RU2311172C2 - Solid medicinal composition comprising derivative of piperazinourea - Google Patents

Abstract

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a solid medicinal composition providing pH-independent release of active substance and comprising (2R)-1-{[4-chloro-2-(ureido)phenoxy]methyl}carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine or one of its salts, polymeric matrix, pharmaceutically acceptable organic acid, lubricating additive and one or some accessory substances and wherein size of 90% of particles in powdery mixtures is from 0.1 to 750 mcm. Except for, invention relates to methods for preparing and using this medicinal composition.

EFFECT: valuable pharmaceutical properties of composition, improved preparing method.

22 cl, 11 dwg, 22 ex

Description

The present invention relates to a solid drug composition containing (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or one of its salts.

WO 98/56771 describes benzylpiperazine urea compounds and in particular (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine and its salts . These substances are antagonists of the CCR-1 receptor and are used in the treatment of inflammatory diseases, in particular multiple sclerosis and rheumatoid arthritis. In addition, they are used in the treatment of psoriasis and atopic dermatitis. At alkaline pH values, these substances are characterized by extremely low solubility. The solubility of (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine solubility at a pH of 1 is only about 5 mg / ml, while at a pH of 6.35 or 6.8, this indicator is approximately 0.15 mg / ml, respectively 0.1 mg / ml. Such extremely low solubility in the gastrointestinal tract does not allow for the oral administration of conventional compositions to achieve a therapeutically necessary uniform plasma level, while avoiding significant side effects. Along with an increase in solubility in the gastrointestinal tract, it is also desirable that the release of the active substance takes place under control over a long period of time, which would significantly increase the intervals between the introduction of the corresponding doses. In addition, it should also be noted that the opportunity arises in this case to manufacture the medicine on an industrial scale.

The literature describes various ways to increase the absorption of poorly soluble active substances (see, for example, "Techniques of solubilization of drugs", edited by S.H. Yalkowsky in Drugs and the Pharmaceutical Sciences). For substances characterized by extremely low solubility, it is especially recommended to use substances that promote dissolution, such as, for example, surfactants (see application WO 01/05376). However, such a path was unsuitable for solving this problem. The addition of SDS surfactant (sodium dodecyl sulfate) to (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine hydrosulfate allowed only insignificantly increase the required release of the active substance.

Other publications address the issue of pH independent release of active ingredients. Streubel et al. (Journ. Controlled Release 67 (2000), pp. 101-110) describe the addition of acids to the corresponding drug substance. However, the solubility of the described drug substance and without the addition of acids at pH 6.35 is already very high (100 mg / ml). The goal of Streubel et al. Was to provide the same degree of solubility regardless of pH. This was achieved by adding acids. The aim of the present invention is not only to solve the problem of solubility due to different pH values, but also to increase the degree of solubility as such. The properties of the drug substance described by Streubel are significantly different from the properties of the active substance used according to the present invention, i.e. (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine. In addition, the composition proposed in this publication is used only for the unit manufacture of tablets and is not intended for mass production. Therefore, doubts arose about the possibility of using this method to solve the problem underlying the present invention.

The task of the invention to increase the degree of solubility and pH-independent release of the active substance while simultaneously realizing this task on an industrial scale is achieved thanks to a solid drug composition containing (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or one of its salts, while for targeted regulation of the release of the active substance regardless of pH (modification of the release) and to affect the mechanical ical strength dosage form of the composition of the drug composition further comprises a polymer matrix, the organic acid and one or more auxiliary substances and 90% of the particles in powder mixtures have a grain size of 0.1 to 750 microns.

(2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine, hereinafter referred to briefly as piperazine urea, has the following structure:

(2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine and its salts are prepared according to the method described in WO 98/56771 in example 2.

Among the salts of said compound, for example, hydrochloride, dihydrogen phosphate, hydrosulfate, sulfate, mesylate, ethyl sulfonate, fumarate and tartrate can be mentioned.

Solid drug compositions according to the invention are in the form of a solid (monolithic) structure, such as, for example, tablets, and in a crushed (powder) form. Such forms, presented in crushed form, can be, for example, granular grains, spherical granules (pellets) or mini-tablets. They can be packaged in hard or soft gelatin capsules or tablets can be compressed from them. The initial form breaks up mainly in the stomach into several parts. Then, such minidepo forms sequentially pass from the stomach to the intestines. In this case, minidepo-forms, as a rule, can pass through the pylorus with the sphincter closed.

