HRP20040435A2 - Solid pharmaceutical formulation for a piperazineurea derivative - Google Patents

Description

This invention relates to a solid pharmaceutical formulation of a reagent containing (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine or a salt thereof.

WO 98/56771 describes benzylpiperazine urea substances and in particular (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine and its salts. These substances are CCR-1 receptor antagonists and are used in the treatment of inflammatory diseases, such as multiple sclerosis and rheumatoid arthritis. They are also used in the treatment of psoriasis and atopic dermatitis. They are poorly soluble at basic pH values. At pH 1, about 5 mg/ml is dissolved from (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine hydrogen sulfate, while at pH values of 6.35 or 6.8, only about 0.15 mg/ml or 0.1 mg/ml is dissolved in each individual case. Thanks to such poor solubility in the intestinal tract, the therapeutically necessary uniform levels in the plasma cannot be reached, with the fact that in the case of using a conventional oral formulation, significant side effects are avoided. Furthermore, it would be convenient in connection with the increase of solubility in the intestinal tract, that the release of the active ingredient is carried out in a controlled manner over a prolonged period, therefore to achieve that the dosing intervals can be significantly extended. At the same time, however, industrial production of the drug should also be possible.

Various methods of increasing the absorption of poorly soluble active ingredients are described in the literature (for example in "Techniques of Solubilization of Drugs" (Techniques of increasing the solubility of drugs) S. H. Ialkowski Ed. in "Drugs and the Pharmaceutical Sciences" (Drugs and pharmaceutical science)). It is particularly recommended to use substances that increase solubility, such as surfactants in the case of very poorly soluble substances (WO01/05376). Unfortunately, this method is only partially satisfactory in solving the said problem. Addition of the surfactant SDS to (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine hydrogen sulfate resulted in a slight increase in release (see Figure 2 ).

Other publications deal with the problem of pH-independent release. Streubel et al. (2000, J Controlled Release 67, 101-110) describes the addition of acids to a pharmaceutical substance. The described pharmaceutical substance dissolves very well, but even without the addition of acids at pH 6.35 (more than 100 mg/ml). The goal set in this paper by Streubel et al. was the equalization of fluctuations that depended on pH. This was achieved by adding acids. In the context of this invention, the problem that arises is equalizing not only the fluctuations caused by pH, but also the increase in solubility. The properties of the pharmaceutical substances described by Streubel are significantly different from those of the active ingredient (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine . Furthermore, the formulation is only used for individual tablet production and not for bulk production. Therefore, it was uncertain whether this method could be used to propose a solution to the problem considered in the context of this invention.

This invention solves the problem of increasing solubility and pH-dependent release, as well as the simultaneous industrial production of a solid pharmaceutical formulation of a reagent containing (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2 -methyl-4-(4-fluorobenzyl)piperazine or its salt, with the fact that the pharmaceutical formulation of the reagent additionally contains a polymer matrix, an organic acid and one or more adjuvants for the directed control of the release of the pharmaceutical substance that is dependent on the pH (release modification) for adjustment mechanical strength of dosage forms, and with the fact that the particle sizes in powder mixtures are in 90% of cases between 0.1 and 750 μm.

(2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine is further referred to as piperazine urea and has the following structure:

[image]

Preparation of (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine and its salts is performed according to the method described in WO98 /56771, Example 2.

Its salts are, for example, hydrochloride, dihydrogen phosphate, hydrogen sulfate, sulfate, mesylate, ethyl sulfonate, malate, fumarate, and tartrate.

Solid formulations of pharmaceutical reagents in the context of consideration of this invention are systems consisting of a single unit such as tablets, as well as multiparticulate systems. Multiparticulate systems can be, for example, granular grains, balls or mini-tablets. The contents can be filled into hard or soft gelatin capsules and can be compressed into tablets. In most cases, the originally formed unit dissolves in the stomach into many sub-units. Such mini-depots are then successively poured from the stomach into the intestinal tract. In this case, mini-depots can generally pass into the pylorus if the sphincter is closed.

