. 3558768 describes coated tablets containing active ingredients in slowly releasing form both in the core and in the shell. The release rates may vary according to this US patent, but they are definitely slow-release forms.

Coated tablets, which in the Mant Jmateria! contain no active ingredient are also in Il Farmaco, No 3, March 84.67 f. (Conte et al.). However, the release kinetics of these tablets differs significantly from the dsm here described core-shell principle of the invention: after a delay time, the active ingredient is released continuously over a long time after a kinetics zero order. The sheath material serves as a diffusion barrier, but not for discontinuous intermittent release of the active ingredient. In contrast to the present! Core-Mantei principle according to the invention, the "Reservoimmanteltablette" can only be used for active ingredients with a certain Mindestwasserlösüchkeit.

Also, Salomon et al. (Pharm. Ind. 41, No. 8, p. 799 f., 1979) describe coated tablets which contain no active ingredient in the shell material. Again, the release occurs continuously (after a root-time kinetics). In principle, the above applies.

Another dosage form, which particularly favorably affects the saturable first pass effect of Psoral, is described in DE3115033 A1. However, the jacket material contains active ingredient. In addition, the delay until the release of active ingredient from the core of the coated tablets or pellets is not achieved by the application of high levels of hydrophilic gel-forming polymers (sheath), but by a coating of the core / pellets (a thin paint film).

In DE-OS 2651176 pellets are described with controlled release of active ingredient. The formulations mentioned there differ from the Mantolzubereitungen invention already characterized by the fact that they also contain active ingredient in the jacket. In addition, the formulations described therein can be obtained only by expensive processes by applying many layers, while the coated tablet according to the invention is prepared by simple pre-pressing and in the case of Mantelpellets only one layer by sin continuous working method is applied to the rapidly releasing cores.

The principle of the preparation according to the invention avoids the usual disadvantages of known sustained-release forms and also of previously known multilayer or coated tablets and pellets or of preparation forms which are based on osmot's principle. In particular, e.g. it can be avoided that the rate of release of the active ingredient is low due to the desired retardation character of the formulation, and thus, e.g. lower bioavailabilities of drugs due to a saturable first pass effect must be accepted. Rather, the entire active substance b? I use of coated tablets or shell pellets is released relatively quickly with a uniform delay time, but in discontinuous thrusts to achieve the desired sustained release effect.

Due to these staggered, take place at predeterminable intervals release, which is also not pH-dependent, the formulation of the invention differs from all previously known Retardierungsprinzipien for solid dosage forms. It is expected that this formulation will result in increased bioavailability, especially in the case of drugs having saturable first pass kinetics.

Another advantage of the drug forms according to the invention is that they are particularly suitable for those drugs which are in deeper sections of the gastrointestinal tract z. B. in the colon show a higher absorption than in the stomach or in the small intestine.

By appropriate design of the shell, the lag phase can be determined so that the active ingredient is released in the effectively resorbing part of the gastrointestinal tract, with it a high bioavailability and a secured effect can be achieved.

The technology according to the invention also makes it possible to adapt the release of active ingredient to the blood pressure daily rhythm.

Another advantage is the simple manufacturing technology.

In the case of the shell pellets (dosage form eg capsule), the possibility of adjusting any release kinetics of the active substance (by combining different shell pellets) can be mentioned as a further additional advantage. As a result, such a sustained-release preparation can be virtually "tailor-made" according to the requirements of a given active ingredient.

In view of the long-felt need for drug delivery forms having a long-lasting effect, it is more than surprising that so far nobody fie easy-producible and very effective Mantelanzneneiform invention with fast-releasing core beschrieber, or produced. By means of the present invention, the patient can be enabled to apply the medicament only once a day, which represents a safer and more convenient type of treatment, especially in long-term therapy.

embodiments

The curves of the A'ib. 1 show, for some selected examples according to the invention, the principle of discontinuous release of active ingredient, in particular the targeted release bursts, which are practically independent of the oH value a few hours after the A ₁ . can be adjusted.

Examples

example 1 8.0 mg Core nitrendipine microfine 8.0 mg lactose 8.0 mg Cellulose microcrystalline 16.0 mg cross-linked PVP are mixed and granulated with: 4.0 mg PVP25 0.8 mg sodium lauryl sulfate q.s. water after drying, it is mixed 0.2 mg Magnesiumstearst and pressed into tablets: 45.0 mg mass 5,0 mn Format 0 50.0 mg Coat: hydroxypropylcellulose type L 87.5 mg Hydroxypropyl cellulose type M m.Oma lactose

are mixed and granulated with water (optionally, a portion of the hydroxypropyl cellulose can be used for granulation). After drying, mix with:

Magnesium Stearate 1.5mg

Core and shell granules are pressed on a coat tablet press to manteitabletten:

Weight 295.0 mg

Format 0 9.0mm

Initial dose: 4mg nitrendipine is applied to the coated tablet using standard procedures. The paint is made

Nitrendipine, hydroxypropylmethylcellulose and polyethylene glycol. He releases the active ingredient quickly. The in vitro release of the active ingredient from this lacquered coated tablet is shown in Fig.