The polymer matrix can be selected from the group consisting of cellulose derivatives [for example, methyl cellulose, hydroxypropyl methyl cellulose (eg, hydroxypropyl methyl cellulose K 4 M, hydroxypropyl methyl cellulose K 15 M), hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, ethyl cellulose, cellulose acetate, cellulose, for example cellulose CA-398-10 NF), cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate butyrate (e.g., cellulose acetate butyrate 171-15 PG), cellulose butyrate, cellulose nitrate yulozy, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate hydroxypropyl] acryl derivatives [e.g., polyacrylates, cross-linked polyacrylates (e.g., polymethacrylates, polyethyl acrylate, ethyl acrylate polimetilovoy acid methyl methacrylates polimetilovoy acid, ethyl methacrylate polimetilovoy acid etilmetakrilohloridy polimetilakrilotrimetil-ammonium etilmetakrilohloridy polietilakrilotrimetilammoniya, copolymers of dimethylaminoethyl methacrylate, Carbopol® 971 P, Carbopol® 974 P, Carbopol® 71 G)], vinyl f polymers (e.g. polyvinyl pyrrolidones, polyvinyl acetates, polyvinyl acetophthalates), polyethylene glycols, polyanhydrides, polyesters, polyorthoesters, polyurethanes, polycarbonates, polyphosphazenes, polyacetals, polysaccharides (e.g. xanthenes, xanthane, sugar, gum) sucrose, sucrose laurate, sucrose behenate, sucrose oleate, sucrose erucate and sucrose and mixed fatty acid esters), diethylene glycol monoethyl ether (e.g. Transcutol® P), monopalmitostearate d ethylene glycol (e.g. Hydrine®), ethylene glycol monopalmitostearate (e.g. Monthyle®), glycerol behenates and glycerol dibegenates (e.g. Compritol® 888 ATO, Compritol® HD 5 ATO and Compritol® E), glycerol distearates, glycerol dipolemitostearate and e.g. Precirol® ATO 5 and Precirol® WL 2155), glycerol monooleate 40 (e.g. Peceol®), glycerol monostearate 40-55 (e.g. Geleol®), macrogolglycerol laurates (e.g. Gelucire® 44/14 and Labrafil® M 2130 CS), macrogolglycerol stearates (e.g. Gelucire® 50/13), propylene glycol monopalmitostearate (e.g. Monosteol®), hit en, galactomannan, pectin, shellac and alginates. The most suitable as a polymer matrix is a physical mixture consisting of water-insoluble polyvinyl acetate and water-soluble polyvinylpyrrolidone. This mixture, additionally containing sodium lauryl sulfate and silicon dioxide, is supplied, in particular, under the trade name Kollidon SR® (Kollidon SR, Technical Information Bulletin, ME 397e, BASF, July 2000, composition: 80% polyvinyl acetate, 19% polyvinylpyrrolidone, 0 , 8% sodium lauryl sulfate and 0.2% silicon dioxide).

Organic acid can be selected from the group consisting of fumaric acid, citric acid, trisodium citrate, Na-hydrocytrate, ascorbic acid, maleic acid, maleic anhydride, tartaric acid, adipic acid, Na-hydrogen phosphate, succinic acid, glutaric acid, anhydride potassium sorbate and sorbic acid. Of these, fumaric acid is preferred.

For the purposeful regulation of the pH-independent release of the drug substance (modification of the release) and for affecting the mechanical strength of the dosage form, water-soluble as well as water-insoluble excipients can be used, such as lactose, calcium diphosphates, mannitol, sorbitol, sucrose, fructose, glucose, starch or a starch derivative. Mixtures of one or more excipients may equally be used. Lactose is preferred. Coarse-grained lactose is particularly preferred.

Cellulose and cellulose derivatives can be used as adjuvants for the targeted regulation of pH-independent drug release (release modification) and for affecting the mechanical strength of the dosage form. Microcrystalline cellulose is particularly preferred. In the aquatic environment, it swells and promotes a more efficient pH-independent release of piperazine urea and its salts.

Lubricating additives can be added to the composition of dosage forms in the form of an integral structure, such as, for example, tablets, in order to reduce the friction force between particles and to reduce sliding friction between the walls of the matrix and the material filling it. As such lubricating additives, substances can be used that have layers due to their lamellar (layered) structure, which are able to easily move relative to each other to a certain extent. Pharmaceutically acceptable organic substances include, among others, soaps of divalent metals, higher fatty alcohols, and higher molecular weight polyethylene glycols. Magnesium and calcium salts of higher fatty acids are particularly preferred.

In the case of dosage forms in the form of an integral structure, to improve the fluidity of the tableted material, you can add the appropriate flow control. Such a fluidity regulator ensures uniform filling of the machine matrix with tableted material with a sufficient packing density. The addition of a flow regulator may be necessary primarily with direct tabletting. Substances having a purely regulating effect with respect to fluidity are mainly highly dispersed silicic acids, i.e. micronized silica gels and silicic acids obtained by pyrolysis. Starches and talc are also suitable, since they are substances that can be used as flow regulators, as well as auxiliary decomposition agents, respectively, as lubricating additives.

In the industrial manufacture of a dosage form in the form of an integral structure, it is important that the tableted material has granular properties such as fluidity, high bulk density and a certain particle size distribution. The grain size of the tableted material depends on the size of the manufactured tablets and varies, as a rule, in the range from 0.1 to 750 microns. In order to avoid delamination (for example, when the tablet machine vibrates) and thereby accumulate larger particles in the upper part of the tableted material, an important factor is the maximum possible uniformity of the granulometric composition of this material, since otherwise more or less significant deviations may occur regarding the intended dosage. The required particle size and particle size distribution are provided by classification (for example, by wet or dry screening) or by granulation of the starting materials. Particle size can be determined using the method described in example 5. Up to 90% of the particles must have a particle size in the range from 0.1 to 750 microns. A range of from 20 to 400 microns is preferred.

Piperazinourea or its salts can be homogeneously distributed in the matrix or enclosed in a matrix. In the latter case, the active substance forms a core surrounded by a matrix shell.

The solid drug composition according to the invention may have a color varnish coating for visual perception and taste reasons. This varnish usually consists of a binder (e.g. hydroxypropyl methylcellulose, polyvinylpyrrolidone or polyethylene glycol), a glidant (e.g. talc), and a suitable dye (e.g. iron oxide, titanium dioxide, etc.).