The polymer matrix can be selected from the group consisting of cellulose derivatives, such as methyl cellulose, hydroxypropyl methyl cellulose, (eg hydroxypropyl methyl cellulose K 4 M, hydroxypropyl methyl cellulose K 15 M), hydroxypropyl cellulose, hydroxyethyl cellulose, sodium -carboxy methyl cellulose, ethyl cellulose (eg, ethyl cellulose 100), cellulose acetate (eg, cellulose acetate CA-398-10 NF), cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate butyrate (eg, cellulose acetate butyrate 171-15 PG), cellulose butyrate, cellulose nitrate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate]; acrylic derivatives [e.g., polyacrylates, cross-linked polyacrylates (e.g., polymethacrylates, polyethylacrylates, ethyl acrylates of polymethyl acid, methyl methacrylates of polymethyl acid, polymethylacrylate trimethylammonium ethyl methacrylate chlorides, polyethylacrylate trimethylammonium ethyl methacrylate chlorides, dimethylaminoethyl methacrylate methacrylate copolymers, Carbopol® 971 P, Carbopol® 974 P, Carbopol® 71 G)], vinyl polymers (eg, polyvinyl pyrrolidones, polyvinyl acetates, polyvinyl acetate phthalates), polyethylene glycols, polyanhydrides, polyester polyorthoesters, polyurethanes, polycarbonates, polyphosphazenes, polyacetals, polysaccharides (eg, xanthans, xanthan gum), sugar esters (eg, sucrose stearate, sucrose palmitate, sucrose laurate, sucrose behenate, sucrose oleate, sucrose erucate, and sucrose mixed fatty acid ester), diethylene glycol monoethyl ethers (eg, Transcutol(R ) P), diethylene glycol monopalmitostearate (eg, Hidrine(R)), ethylene glycol monopalmitostearate (eg, Montile(R)), glycerol behenates and glycerol dibehenates (eg, Compritol(R) 888 ATO, Compritol(R) HD 5 ATO and Compritol(R) E), glycerol distearates, glycerol dipalmitostearates and glycerol palmitostearates (eg, Precirol(R) ATO 5 and Precirol (R) WL 2155), glycerol monooleate 40 (eg, Peceol(R)), glycerol monostearate 40-55 (eg, Geleol(R)), macrogolglycerol laurates (eg, Gelucire(R) 44/ 14 and Labrafil(R) M 2130 CS), macrogolglycerol stearates (eg, Gelucire(R) 50/13), propylene glycol monopalmitostearate (eg, Monosteol(R)), chitosan, galactomannan, pectin, shellac and alginates . The physical mixture that will serve as a polymer matrix is of particularly suitable properties, consisting of polyvinyl acetate, which is not soluble in water, and polyvinyl pyrrolidone, which is soluble in water. This mixture, which additionally contains sodium lauryl sulfate and silicon dioxide, is sold for example under the name Kollidon SR(R) (Kollidon SR, Technical characteristics, ME 397e, BASF, July 2000: 80% polyvinyl acetate, 19% polyvinyl pyrrolidone, 0.8% sodium lauryl sulfate and 0.2% silicon dioxide).

The organic acid is selected from the group consisting of fumaric acid, citric acid, trisodium citrate, Na-hydrogen citrate, ascorbic acid, maleic acid, maleic anhydride, tartaric acid, adipic acid, Na-hydrogen phosphate, succinic acid, glutaric acid , glutaric anhydride, potassium sorbate and sorbic acid. Fumaric acid is preferred.

For targeted control of the release of a pharmaceutical substance that is independent of the pH value, and for influencing the mechanical strength of the dosage form, water-soluble or other water-insoluble adjuvants can be used, such as lactose, calcium diphosphates, mannitol, sorbitol , sucrose, fructose, glucose, starch or its derivatives. Mixtures consisting of one or more adjuvants can also be used. Lactose is preferred. Granular lactose is particularly suitable.

As an additional adjuvant for targeted control of the release of pharmaceutical substances independent of pH values (modified release) as well as for influencing the mechanical strength of the dosage form, cellulose or cellulose dervates can be used. Microcrystalline cellulose is particularly preferred. The content is released into the water environment, which results in an improved release of piperazine urea and its salts, regardless of the pH value.

Furthermore, lubricants can be added to single doses such as tablets for the purpose of reducing the interparticulate fraction and reducing slippage between the material and the matrix wall. Lubricants are substances that, due to their lamellar structure, have layers that can slide against each other. Pharmaceutically useful organic substances are, for example, divalent metal soaps, higher fatty alcohols and polyethylene glycols of higher molecular weights. Magnesium and calcium salts of higher fatty acids are especially preferred.

In the case of single dosage forms, a flow control reagent may be added to improve the flow properties of the material from which the tablets are formed. This will result in the material from which the tablets are obtained filling the matrix uniformly, implying sufficient packing density. Addition of reagents for flow regulation may be necessary in the case of immediate tableting. Substances with a simple effect on flow regulation are mainly highly dispersed silicic acids, such as micronized silica gels and pyrolytically obtained silicic acids. Starches and talc are substances that can be used as reagents for flow regulation, as decomposition adjuvants or as lubricants.

In the case of single dosage forms, it is important for industrial production that the material of the tablet has granulate properties and good flowability, high density and a defined particle size distribution. The particle size of the tableting material will depend in this case on the size of the tablets that are planned to be produced, and generally varies between 0.1-750 μm. In the material for tableting, it is important to achieve a uniform distribution of particles according to size in order to prevent separation (e.g., during the vibration of the tableting apparatus) and in this way also to prevent the accumulation of larger particles in the upper layer of the material, since otherwise there may be a larger fluctuations in dose. Defined particle size and defined distribution of particles according to size is achieved by a kind of classification (eg, wet or dry classification) or by means of granulation of starting substances. The particle size can be measured using the process described in Example 5. The particle size should be between 0.1-750 μm in 90% of cases. A size range of 20-400 μm is preferred.

Piperazine urea or its salts can be homogeneously dispersed in the matrix or surrounded by the matrix. The active forms of the ingredient can form a core surrounded by a matrix shell.

A solid formulation of a pharmaceutical reagent in the context of the present invention may also be coated with a dye to improve optical or taste conditions. The material generally consists of binders such as hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyethylene glycol; lubricants (eg talc) and pigments (eg iron oxide pigment, titanium dioxide).