Example 2

Core: Niluuipine microfine 5.0mg

Lactose 38.8 mg

Corn starch 15.0 mg

are mixed and granulated with starch paste:

Corn starch 1.0 mg

Water q.s.

after drying, it is mixed in:

Magnesium stearate 0.2 mg

Cellulose microcrystalline 5.0 mg

and pressed into tablets:

Weight 65.0 mg

Format 0 6,0mm

Coat: hydroxypropyl cellulose Type M 126.0mr;

Lactose 145.6 mg

are then mixed and granulated with water (if necessary, a part of the hydroxypropyl cellulose can be used for granulation). After drying, mix with:

Magnesium stearate 8.4 mg

Core and shell granules are pressed on a coat tablet press to coat tablets:

Weight 345.0 mg

Format 0 9.0mm

Initial dose: On the metal tablets is a zwoite layer of active ingredient-containing granules (composition as under

"Kern" described), dose nifedipine 5mg.

Dia in vitro release of the active ingredient from this two - layered tablet shows Fig.

Example 3

Core: Nisoldipine microfine 10.0mg

Lactose 12.0 mg

Cellulose microcrystalline 10.0mg

Crosslinked PVP 7.5 mg are mixed and granulated with:

PVP25 2.5mg

Sodium Lauryl Sulfate 0.5mg

Water q.s

 after drying, mix:

, Magnesium stearate 0.2 mg

PVP crosslinked 2,3mg

and pressed into tablets:

Weight 45.0 mg

Format 0 5 mm

Coat: hydroxypropylcellulose type L 31.0 mg

Hydroxipropylcellulose Type M 106.0 mg

Lactose 11.5mg

are mixed and granulated with water (if necessary, a part of the hydroxypropylcellulose can be used for granulation). After drying, mix with:

Magnesium Stearate 1.5mg

Core and shell granules are pressed on a coat tablet press to coat tablets:

Weight 295 mg

Format 0 9 mm

Initial dose: On the coated tablets is with the usual methods and paint auxiliaries (see ι B. Example 1)

Nisoldipine 10mg varnished.

Example 4

Core: as Example 3, but containing nitrendipine microfine instead of nisoldipine microfine.

Coat: as example 3

Coated tablet: weight 295,0 rrg

Format 0 9.0mm

Initial dose: as in Example 3, but nitrendipine microfine instead of nisoldipine microfine.

The in vitro release of the active ingredient from these lacquered sheath cells is shown in Fig.

Example 5

Core: as Example 2, but additionally 2.6mg of 2-methyl-4- (4-oxo-2-phenyl-4H-thiochromen-8-yl) -5-oxo-1,4,5,7-

tetrahydrofuro- [3,4-bl-pyridine-3-carboxylic acid ethyl ester-containing (balancing to the core weight of 65 mg with corn starch)

Coat: as example 2

Initial dose: On the coated tablets, a second layer of active ingredient-containing granules (composition as under

"Core" described) pressed.

Example β

Core: as in Example 4

Coat: methyl cellulose 250.0mg

Lactose 65 mg

are mixed and granulated with water (if necessary, part of the methylcellulose can be used for granulation). After drying, mix with:

Magnesium Stearate 5.0mg

Core and shell granules are pressed on a coat tablet press to coat tablets:

Weight 365.0mg

Format 0 9.0 mm

Initial dose; as in Example 4

Example 7

Core: as in example 5

Coat: pre-gelatinized starch, 225mg

Lactose 90 mg are mixed and granulated u / id with water. After drying, mix with:

Magnesium stearate 5mg and pressed into coated tablets:

Weight 385.0mg

Format 0 9.0 mm

Examples

In a raw granulator pellets are produced with the following structure:

Core: Diameter: 1.00-1.25mm 70% Composition: 28% Nitrendipine microfine 2% Hydroxypropylcellulose type L sodium lauryl sulfate 30% Coat: Composition: 4ü% pre-gelatinized starch 30% HydroxypropylcoiluloiTType M hydrogenated castor oil Order quantity (in relation to the core weight): 300% depending on the desired delay time, any adjustable, z. B.

Example 9

In a coating pan, pellets are produced with the following structure:

Core: Diameter: 0.63-0.Smm

Composition:

Nisoldipine microfine 70%

HydroxypropylcelluloseTypL. 28%

Sodium lauryl sulfate 2%

Coat: Composition:

hydrated castor oil 70%

Hydroxypropylcellulose type M 30%

Order quantity (in relation to the core weight):

1. 0%

2. 100%

3. 200%

4. 300%

Pellets 1-4 are mixed so that 30 mg of nisoldipine microfine is distributed among the pellets as follows:

13% of the dose pellet 16% of the dose pellet 27% of the dose pellet

44% of the dose pellet The pellet mixture is filled into hard gelatin canning capsules.