The composition of the preferred solid drug composition includes (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or one of its salts, lactose, Kollidon SR®, silicon dioxide and magnesium stearate, with 90% of the particles having a particle size in the range from 0.1 to 750 microns. It is particularly preferred to use hydrosulfate as a salt. A tablet containing such a composition is characterized by 60% piperazine urea release after 6 hours.

Another preferred solid drug composition includes (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or one of its salts, microcrystalline cellulose, lactose, Kollidon SR®, silicon dioxide and magnesium stearate, with 90% of the particles having a particle size in the range from 0.1 to 750 microns. It is particularly preferred to use hydrosulfate as a salt. A tablet containing such a composition is characterized by 80-90% piperazine urea release after 4 hours.

The composition of another preferred solid drug composition is (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or one of its salts, lactose, Kollidon SR®, silicon dioxide and magnesium stearate, with 90% of the particles having a particle size in the range from 0.1 to 750 μm, and then the tablet is coated with a colored lacquer consisting of hydroxypropyl methylcellulose, talc, titanium dioxide and iron oxide dye. It is particularly preferred to use hydrosulfate as a salt. A tablet containing such a composition is characterized by 60% piperazine urea release after 6 hours.

The pharmaceutical composition of the invention substantially increases the solubility and release of piperazinourea and its salts. When using a traditional composition, the composition of which includes (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or one of its salts, lactose , corn starch, polyvinylpyrrolidone, Na-croscarmellose and magnesium stearate, after 8-10 hours at pH 6.8 only about 10% piperazine urea is released, while when using the composition proposed in the invention, this indicator rises to about 60-90%. The advantage of the drug composition of the invention is also confirmed by the results of clinical trials. Compared to the traditional oral composition, the level of (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine in patients who were administered the proposed in the invention, the composition remained high for a long period of time (see Fig. 11 in the accompanying drawings).

The composition proposed in the invention has all the properties necessary for industrial production, such as, for example, good fluidity, high bulk density, high metering accuracy, high ductility, which ultimately allows tablets with high mechanical strength to be pressed without problems.

A subject of the invention is a further method for preparing a solid drug composition according to the invention, comprising (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4- fluorobenzyl) piperazine or one of its salts is mixed with a polymer matrix, an organic acid, a lubricating additive and an appropriate auxiliary substance, and then this mixture is tabletted (direct tabletting). In this case, the direct tabletting process is carried out, as a rule, by mixing the powder components, dosing using a tablet machine loading device and then compacting the powder mixture. In direct tabletting, the particle size and particle size distribution of the used piperazinourea and its salts, a polymer matrix, an organic acid and an excipient have a practically decisive effect on the industrial production of tablets. Therefore, before mixing the powder components, they should be classified separately (for example, by sieving). Alternatively, you can either classify the entire powder mixture as a whole or classify the individual components of the powder mixture together (for example, sift them). As indicated in the examples, after weighing the required quantities (weighed) of the powder components, they are mixed for a sufficiently long period of time in a free-fall mixer (for example, in a turbulent mixer or in a mixer with a V-shaped mixing organ) or in a mixer with forced mixing ( for example, in a mixer with plow blades or in a planetary mixer). First of all, a flow regulator and a lubricating additive (collectively referred to as the RTS complex) are added shortly before loading the tabletting machine. At the same time, the indicated RTS complex must be sprayed onto the pre-mixed tableted material by fine sieving and then mixed everything as described above, and the mixing time should be chosen neither too short (danger of inhomogeneous distribution), nor too long (danger of overly fine grinding of the material).

The present invention further relates to a method for preparing a solid drug composition according to the invention, comprising (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4 -fluorobenzyl) piperazine or one of its salts, a polymer matrix, organic acid and excipients is subjected to another operation, referred to as granulation, before mixing and tabletting. After granulation and the introduction of a lubricating additive according to the technology described above, tableting is carried out. In this case, granulation can be carried out by stepwise enlargement or agglomeration of the primary particles of the powder mixture to form granules of the desired secondary size (granulation by growth) or by crushing the paste-like powder mass to form granules of the required size (granulation by crushing). For granulation by extension, plate granulators and fluidized bed granulators can be used. Granulation by crushing can be carried out, for example, by compaction (compaction) of the starting materials and subsequent mechanical grinding and sieving of comprimates (compacted products). Both types of granulation can be carried out in this case by wet granulation (obtaining, for example, sticky granules or coated granules in the form of a crust) or by dry granulation (obtaining, for example, briquetted granules or melt-cured granules).

Another object of the present invention is a method for producing the solid drug composition in it in a crushed (powder) form, which consists in the fact that (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2 -methyl-4- (4-fluorobenzyl) piperazine or one of its salts, a polymer matrix, organic acid and excipients (preferably cellulose, cellulose derivatives and lactose) are processed by extrusion and subsequent spheroidization to form spherical granules (pellets).

Another object of the present invention is a method for producing the solid drug composition in it in a crushed (powder) form, which consists in the fact that (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2 -methyl-4- (4-fluorobenzyl) piperazine or one of its salts, organic acid and excipients (preferably cellulose, cellulose derivatives and lactose) are processed by extrusion and subsequent spheroidization to form spherical granules. Then, a polymer matrix is applied to the spherical granules containing the active substance (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac). Under certain conditions, a spherical granule can be applied to the spherical granules containing the active substance before applying the polymer matrix (preferably cellulose derivatives and vinyl polymers). The sublayer is intended to prevent incompatibilities between (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or its salt and polymer matrix, respectively prevent premature diffusion of (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or its salt into the polymer matrix during storage of spherical granules.