A solid pharmaceutical reagent formulation preferably comprises (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine or a salt thereof, lactose, Kollidon SR(R), silicon dioxide and magnesium stearate, with the fact that about 90% of the particles are 0.1-750 μm in size. The use of hydrogen sulfate as a salt is particularly preferred. A tablet with this formulation shows 60% release of piperazine urea after 6 hours.

Another form of solid formulation of the pharmaceutical reagent preferably contains (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine or a salt thereof, microcrystalline cellulose, lactose, Kollidon SR(R), silicon dioxide and magnesium stearate, with the fact that about 90% of the particles are 0.1-750 μm in size. The use of hydrogen sulfate as a salt is particularly preferred. A tablet with this formulation shows 80-90% release of piperazine urea after 4 hours.

Another form of solid formulation of the pharmaceutical reagent preferably contains (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine or a salt thereof, lactose, Kollidon SR(R), silicon dioxide and magnesium stearate, with the fact that about 90% of the particles are 0.1-750 μm in size, and the tablet is then coated with paint consisting of hydroxypropyl methyl cellulose, talc, titanium oxide and iron oxide pigment. A tablet with this formulation shows 60% release of piperazine urea after 6 hours.

The pharmaceutical reagent formulation in accordance with the context of consideration of this invention is characterized by significantly increased solubility and release of piperazine urea and its salts. Since in this case the conventional formulation containing (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine or its salt, lactose, corn starch, polyvinyl pyrrolidone, croscarmellose sodium and magnesium stearate, shows only about 10% release after 8-10 hours at pH 6.8, the release rate is increased to about 60-90% using the formulation considered in the context of this invention. The advantage of formulating a pharmaceutical reagent in accordance with the context of the present invention is also demonstrated through clinical trials. Compared with the conventional oral formulation, plasma levels of (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine in subjects treated , are increased during prolonged application of the formulation according to the present invention (see Illustration 11).

The formulation according to this invention has all the properties that are necessary for industrial production, such as good flow properties, high density, the possibility of dosing accuracy, high plastic deformability and the small compressibility associated with it, as well as high mechanical strength of tablets. which are produced.

The subject of consideration of this invention is also a process for obtaining solid formulations of a pharmaceutical reagent in accordance with the context of consideration of this invention, with the fact that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2 -methyl-4-(4-fluorobenzyl)piperazine or its salt is mixed with a polymer matrix, organic acid, lubricant and adjuvant, after which it is brought into tablet form (direct tableting). The direct production of tablets is performed in this case basically by mixing the powder components, dosing through the tablet filling apparatus, and compression of the mixed powder. In the case of immediate tableting, particle size and particle size distribution of the piperazine urea used as well as its salts, polymer matrix, organic acid and adjuvants have a significant impact on the process of industrial tablet production. The material can therefore be classified separately before mixing the powder components. Alternatively, the entire quantity of the powder mixture or the individual components of the powder mixture may be jointly classified. The powder components are weighed, as indicated in the Examples, and then mixed for a sufficiently long period in a gravity mixer (eg, turbulent mixer, V-mixer) or circulation mixer. Of particular note is that the flow control reagent and lubricant (both together are also referred to as the FST complex) are added only a short time before the tableting apparatus is filled. In this case, the FST complex should finally be incorporated into the previously mixed tablet material, and additionally mixed as stated above, with the fact that the mixing time should be adjusted so that it is not too short (inhomogeneous distribution), nor too long ( excessive mixing of materials).

Furthermore, the invention relates to a process for obtaining solid formulations of a pharmaceutical reagent in accordance with the context of consideration of this invention, with (2R)-1-((4-chloro-2-(ureido)phenoxy)-methyl)carbonyl-2-methyl -4-(4-Fluorobenzyl)piperazine or its salt, polymer matrix, organic acid and adjuvant are subjected to a granulation operation before mixing and tableting. After granulation and addition of lubricant, the material is tableted as described above. Granulation can be carried out in this case by step-by-step increase or agglomeration of the primary particles of the powder mixture, up to the desired secondary size (construction granulation) or by dividing the powder material from which the paste is made to the desired size of granulated particles (decomposing granulation). Structural granulation includes, for example, circular granulation and fluidized granulation. Decomposing granulation can be performed by, for example, compacting the starting substances and immediately afterwards mechanically separating and fitting the compressed material. In this case, decomposing and building granulation can be performed in wet conditions (eg adhesive or surface granulates) or in dry conditions (eg briquettes or melt-solidification granulates).

The next object of consideration of this invention is the process of obtaining a solid formulation of a multiparticulate pharmaceutical reagent in accordance with this invention, with the fact that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl- 4-(4-Fluorobenzyl)piperazine or its salt, polymer matrix, organic acid and adjuvant (preferably cellulose, cellulose derivatives and lactose) processed into balls by extrusion and spherization will follow immediately.

The next object of consideration of this invention is the process of obtaining a solid formulation of a multiparticulate pharmaceutical reagent in accordance with this invention, with the fact that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl- 4-(4-Fluorobenzyl)piperazine or its salt, polymer matrix, organic acid and adjuvant (preferably cellulose, cellulose derivatives and lactose) processed into balls by extrusion and spherization will follow immediately.