Example 10

Core: Nimodipine microfine 70%

Hydroxypropylcellulose type L 28%

Sodium lauryl sulfate 2%

are mixed and converted by pelletization with water as granulating into spherical particles with a mean diameter of 0.5-1.5 mm.

coat

In a continuously operating rotor granulator, nimodipine cores and shell powder are mixed simultaneously and water is added as granulating liquid. The shell powder mixture is composed as follows:

10a) Cellulose microcrystalline 86% calcium stearate 9% Hydroxypropyl cellulose type M 5% 10b) rice starch 20% Castor oil hydrogenated 50% Hydroxypropyl cellulose type M 30% 10c) Cellulose microcrystalline 70% stearic acid 15% sodium 10% HydroxypropyJmethylellulosegemisch (1: 1) 10d) • Cornified maize starch 30% HydroxypropylcelluloseTypM 40% hydrogenated castor oil 30% 10e) hydrogenated castor oil 70% Hydroxypropyl cellulose type M 30%

The iVlantelpulvergemisch Examples 10a-e is applied to the cores in the following amounts:

Example 10a -150% of the core weight 10b - 250% of the core weight IOc -100% of the core weight 10d - 300% of the core weight 10e -150% of the core weight.

Claims (8)

1. A process for the preparation of solid pharmaceutical preparations with a long-lasting effect for 1 to 2 times daily application ₍ containing at least one dihydropyridine of the general formula I. K ³ OOO in which R ^{1 represents} a phenyl radical bearing one or two identical or different substituents ausdei group nitro, halogen or trifluoromethyl or for the rest R ^{2 is} a nitro group or the radical COOR ₆ , wherein Re is alkyl having 1 to 10 carbon atoms, which is optionally substituted by alkoxy with 1 to 4 carbon atoms or by one or more halogens or R ² together with R ^{5 represents} the lactone group -CO-O-CH ₂ -, R ^{3 represents} alkyl having 1 to 10 C atoms, which is optionally substituted by alkoxy 1 to 4 C atoms or by one or more fluorines and R ⁴ and R ^{5 are} Lich or different and are each alkyl of 1 to 4 carbon atoms, which is optionally substituted by hydroxy, are, consisting of a rapidly releasing nucleus and a coat delaying the start of release, this dosage form a) consists of a core containing at least one of the above-mentioned dihydropyridines in fast-release form b) consists of a jacket lying around the core, which contains kuinen active ingredient and which dissolves only slowly in an aqueous environment, c) optionally on the coat additionally contains a fast-releasing initial dose of a Dihydropyridinwirkstoffes, wherein the diameter of the preparation form is between 0.5 and 15 mm, characterized in that A) produces Mcinteltabletten by first producing the wirstoffstoff, fast-releasing core by means of conventional TaLiettierprozesse by pressing powder mixtures or granules and then around this core using a coated tablet press a drug-free Placebomantel, the shell material consists of a free-flowing powder mixture or granules and optionally on this coated tablet, a lacquer layer with conventional methods such as spraying or another layer by pressing a powder mixture or granules applies, this additional * Layer is optionally admixed with an initial dose of the active substance, or B) preparing shell pellets by either preparing the pellet cores in advance in a separate operation or continuously building directly in a pelletizer or granulator and then applying the shell material by means of an uplifting granulation in a granulator or pelletizer such as pelletizer, rotor granulator, fluidized bed granulator or coating pan. 2. The method according to claim 1 B), characterized in that it is carried out in a rotor granulator. 3. The method according to claim 1, characterized in that the solid pharmaceutical preparations in the core contain 20 to 100 wt .-% of the total active ingredient content. 4. The method according to claim 1, characterized in that the medicament preparation contains a total of 1 to 200 mg Dihydropyridinwirkstoff. 5. The method according to claim 1, characterized in that the rapidly releasing »core of the pharmaceutical preparation contains the active ingredient in amorphous form or in finely ground or micronized crystalline form, optionally in addition to readily water-soluble excipients and / or disintegrants and / or wetting agents. 6. The method according to claim 1, characterized in that the rapidly releasing core of the pharmaceutical preparation contains amorphous dihydro pyridine together with water-soluble polymers wio polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose, wherein per 1 part by weight of dihydropyridine 2-10Gew.-parts of the water-soluble Polymers come or wherein the core contains the Dihydropyridinwirkstoffe in crystalline form with a maximum mean particle size of 25pm. 7. The method according to claim 1, characterized in that the drug-free coat of the pharmaceutical preparation contains a hydrophilic, gel-forming polymer and optionally further conventional auxiliaries. 8. The method according to claim 1, characterized in that the drug-free coat of the pharmaceutical preparation as hydrophilic gel-forming polymers modified starches, cellulosic polymers such. As methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or sodium carboxymethylcellulose and optionally as a modulator hydrophobic excipients such as hydrogenated castor oil, calcium stearate, magnesium stearate, stearic acid, cetyl palmitate or waxes, such as beeswax.