Another object of the present invention is a method for producing the solid drug composition in it in a crushed (powder) form, which consists in the fact that (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2 -methyl-4- (4-fluorobenzyl) piperazine or one of its salts and excipients (preferably cellulose, cellulose derivatives and lactose) are processed by extrusion and subsequent spheroidization to form spherical granules. Then, organic acid and a polymer matrix (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac) are applied to the spherical granules containing the active substance. Under certain conditions, a spherical granule can be applied to the spherical granules containing the active substance before applying the polymer matrix (preferably cellulose derivatives and vinyl polymers).

Another object of the present invention is a method for producing the solid drug composition in it in a crushed (powder) form, which consists in the fact that (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2 -methyl-4- (4-fluorobenzyl) piperazine or one of its salts, a polymer matrix, organic acid and excipients are subjected to direct granulation with the formation of spherical granules. In this case, the starting materials are mixed with each other and then processed using a solution of binders (wet granulation) or molten additional substances (for example, fats) to obtain spherical granules.

Another object of the present invention is a method for producing the solid drug composition in it in a crushed (powder) form, which consists in the fact that (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2 -methyl-4- (4-fluorobenzyl) piperazine or one of its salts, a polymer matrix, an organic acid and auxiliary substances are subjected to spray drying or spray curing to obtain spherical granules.

Another object of the present invention is a method for producing the solid drug composition in it in a crushed (powder) form, which consists in the fact that (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2 -methyl-4- (4-fluorobenzyl) piperazine or one of its salts, a polymer matrix, organic acid and excipients are subjected to rotary granulation to obtain spherical granules.

The invention further relates to a method for preparing a solid drug composition according to the invention, comprising applying a polymer matrix, organic acid and excipients in layers to (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or its salt to obtain spherical granules as a result of such processing (layering).

The invention further relates to a method for preparing a solid drug composition according to the invention, comprising (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4- fluorobenzyl) piperazine or one of its salts, a polymer matrix, organic acid and excipients are applied in layers to the core containing no active substance (the so-called nonparelli) to obtain spherical granules as a result of such processing. In this method, as a rule, (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof is first applied without active substance core. An organic acid is then applied and finally a polymer matrix is applied to the obtained spherical granules (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac). Under certain conditions, a sublayer (preferably cellulose derivatives and vinyl polymers) can be applied to the spherical granules before applying the polymer matrix.

The invention further relates to a method for packaging the obtained spherical granules into capsules used in pharmaceuticals (preferably gelatin capsules, starch capsules or capsules from cellulose derivatives), respectively, compressing tablets from the obtained spherical granules. When filling spherical granules into capsules, respectively, when processing such granules into tablets, if necessary, some other auxiliary substances can be added (preferably cellulose, cellulose derivatives, lactose, lubricants and flow regulators).

The object of the present invention is also a method for preparing the solid drug composition according to the invention, comprising (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4 -fluorobenzyl) piperazine or one of its salts is mixed with a polymer matrix, an organic acid, a lubricating additive and excipients, and then mini-tablets are directly pressed (by direct tabletting; preferred tablet diameter is 1-5 mm).

The invention further relates to a method for preparing a solid drug composition according to the invention, comprising (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4- fluorobenzyl) piperazine or one of its salts, a polymer matrix, organic acid and excipients is subjected to another operation, referred to as granulation, before mixing and tabletting. After granulation and the introduction of a lubricating additive, mini-tablets are pressed from the starting materials (the preferred tablet diameter is 1-5 mm).

The invention further relates to a method for packaging the resulting mini-tablets in capsules used in pharmaceuticals (preferably gelatin capsules, starch capsules or capsules from cellulose derivatives). When packaging minitabs in capsules, if necessary, you can add some other excipients (preferably cellulose, cellulose derivatives, lactose, etc.).

The object of the present invention is the use of the proposed solid drug composition therein for the manufacture of a medicament for the treatment of inflammatory diseases. Such diseases may include, for example, multiple sclerosis, rheumatoid arthritis, psoriasis or atonic dermatitis. When treating a patient suffering from any kind of inflammatory disease, it is preferable to prescribe one tablet per day.

Description of drawings

Figure 1 shows the solubility of piperazinourea hydrosulfate depending on the pH value.

Figure 2 shows the effect achieved by the addition of SDS (sodium dodecyl sulfate) the release of piperazine urea hydrosulfate in a phosphate buffer solution at pH 6.8 (33% piperazine urea hydrosulfate and 25% Kollidon SR® based on the total tablet weight).

Figure 3 shows the effect of fumaric acid (in%, calculated on the total weight of the tablet) of the release of piperazine urea hydrosulfate in phosphate buffer solution at pH 6.8 (33% piperazine urea hydrosulfate and 25% Kollidon SR®, calculated on the total weight of the tablet).

Figure 4 shows the effect achieved by adding fumaric acid in various concentrations (in%, calculated on the total weight of the tablet), the effect of the release of piperazine urea hydrosulfate in phosphate buffer solution at pH 6.8 (33% piperazine urea hydrosulfate and 25% Kollidon SR® in terms of total weight of the tablet).

Figure 5 shows the dependence of the release of piperazinourea hydrosulfate (33% piperazinourea hydrosulfate, 25% Kollidon SR® and 16% fumaric acid, calculated on the total weight of the tablet) on the pH value.

Figure 6 shows the dependence of the release of piperazinourea hydrosulfate (33% piperazinourea hydrosulfate, 12.5% Kollidon SR® and 16% fumaric acid, calculated on the total weight of the tablet) on the pH value.