Balls containing the active ingredient are then wrapped in a polymer matrix (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac). Under certain conditions, the beads containing the active ingredient can be coated with a ddate coating (preferably cellulose derivatives and vinyl polymers) before the polymer matrix is applied. The purpose of such a coating is to inhibit incompatibility between (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine or its salt and the polymer matrix, or on the other hand, 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 the beads.

The next object of consideration of this invention is the process of obtaining a solid formulation of a multiparticulate pharmaceutical reagent in accordance with this invention, with the fact that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl- 4-(4-Fluorobenzyl)piperazine or its salt and adjuvants (preferably cellulose, cellulose derivatives and lactose) processed into balls by extrusion and immediately followed by spherization. Balls containing the active ingredient are then coated with an organic acid and a polymer matrix (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac). Under certain conditions, the beads containing the active ingredient can be coated with an additional coating (preferably cellulose derivatives and vinyl polymers) before the polymer matrix is applied.

The next object of consideration of this invention is the process of obtaining a solid formulation of a multiparticulate pharmaceutical reagent in accordance with this invention, with the fact that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl- 4-(4-Fluorobenzyl)piperazine or its salt, polymer matrix, organic acid and adjuvants processed into balls in an immediate way. In this case, the starting substances are mixed and processed into balls by using a solution of the binding component (wet granulation) or with the help of melted additives (eg fat).

The next object of consideration of this invention is the process of obtaining a solid formulation of a multiparticulate pharmaceutical reagent in accordance with this invention, with the fact that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl- 4-(4-Fluorobenzyl)piperazine or its salt, polymer matrix, organic acid and adjuvants processed into balls by means of spray drying or spray hardening.

The next object of consideration of this invention is the process of obtaining a solid formulation of a multiparticulate pharmaceutical reagent in accordance with this invention, with the fact that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl- 4-(4-Fluorobenzyl)piperazine or its salt, polymer matrix, organic acid and adjuvants processed into balls using rotary granulation.

The invention also relates to a process for obtaining a solid formulation of a pharmaceutical reagent in accordance with the context of consideration of this invention, with the fact that the polymer matrix, organic acid and adjuvant are processed into beads in the manner of layered application on (2R)-1-((4-chloro- 2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine or a salt thereof (layering).

The invention also relates to a process for obtaining a solid formulation of a pharmaceutical reagent in accordance with the context of consideration of this invention, provided that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4 -(4-fluorobenzyl)piperazine or its salt, polymer matrix, organic acid and adjuvant are processed into balls by layered application on the core, which is freed from the content of the active substance. In this process, (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine or a salt thereof generally taken, is first applied to said core . Then organic acid is applied. At the end of the procedure, the balls are coated with a polymer matrix (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac). Under certain conditions, the beads containing the active ingredient can be coated with an additional coating (preferably cellulose derivatives and vinyl polymers) before the polymer matrix is applied.

This invention also relates to the process of filling balls formed into capsules, which are used in pharmaceuticals (preferably gelatin capsules, starch capsules or capsules with cellulose derivatives) or to pressing the balls into a tablet. Filling the beads in capsules or processing the beads into tablets can optionally be performed with the addition of other adjuvants (preferably cellulose, cellulose derivatives, lactose, lubricants and reagents for flow regulation).

The subject of consideration of this invention is also the process of obtaining a solid formulation of a pharmaceutical reagent in accordance with the context of consideration of this invention, with the fact that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl -4-(4-Fluorobenzyl)piperazine or its salt is mixed with a polymer matrix, organic acid, lubricant and adjuvant and then processed by direct tableting into minitablets (preferred tablet diameter is 1-5 mm).

Furthermore, this invention relates to a process for obtaining a solid formulation of a pharmaceutical reagent in accordance with the context of consideration of this invention, with (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl -4-(4-Fluorobenzyl)piperazine or its salt, polymer matrix, organic acid and adjuvant undergo a granulation operation before mixing and tableting. After granulation and addition of lubricant, the starting substances are processed into minitablets (the preferred diameter of the tablets is 1-5 mm).

Furthermore, this invention relates to the process of filling minitablets which are formed into capsules used for pharmaceutical purposes (preferably gelatin capsules, starch capsules or capsules from cellulose derivatives). Filling of minitablets can optionally be performed by adding other adjuvants (preferably cellulose, cellulose derivatives, lactose).

The object of consideration of this invention is also the use of solid formulations of a pharmaceutical reagent in accordance with the context of consideration of this invention, for the purpose of producing drugs for the treatment of inflammatory diseases. An inflammatory disease can be, for example, multiple sclerosis, rheumatoid arthritis, psoriasis or atopic dermatitis. The treatment of a patient suffering from an inflammatory disease is preferably carried out through the application of one tablet per day.

Description Illustration

Illustration 1 describes the solubility of piperazine urea-hydrogen sulfate, which is dependent on the value of pH.

Illustration 2 shows the effects of adding SDS (sodium dodecyl sulfate) on the release of piperazine urea-hydrogen sulfate in phosphate buffer solution, pH 6.8 (33% piperazine urea-hydrogen sulfate and 25% Kollidon SR(R), relative value to total tablet weight ).