7 shows the dependence of the release of piperazinourea hydrosulfate (33% piperazinourea hydrosulfate, 25% Kollidon SR®, 16% fumaric acid and 10% microcrystalline cellulose, calculated on the total weight of the tablet) on the pH value.

FIG. 8 shows the particle size distribution of a typical pressed powder for direct tabletting, determined by laser diffractometry.

Figure 9 shows the effect achieved by the addition of various polymer matrices (Examples 3–9) in the release of piperazine urea hydrosulfate in a phosphate buffer solution at pH 6.8.

Figure 10 shows the effect achieved by the addition of various organic acids (examples 10-13) the release of piperazinourea hydrosulfate in phosphate buffer solution at pH 6.8.

11 on a semi-logarithmic scale shows the effect of the drug composition on the in vivo plasma level in humans after administration of 100 mg of piperazinourea hydrosulfate in the form of a traditional oral preparation, as well as after taking the preparations indicated in examples 1 (tablet with matrix C) and 2 (matrix E tablet).

Examples

Example 1: Preparation of a matrix tablet by direct tabletting

Composition based on the standard dosage form:

piperazine urea hydrosulfate 100 mg lactose 69 mg Kollidon SR® 75 mg fumaric acid 50 mg fine silica 3 mg magnesium stearate 3 mg

Lactose, piperazine urea hydrosulfate and Kollidon SR® are sieved separately and then mixed in a turbomixer for 10 minutes in this order. After this, sifted fumaric acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. Finally, the pressed powder mass is tabletted using an eccentric or rotary tablet press.

Example 2: Preparation of a matrix tablet by direct tabletting

Composition based on the standard dosage form:

piperazine urea hydrosulfate 100 mg lactose 39 mg Kollidon SR® 75 mg fumaric acid 50 mg microcrystalline cellulose 30 mg fine silica 3 mg magnesium stearate 3 mg

Lactose, piperazine urea hydrosulphate, Kollidon SR® and microcrystalline cellulose are sieved separately and then mixed in a turbo mixer for 10 minutes in this order. After this, sifted fumaric acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. Finally, the pressed powder mass is tabletted using an eccentric or rotary tablet press.

Example 3: Preparation of a matrix tablet by direct tabletting

Composition based on the standard dosage form:

piperazine urea hydrosulfate 100 mg lactose 104 mg Precirol® ATO 5 40 mg fumaric acid 50 mg fine silica 3 mg magnesium stearate 3 mg

Lactose, piperazine urea hydrosulfate and Precirol® ATO 5 (glycerol dipalmitostearate) are sieved separately and then mixed in a turbomixer for 10 minutes in this order. After this, sifted fumaric acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. Finally, the pressed powder mass is tabletted using an eccentric or rotary tablet press.

Example 4: Preparation of a matrix tablet by direct tabletting

Composition based on the standard dosage form:

piperazine urea hydrosulfate 100 mg lactose 104 mg Compritol® 888 ATO 40 mg fumaric acid 50 mg fine silica 3 mg magnesium stearate 3 mg

Lactose, piperazine urea hydrosulfate and Compritol® 888 ATO (glycerol dibegenate) are sieved separately and then mixed in a turbomachine for 10 minutes in this order. After this, sifted fumaric acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. Finally, the pressed powder mass is tabletted using an eccentric or rotary tablet press.

Example 5: Preparation of a matrix tablet by direct tabletting

Composition based on the standard dosage form:

piperazine urea hydrosulfate 100 mg lactose 69 mg Carbopol® 71 G 75 mg fumaric acid 50 mg fine silica 3 mg magnesium stearate 3 mg

Lactose, piperazine urea hydrosulfate and Carbopol® 71 G (cross-linked polyacrylate) are sieved separately and then mixed in a turbomachine for 10 minutes in this order. After this, sifted fumaric acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. Finally, the pressed powder mass is tabletted using an eccentric or rotary tablet press.

Example 6: Preparation of a matrix tablet by direct tabletting

Composition based on the standard dosage form:

piperazine urea hydrosulfate 100 mg lactose 69 mg Xantural® 75 75 mg fumaric acid 50 mg fine silica 3 mg magnesium stearate 3 mg

Lactose, piperazine urea hydrosulfate and Xantural® 75 (xanthen gum) are sieved separately and then mixed in a turbomixer for 10 minutes in this order. After this, sifted fumaric acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. Finally, the pressed powder mass is tabletted using an eccentric or rotary tablet press.

Example 7: Preparation of a matrix tablet by direct tabletting

Composition based on the standard dosage form:

piperazine urea hydrosulfate 100 mg lactose 84 mg ethyl cellulose 100 60 mg fumaric acid 50 mg fine silica 3 mg magnesium stearate 3 mg

Lactose, piperazine urea hydrosulfate and ethyl cellulose 100 are sieved separately and then mixed in a turbomixer for 10 minutes in this order. After this, sifted fumaric acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. Finally, the pressed powder mass is tabletted using an eccentric or rotary tablet press.

Example 8: Preparation of a matrix tablet by direct tabletting

Composition based on the standard dosage form:

piperazine urea hydrosulfate 100 mg lactose 10 mg cellulose acetate butyrate 171-15 PG 134 mg fumaric acid 50 mg fine silica 3 mg magnesium stearate 3 mg

Lactose, piperazine urea hydrosulfate and cellulose acetate butyrate 171-15 PG (cellulose acetate butyrate) are sieved separately and then mixed in a turbomachine for 10 minutes in this order. After this, sifted fumaric acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. Finally, the pressed powder mass is tabletted using an eccentric or rotary tablet press.