Illustration 3 shows the effect of fumaric acid (%, relative value in relation to the total tablet weight) on the release of piperazine urea-hydrogen sulfate in phosphate buffer solution, pH 6.8 (33% piperazine urea-hydrogen sulfate and 25% Kollidon SR(R), relative value in relation to the total weight of the tablet).

Illustration 4 shows the effect of adding different concentrations of fumaric acid (%, relative value in relation to the total tablet weight) on the release of piperazine urea-hydrogen sulfate in phosphate buffer solution, pH 6.8 (33% piperazine urea-hydrogen sulfate and 25% Kollidon SR(R ), relative value in relation to the total weight of the tablet).

Illustration 5 shows the effect of pH value on the release of piperazine urea-hydrogen sulfate in phosphate buffer solution, pH 6.8 (33% piperazine urea-hydrogen sulfate and 25% Kollidon SR(R) and 16% fumaric acid, relative value in relation to the total weight of the tablet ).

Illustration 6 shows the effect of pH value on the release of piperazine urea-hydrogen sulfate in phosphate buffer solution, pH 6.8 (33% piperazine urea-hydrogen sulfate and 12.5% Kollidon SR(R) and 16% fumaric acid, relative value in relation to the total weight of the tablet ).

Illustration 7 shows the effect of pH value on the release of piperazine urea-hydrogen sulfate (33% piperazine urea-hydrogen sulfate and 12.5% Kollidon SR(R) and 16% fumaric acid and 10% microcrystalline cellulose, relative value in relation to the total weight of the tablet).

Illustration 8 shows the particle size distribution, as determined by laser diffractometry, of a typical powder substance used for tableting.

Illustration 9 shows the effect of adding different polymer matrices (Examples 3-9) on the release of piperazine urea-hydrogen sulfate in phosphate buffer solution, pH 6.8.

Illustration 10 shows the effect of addition of various organic acids (Examples 10-13) on the release of piperazine urea-hydrogen sulfate in phosphate buffer solution, pH 6.8.

Illustration 11 semilogarithmically shows the effect of the formulation of the pharmaceutical substance on the in-vivo levels in the plasma in humans after the application of 100 mg of piperazine urea-hydrogen sulfate in the form of a conventional oral formulation, as well as after the application of the formulations mentioned in Example 1 (tablet matrix C) and 2 (tablet E matrix).

Examples

Example 1

Production of tablet matrix by direct tableting method

Composition of the basic unit:

100 mg of piperazine urea-hydrogen sulfate

69 mg of lactose

75 mg Kollidon SR(R)

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

3 mg of magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Kollidon SR(R) are individually sieved and mixed into the above mixture in a vortex for 10 minutes. Sifted fumaric acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Then highly dispersed sieved silicon dioxide is added, after which all components are mixed in a vortex for the next 5 minutes. Sifted magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. Tableting of the powdery substance is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet.

Example 2

Production of tablet matrix by direct tableting method

Composition of the basic unit:

100 mg of piperazine urea-hydrogen sulfate

39 mg of lactose

75 mg Kollidon SR(R)

50 mg fumaric acid

30 mg microcrystalline cellulose

3 mg of highly dispersed silicon dioxide

3 mg of magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Kollidon SR(R) and microcrystalline cellulose are individually sieved and mixed into the above mixture in a vortex for 10 minutes. Sifted fumaric acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Sifted highly dispersed silicon dioxide is then added, after which all components are mixed in a vortex for the next 5 minutes. The sieved magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. Tableting of the powdery substance is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet.

Example 3

Production of tablet matrix by direct tableting method

Composition of the basic unit:

100 mg of piperazine urea-hydrogen sulfate

104 mg of lactose

40 mg Precirol® ATO 5

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

3 mg of magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Precirol® ATO 5 (glycerol dipalmitostearate) are individually sieved and mixed into the above-mentioned mixture in a vortex for 10 minutes. Sifted fumaric acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Sifted highly dispersed silicon dioxide is then added, after which all components are mixed in a vortex for the next 5 minutes. The sieved magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. Tableting of the powdery substance is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet.

Example 4

Production of tablet matrix by direct tableting method

Composition of the basic unit:

100 mg of piperazine urea-hydrogen sulfate

104 mg of lactose

40 mg Compritol® 888 ATO

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

3 mg of magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Compritol® 888 ATO (glycerol dibehenate) are individually sieved and mixed into the above mixture in a vortex for 10 minutes. Sifted fumaric acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Sifted highly dispersed silicon dioxide is then added, after which all components are mixed in a vortex for the next 5 minutes. The sieved magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. Tableting of the powdery substance is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet.

Example 5

Production of tablet matrix by direct tableting method

Composition of the basic unit:

100 mg of piperazine urea-hydrogen sulfate

69 mg of lactose

40 mg Carbopol® 71 G

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

3 mg of magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Carbopol® 71 G (cross-linked polyacrylate) are individually sieved and mixed into the above-mentioned mixture in a vortex for 10 minutes. Sifted fumaric acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Sifted highly dispersed silicon dioxide is then added, after which all components are mixed in a vortex for the next 5 minutes. The sieved magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. Tableting of the powdery substance is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet.