Example 9: Preparation of a matrix tablet by direct tabletting

Composition based on the standard dosage form:

piperazine urea hydrosulfate 100 mg lactose 94 mg hydroxypropyl methylcellulose K 15 M 50 mg fumaric acid 50 mg fine silica 3 mg magnesium stearate 3 mg

Lactose, piperazine urea hydrosulphate and K 15 M hydroxypropyl methylcellulose are sieved separately and then mixed in a turbomachine for 10 minutes in this order. After this, sifted fumaric acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. Finally, the pressed powder mass is tabletted using an eccentric or rotary tablet press.

Example 10: Preparation of a matrix tablet by direct tabletting

Composition based on the standard dosage form:

piperazine urea hydrosulfate 100 mg lactose 69 mg Kollidon SR® 75 mg glutaric acid 50 mg fine silica 3 mg magnesium stearate 3 mg

Lactose, piperazine urea hydrosulfate and Kollidon SR® are sieved separately and then mixed in a turbomixer for 10 minutes in this order. After this, sieved glutaric acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. Finally, the pressed powder mass is tabletted using an eccentric or rotary tablet press.

Example 11: Preparation of a matrix tablet by direct tabletting

Composition based on the standard dosage form:

piperazine urea hydrosulfate 100 mg lactose 69 mg Kollidon SR® 75 mg wine acid 50 mg fine silica 3 mg magnesium stearate 3 mg

Lactose, piperazine urea hydrosulfate and Kollidon SR® are sieved separately and then mixed in a turbomixer for 10 minutes in this order. After this, sifted tartaric acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. Finally, the pressed powder mass is tabletted using an eccentric or rotary tablet press.

Example 12: Preparation of a matrix tablet by direct tabletting

Composition based on the standard dosage form:

piperazine urea hydrosulfate 100 mg lactose 69 mg Kollidon SR® 75 mg adipic acid 50 mg fine silica 3 mg magnesium stearate 3 mg

Lactose, piperazine urea hydrosulfate and Kollidon SR® are sieved separately and then mixed in a turbomixer for 10 minutes in this order. After this, sifted adipic acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. Finally, the pressed powder mass is tabletted using an eccentric or rotary tablet press.

Example 13: Preparation of a matrix tablet by direct tabletting

Composition based on the standard dosage form:

piperazine urea hydrosulfate 100 mg lactose 69 mg Kollidon SR® 75 mg vitamin C 50 mg fine silica 3 mg magnesium stearate 3 mg

Lactose, piperazine urea hydrosulfate and Kollidon SR® are sieved separately and then mixed in a turbomixer for 10 minutes in this order. After this, sifted ascorbic acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. Finally, the pressed powder mass is tabletted using an eccentric or rotary tablet press.

Example 14: Preparation of a matrix tablet by direct tabletting followed by varnish coating

Composition based on the standard dosage form:

piperazine urea hydrosulfate 100 mg lactose 82.5 mg Kollidon SR® 60 mg fumaric acid 50 mg fine silica 3 mg magnesium stearate 4,5 mg hydroxypropyl methyl cellulose visc. 5 7.6 mg talc 1.5 mg titanium dioxide, E 171 5.9 mg yellow iron oxide dye, E 172 0.02 mg

Lactose, piperazine urea hydrosulfate and Kollidon SR® are sieved separately and then mixed in a turbomixer for 10 minutes in this order. After this, sifted fumaric acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. Finally, the pressed powder mass is tabletted using an eccentric or rotary tablet press (tablet core). Then, with stirring (for example, using an Ultra-Turrax mixer or a colloid mill), talc, yellow iron oxide dye and titanium dioxide (dye suspension) are suspended in water. Then, with stirring (for example, using an Ultra-Turrax type mixer or a colloid mill), hydroxypropyl methylcellulose (binder solution) is dissolved in water. Then, the dye suspension and the binder solution are combined (for example, using an Ultra-Turrax mixer or colloid mill) (varnish coating). The obtained lacquer coating is sprayed with heat in a drum machine for coating the core of tablets, while the water used evaporates.

Example 15: Preparation of a matrix tablet by direct tabletting followed by varnish coating

Composition based on the standard dosage form:

piperazine urea hydrosulfate 300 mg lactose 247.5 mg KollidonSR® 180 mg fumaric acid 150 mg fine silica 9 mg magnesium stearate 13.5 mg hydroxypropyl methyl cellulose visc. 5 10.1 mg talc 2 mg titanium dioxide, E 171 7.8 mg yellow iron oxide dye, E 172 0.03 mg

Lactose, piperazine urea hydrosulfate and Kollidon SR® are sieved separately and then mixed in a turbomixer for 10 minutes in this order. After this, sifted fumaric acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. Finally, the pressed powder mass is tabletted using an eccentric or rotary tablet press (tablet core). Then, with stirring (for example, using an Ultra-Turrax mixer or a colloid mill), talc, yellow iron oxide dye and titanium dioxide (dye suspension) are suspended in water. Then, with stirring (for example, using an Ultra-Turrax type mixer or a colloid mill), hydroxypropyl methylcellulose (binder solution) is dissolved in water. Then, the dye suspension and the binder solution are combined (for example, using an Ultra-Turrax mixer or colloid mill) (varnish coating). The obtained lacquer coating is sprayed with heat in a drum machine for coating the core of tablets, while the water used evaporates.