Example 6

Production of tablet matrix by direct tableting method

Composition of the basic unit:

100 mg of piperazine urea-hydrogen sulfate

69 mg of lactose

40 mg KSantural® 75

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

3 mg of magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and KSantural® 75 (xanthan gum) are individually sieved and mixed into the above mixture in a vortex for 10 minutes. Sifted fumaric acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Sifted highly dispersed silicon dioxide is then added, after which all components are mixed in a vortex for the next 5 minutes. The sieved magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. Tableting of the powdery substance is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet.

Example 7

Production of tablet matrix by direct tableting method

Composition of the basic unit:

100 mg of piperazine urea-hydrogen sulfate

84 mg of lactose

60 g of ethyl cellulose 100

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

3 mg of magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and ethyl cellulose 100 are individually sieved and mixed into the above-mentioned mixture in a vortex for 10 minutes. Sifted fumaric acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Sifted highly dispersed silicon dioxide is then added, after which all components are mixed in a vortex for the next 5 minutes. The sieved magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. Tableting of the powdery substance is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet.

Example 8

Production of tablet matrix by direct tableting method

Composition of the basic unit:

100 mg of piperazine urea-hydrogen sulfate

10 mg of lactose

134 mg cellulose acetate butyrate 171-15 PG

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

3 mg of magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and cellulose acetate butyrate 171-15 PG (cellulose acetate butyrate) are individually sieved and mixed into the above-mentioned mixture in a vortex for 10 minutes. Sifted fumaric acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Sifted highly dispersed silicon dioxide is then added, after which all components are mixed in a vortex for the next 5 minutes. The sieved magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. Tableting of the powdery substance is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet.

Example 9

Production of tablet matrix by direct tableting method

Composition of the basic unit:

100 mg of piperazine urea-hydrogen sulfate

94 mg of lactose

50 mg of hydroxypropyl methyl cellulose K 15 M

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

3 mg of magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and hydroxypropyl methyl cellulose K 15 M are individually sieved and mixed into the above-mentioned mixture in a vortex for 10 minutes. Sifted fumaric acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Sifted highly dispersed silicon dioxide is then added, after which all components are mixed in a vortex for the next 5 minutes. The powdered magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. Tableting of the powdery substance is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet.

Example 10

Production of tablet matrix by direct tableting method

Composition of the basic unit:

100 mg of piperazine urea-hydrogen sulfate

69 mg of lactose

75 mg Kollidon SR®

50 mg glutaric acid

3 mg of highly dispersed silicon dioxide

3 mg of magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Kollidon SR® are individually sieved and mixed into the above mixture in a vortex for 10 minutes. The sieved glutaric acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Sifted highly dispersed silicon dioxide is then added, after which all components are mixed in a vortex for the next 5 minutes. The sieved magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. Tableting of the powdery substance is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet.

Example 11

Production of tablet matrix by direct tableting method

Composition of the basic unit:

100 mg of piperazine urea-hydrogen sulfate

69 mg of lactose

75 mg Kollidon SR®

50 mg tartaric acid

3 mg of highly dispersed silicon dioxide

3 mg of magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Kollidon SR® are individually sieved and mixed into the above mixture in a vortex for 10 minutes. Sifted tartaric acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Sifted highly dispersed silicon dioxide is then added, and after that all components are mixed in a vortex for the next 5 minutes. The sieved magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. Tableting of the powdery substance is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet.

Example 12

Production of tablet matrix by direct tableting method

Composition of the basic unit:

100 mg of piperazine urea-hydrogen sulfate

69 mg of lactose

75 mg Kollidon SR®

50 mg adipic acid

3 mg of highly dispersed silicon dioxide

3 mg of magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Kollidon SR® are individually sieved and mixed into the above mixture in a vortex for 10 minutes. Sifted adipic acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Sifted highly dispersed silicon dioxide is then added, and after that all components are mixed in a vortex for the next 5 minutes. The sieved magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. Tableting of the powdery substance is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet.

Example 13

Production of tablet matrix by direct tableting method

Composition of the basic unit:

100 mg of piperazine urea-hydrogen sulfate

69 mg of lactose

75 mg Kollidon SR®

50 mg of ascorbic acid

3 mg of highly dispersed silicon dioxide

3 mg of magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Kollidon SR® are individually sieved and mixed into the above mixture in a vortex for 10 minutes. Sifted ascorbic acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Sifted highly dispersed silicon dioxide is then added, after which all components are mixed in a vortex for the next 5 minutes. The sieved magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. Tableting of the powdery substance is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet.

Example 14

Production of the tablet matrix by direct tableting followed by coating with a protective film

Composition of the basic unit:

100 mg of piperazine urea-hydrogen sulfate

82.5 mg of lactose

60 mg Kollidon SR®

50 mg fumaric acid

3 mg of highly dispersed silicon dioxide

4.5 mg magnesium stearate

7.6 mg of hydroxypropyl methyl cellulose, visc. 5

1.5 mg of talc

5.9 mg titanium dioxide, E 171

0.02 mg yellow iron oxide pigment, E 172 (EOP yellow)

Lactose, piperazine urea-hydrogen sulfate and Kollidon SR® are individually sieved and mixed into the above mixture in a vortex for 10 minutes. Sifted fumaric acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Sifted highly dispersed silicon dioxide is then added, after which all components are mixed in a vortex for the next 5 minutes. The sieved magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. Tableting of the powdery substance is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet. Talc, yellow iron oxide pigment and titanium dioxide are suspended in water with stirring (eg Ultra-Turraks mixer or colloid mill). Hydroxypropyl methyl cellulose is dissolved in water (binding material solution) with stirring (eg Ultra-Turrax mixer or colloid mill). Said suspension and binder solution are combined (film coating) with mixing (eg Ultra-Turraks mixer or colloid mill). The coating film material obtained in this way is sprayed onto the tablet core in the drum while maintaining heat, while the water used in this process evaporates.