Example 16: Preparation of Mini-Tablets by Direct Tableting

Composition based on the standard dosage form:

piperazine urea hydrosulfate 10 mg lactose 6.9 mg Kollidon SR® 7.5 mg fumaric acid 5 mg fine silica 0.3 mg magnesium stearate 0.3 mg

Lactose, piperazine urea hydrosulfate and Kollidon SR® are sieved separately and then mixed in a turbomixer for 10 minutes in this order. After this, sifted fumaric acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. After that, the pressed powder mass is tabletted using an eccentric or rotary tablet press to produce mini-tablets. Finally, the resulting mini-tablets are packaged in hard gelatin capsules.

Example 17: Preparation of mini-tablets followed by lacquering

Composition based on the standard dosage form:

piperazine urea hydrosulfate 10 mg lactose 8.25 mg Kollidon SR® 6 mg fumaric acid 5 mg fine silica 0.3 mg magnesium stearate 0.45 mg hydroxypropyl methyl cellulose visc. 5 0.76 mg talc 0.15 mg titanium dioxide, E 171 0.59 mg yellow iron oxide dye, E 172 0.002 mg

Lactose, piperazine urea hydrosulfate and Kollidon SR® are sieved separately and then mixed in a turbomixer for 10 minutes in this order. After this, sifted fumaric acid is added and all components are mixed in a turbo mixer over the next 5 minutes. Next, sieved fine silica is added and all components are mixed in a turbo mixer over the next 5 minutes. The sieved magnesium stearate is then sprayed onto the mixture and all components are mixed in a turbo mixer for the next 30 s. Finally, the pressed powder mass is tabletted using an eccentric or rotary tablet press (tablet core). Then, with stirring (for example, using an Ultra-Turrax mixer or a colloid mill), talc, yellow iron oxide dye and titanium dioxide (dye suspension) are suspended in water. Then, with stirring (for example, using an Ultra-Turrax type mixer or a colloid mill), hydroxypropyl methylcellulose (binder solution) is dissolved in water. Then, the dye suspension and the binder solution are combined (for example, using an Ultra-Turrax mixer or colloid mill) (varnish coating). The obtained lacquer coating is sprayed with heat in a drum machine for coating the core of tablets, while the water used evaporates. Finally, the resulting mini-tablets are packaged in hard gelatin capsules.

Example 18: Preparation of a matrix tablet after granulation

Composition based on the standard dosage form:

piperazine urea hydrosulfate 100 mg lactose 72 mg Kollidon SR® 75 mg fumaric acid 50 mg magnesium stearate 3 mg

Lactose, piperazine urea hydrosulfate, Kollidon SR® and fumaric acid are placed in a fluidized bed granulator and granulated when sprayed with water. Magnesium stearate is sprayed onto the dried granulate and mixed in a turbo mixer for 30 s. Finally, the granules are pelletized using an eccentric or rotary tablet press.

Example 19: Obtaining mini-tablets after granulation

Composition based on the standard dosage form:

piperazine urea hydrosulfate 10 mg lactose 7.2 mg Kollidon SR® 7.5 mg fumaric acid 5 mg magnesium stearate 0.3 mg

Lactose, piperazine urea hydrosulfate, Kollidon SR® and fumaric acid are placed in a fluidized bed granulator and granulated when sprayed with water. Magnesium stearate is sprayed onto the dried granulate and mixed in a turbo mixer for 30 s. Then the granulate is pelletized using an eccentric or rotary tablet press to produce mini-tablets. At the end of the mini-tablets are packaged in hard gelatin capsules.

Example 20: Obtaining spherical granules (pellets) by extrusion and spheroidization

Composition per capsule:

piperazine urea hydrosulfate 60 mg microcrystalline cellulose 30 mg fumaric acid 10 mg Eudragit® NE 30 D 25.5 mg talc 4.25 mg fine anhydrous silica 0.18 mg

Piperazinourea hydrosulfate, microcrystalline cellulose and fumaric acid are processed using a Nica granulation system to produce spherical granules. According to this technology, piperazine urea hydrosulfate, microcrystalline cellulose and fumaric acid are first mixed in a dry state, after which this powder mixture is extruded with the addition of water. Using a spheroidizer, spherical granules are obtained by appropriate processing of the extrudate. Then, an aqueous suspension consisting of Eudragit® NE 30 D and talc is sprayed on the obtained granules using a fluidized bed granulator equipped with the corresponding Wurster nozzle. Finally, the varnished coated spherical granules are packaged by adding silica to hard gelatine capsules.

Example 21: Analysis of the release of piperazinourea hydrosulfate

The release of the active substance was analyzed, carried out according to the method based on a single-compartment model (using an apparatus with a paddle mixer), described in USP XXIV. The release of piperazine urea hydrosulfate was investigated at pH 1 (0.1 N hydrochloric acid) and in phosphate buffered saline at pH 4.5 and 6.8 (see USP XXIV for composition). To regulate the conditions of deposition, which provide the possibility of primary control of the release of piperazinourea hydrosulfate due to the proposed composition, if necessary, a surfactant (for example, SDS) or hydroxypropyl-β-cyclodextrin can be added to the release medium.