Example 15

Production of the tablet matrix by direct tableting followed by coating with a protective film

Composition of the basic unit:

300 mg of piperazine urea-hydrogen sulfate

247.5 mg of lactose

180 mg Kollidon SR®

150 mg fumaric acid

9 mg of highly dispersed silicon dioxide

13.5 mg magnesium stearate

10.1 mg of hydroxypropyl methyl cellulose, visc. 5

2 mg of talc

7.8 mg titanium dioxide, E 171

0.03 mg of yellow iron oxide pigment, E 172 (EOP yellow)

Lactose, piperazine urea-hydrogen sulfate and Kollidon SR® are individually sieved and mixed into the above mixture in a vortex for 10 minutes. Sifted fumaric acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Sifted highly dispersed silicon dioxide is then added, after which all components are mixed in a vortex for the next 5 minutes. The sieved magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. Tableting of the powdery substance is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet. Talc, yellow iron oxide pigment and titanium dioxide are suspended in water with stirring (eg Ultra-Turraks mixer or colloid mill). Hydroxypropyl methyl cellulose is dissolved in water (binding material solution) with stirring (eg Ultra-Turrax mixer or colloid mill). Said suspension and binder solution are combined (film coating) with mixing (eg Ultra-Turraks mixer or colloid mill). The coating film material obtained in this way is sprayed onto the tablet core in the drum while maintaining heat, while the water used in this process evaporates.

Example 16

Production of minitablets by direct tableting method

Composition of the basic unit:

10 mg of piperazine urea-hydrogen sulfate

6.9 mg of lactose

7.5 mg Kollidon SR®

5 mg of fumaric acid

0.3 mg of highly dispersed silicon dioxide

0.3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate and Kollidon SR® are individually sieved and mixed into the above mixture in a vortex for 10 minutes. Sifted fumaric acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Sifted highly dispersed silicon dioxide is then added, after which all components are mixed in a vortex for the next 5 minutes. The sieved magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. Tableting of the powdery substance is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet. The minitablets that have been produced are shaped into solid gelatin capsules.

Example 17

Production of minitablets by direct tableting method

Composition of the basic unit:

10 mg of piperazine urea-hydrogen sulfate

8.25 mg of lactose

6 mg Kollidon SR®

5 mg of fumaric acid

0.3 mg of highly dispersed silicon dioxide

0.45 mg magnesium stearate

0.76 mg of hydroxypropyl methyl cellulose, visc. 5

0.15 mg of talc

0.59 mg titanium dioxide, E 171

0.002 mg of yellow iron oxide pigment, E 172 (EOP yellow)

Lactose, piperazine urea-hydrogen sulfate and Kollidon SR® are individually sieved and mixed into the above mixture in a vortex for 10 minutes. Sifted fumaric acid is then added, and then all components are mixed in a vortex for the next 5 minutes. Sifted highly dispersed silicon dioxide is then added, after which all components are mixed in a vortex for the next 5 minutes. Sifted magnesium stearate is dispersed, after which all components are mixed in a vortex for the next 30 seconds. The tableting of the powdery substance into minitablets is then performed by applying eccentric tablet compression or rotary tablet compression. Talc, yellow iron oxide pigment and titanium dioxide are suspended in water with stirring (eg Ultra-Turraks mixer or colloid mill). Hydroxypropyl methyl cellulose is dissolved in water (binding material solution) with stirring (eg Ultra-Turrax mixer or colloid mill). Said suspension and binder solution are combined (film coating) with mixing (eg Ultra-Turraks mixer or colloid mill). The obtained material, which will be used to obtain film, is sprayed onto the core of the tablet in a drum while maintaining heat, while the water used in this process evaporates. The minitablets that have been produced are shaped into solid gelatin capsules.

Example 18

Production of tablet matrix after granulation

Composition of the basic unit:

100 mg of piperazine urea-hydrogen sulfate

72 mg of lactose

75 mg Kollidon SR®

50 mg fumaric acid

3 mg of magnesium stearate

Lactose, piperazine urea-hydrogen sulfate, Kollidon SR® and fumaric acid are introduced into a fluidizing granulator and subjected to granulation with water spray. Magnesium stearate is sprayed onto the dry granulate and mixed in a vortex for 30 seconds. Tableting of the granulate is then carried out by applying eccentric compression of the tablet or rotary compression of the tablet.