Example 22: Determination of particle size

фумаровой кислоты, микрокристаллической целлюлозы или указанных в примерах 1-9 порошковых смесей определяли с помощью лазерной дифрактометрии (R.H.Müller, R.Schuhmann, TeilchengröBenmessung in der Laborpraxis, изд-во Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1996). В качестве измеряемых параметров дополнительно использовали объемное распределение частиц по крупности.The particle size of the piperazine urea hydrosulfate, lactose, Kollidon product

fumaric acid, microcrystalline cellulose, or the powder mixtures indicated in Examples 1-9 were determined by laser diffractometry (RHMüller, R. Schuhmann, Teilchengrö Benmessung in der Laborpraxis, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1996). As measured parameters, we additionally used the volume distribution of particles by size.

Claims (22)

1. A solid drug composition providing a pH independent release of the active substance, including (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or one of its salts, a polymer matrix, a pharmaceutically acceptable organic acid, a lubricating additive and one or more excipients, with 90% of the particles in powder mixtures ranging from 0.1 to 750 microns. 2. The solid drug composition according to claim 1, wherein the polymer matrix is selected from the group consisting of cellulose derivatives, acrylic derivatives, vinyl polymers, polyanhydrides, polyesters, polyorthoesters, polyurethanes, polycarbonates, polyphosphazenes, polyacetals, polysaccharides, sugar esters, diethylene glycol monoethyl esters, diethylene glycol monopalmitostearate, ethylene glycol monopalmitostearate, glycerol behenates and glycerol dibegenates, glycerol distearates and glycerol palmitostearates, glycerol monooleate and 40, glycerol monostearate 40-55, macrogolglycerol laurates, macrogolglycerol stearates, propylene glycol monopalmitostearate, chitosan, galactomannan, pectin, shellac and alginates. 3. The solid drug composition according to claim 1, wherein the polymer matrix is a mixture of water-soluble polyvinylpyrrolidone and water-insoluble polyvinyl acetate. 4. The solid drug composition according to claim 1, wherein the polymer matrix has the following composition: 80% polyvinyl acetate, 19% polyvinylpyrrolidone, 0.8% sodium lauryl sulfate, and 0.2% silicon dioxide. 5. The solid drug composition according to claim 1, wherein the organic acid is selected from the group consisting of fumaric acid, citric acid, trisodium citrate, Na-hydrocytrate, ascorbic acid, maleic acid, maleic anhydride, tartaric acid, adipic acid, Na- hydrogen phosphate, succinic acid, glutaric acid, glutaric anhydride, potassium sorbate and sorbic acid. 6. The solid drug composition according to claim 1, wherein the excipient is lactose, calcium diphosphate, mannitol or starch. 7. The solid drug composition according to claim 1, wherein it contains microcrystalline cellulose as an additional auxiliary substance. 8. The solid drug composition according to claim 1, wherein it further comprises a flow regulator. 9. The solid drug composition according to claim 1, wherein 90% of the particles in the powder mixtures have a size of from 20 to 400 microns. 10. The solid drug composition according to claim 1, wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine is distributed or the salt is homogeneously distributed in the matrix. 11. The solid drug composition according to one of claims 1 to 10, wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine is enclosed or its salt is enclosed in a matrix. 12. The method of obtaining a solid drug composition according to one of claims 1 to 11, which consists in the fact that (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-Fluorobenzyl) piperazine or one of its salts is mixed with one or more excipients, a polymer matrix, an organic acid and a lubricating additive and then the mixture is tableted, while all substances are presented in powder form and are classified either separately or after mixing offsets together. 13. The method of obtaining a solid drug composition according to one of claims 1 to 11, which consists in the fact that (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-Fluorobenzyl) piperazine or one of its salts is mixed with one or more excipients, a polymer matrix and an organic acid and then granulated, after which a lubricant is added and the mixture is finally tabletted. 14. The method of obtaining a solid drug composition according to one of claims 1 to 11, which consists in the fact that (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-Fluorobenzyl) piperazine or one of its salts, a polymer matrix, organic acid and auxiliary substances are processed by extrusion and subsequent spheroidization to obtain spherical granules. 15. The method of obtaining in a crushed (powder) form of a solid drug composition according to one of claims 1 to 11, which consists in the fact that (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl- 2-Methyl-4- (4-fluorobenzyl) piperazine or one of its salts, a polymer matrix, organic acid and excipients are mixed together and processed using a binder solution or molten additives to obtain spherical granules. 16. The method of obtaining in a crushed (powder) form of a solid drug composition according to one of claims 1 to 11, which consists in the fact that (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl- 2-methyl-4- (4-fluorobenzyl) piperazine or one of its salts, a polymer matrix, organic acid and excipients are spray dried or spray cured to produce spherical granules. 17. The method of obtaining in a crushed (powder) form of a solid drug composition according to one of claims 1 to 11, which consists in the fact that (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl- 2-methyl-4- (4-fluorobenzyl) piperazine or one of its salts, a polymer matrix, organic acid and excipients are subjected to rotary granulation to obtain spherical granules. 18. The method of obtaining a solid drug composition according to one of claims 1 to 11, which consists in the fact that the polymer matrix, organic acid and auxiliary substances are applied in layers to (2R) -1 - ((4-chloro-2- (ureido) phenoxy ) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or its salt to obtain spherical granules in this way. 19. The use of a solid medicinal composition according to one of claims 1 to 11 to obtain a medication intended for the treatment of inflammatory diseases. 20. The use according to claim 19, wherein the inflammatory disease is multiple sclerosis. 21. The use of claim 19, wherein the inflammatory disease is rheumatoid arthritis. 22. The use of claim 19, wherein the inflammatory disease is atopic dermatitis.

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