Example 19

Production of minitablets after granulation

Composition of the basic unit:

10 mg of piperazine urea-hydrogen sulfate

7.2 mg of lactose

7.5 mg Kollidon SR®

5 mg fumaric acid

0.3 mg magnesium stearate

Lactose, piperazine urea-hydrogen sulfate, Kollidon SR® and fumaric acid are introduced into a fluidizing granulator and subjected to granulation with water spray. Magnesium stearate is sprayed onto the dry granulate and mixed in a vortex for 30 seconds. Tableting of the granulate into minitablets is then carried out by applying eccentric tablet compression or rotary tablet compression. The minitablets obtained in this way are shaped into solid gelatin capsules.

Example 20

Production of balls by means of extrusion and spheronization

Composition per capsule:

60 mg of piperazine urea-hydrogen sulfate

30 mg of microcrystalline cellulose

10 mg of fumaric acid

25.5 mg Eudragit® NE 30 D

4.25 mg of talc

0.18 mg of anhydrous highly dispersed silicon dioxide

Piperazine urea-hydrogen sulfate, microcrystalline acid and fumaric acid are processed into pellets using the Nice-palletizing system. In this process, piperazine urea-hydrogen sulfate, microcrystalline cellulose and fumaric acid are first mixed in a dry state. The powder mixture is then extruded with the addition of water. Processing of the extrudate into balls is performed using a spheronizer. An aqueous suspension consisting of Eudragit® NE 30 D and talc is sprayed onto the pellets while maintaining heat by using a Wurster fluidized granulator. Film-coated balls in hard gelatin capsules are obtained by adding silicon dioxide.

Example 21

Measurement of piperazine urea-hydrogen sulfate release

The measurement of the release of the active substance is performed according to the one-compartment method (vane-mixer apparatus), as described in U.S. Pat. Pharmacopoeia USP KXXIV. The release of piperazine urea-hydrogen sulfate is tested at pH 1 (0.1 N hydrochloric acid) and in phosphate buffer solution 4.5 and 6.8 (composition, see USP KSKSIV). In order to adjust the flow conditions that allow the release of piperazine urea-hydrogen sulfate to be controlled primarily by the formulation, surfactant (SDS) or hydroxypropyl-β-cyclodextrin can be added to the release media if necessary.

Example 22

Particle size measurement

The particle size of piperazine urea-hydrogen sulfate, lactose, Kollidon SR(R), fumaric acid, microcrystalline cellulose or powder mixtures is given in Examples 1 to 9 and determined by laser diffractometry (Müller, R.H., Schuhmann, R., Teilchengrößenmessung in der Laborpraksis [Particle size measurement in laboratory practice], Wissenschaftliche erlagsgesellschaft mbH, Stuttgart, 1996). The values of the volume distribution of particles by size are used as measurement parameters.

Claims (25)

1. A solid formulation of a pharmaceutical reagent containing (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine or a salt thereof, which is indicated in that it also contains a polymer matrix, an organic acid, a lubricant and one or more adjuvants, and that in 90% of cases the particle size in powder mixtures is between 0.1 and 750 μm. 2. A solid formulation of a pharmaceutical reagent according to claim 1, which is characterized in that the polymer matrix is selected from the group consisting of cellulose derivatives, acrylic derivatives, vinyl polymers, polyanhydrides, polyester polyorthoesters, polyurethanes, polycarbonates, polyphosphazenes, polyacetals, polysaccharides, sugar esters, diethylene glycol monoethyl ether, diethylene glycol monopalmitostearate, ethylene glycol monopalmitostearate, glycerol behenate and glycerol dibehenate, glycerol distearate and glycerol palmitostearate, glycerol monooleate 40, glycerol monostearate 40-55, macrogolglycerol laurate, macrogolglycerol- stearate, propylene glycol-monopalmitostearate, chitosan, galactomannan, pectin, shellac and alginate. 3. A solid formulation of a pharmaceutical reagent according to claim 1 or 2, characterized in that the polymer matrix consists of a mixture of water-soluble polyvinyl pyrrolidone and water-insoluble polyvinyl acetate. 4. A solid formulation of a pharmaceutical reagent in accordance with claims 1 to 3, which is indicated by the fact that the polymer matrix has the following composition: 80% polyvinyl acetate, 19% polyvinyl pyrrolidone, 0.8% sodium lauryl sulfate and 0.2% silicon dioxide. 5. A solid formulation of a pharmaceutical reagent according to patent claims 1 to 4, which is indicated by the fact that the organic acid is selected from the group consisting of fumaric acid, citric acid, tri-sodium citrate, Na-hydrogen citrate, ascorbic acid, maleic acid acid, maleic anhydride, tartaric acid, adipic acid, Na-hydrogen phosphate, succinic acid, glutaric acid, glutaric anhydride, potassium sorbate and sorbic acid. 6. A solid formulation of a pharmaceutical reagent in accordance with claims 1 to 5, characterized in that a lubricant is also added. 7. A solid formulation of a pharmaceutical reagent according to claims 1 to 6, characterized in that the adjuvant is lactose, calcium diphosphate, mannitol or starch. 8. A solid formulation of a pharmaceutical reagent in accordance with claims 1 to 7, which is characterized in that it contains microcrystalline cellulose as an additional adjuvant. 9. A solid formulation of a pharmaceutical reagent in accordance with patent claims 1 to 8, which is characterized by the fact that it additionally contains a reagent for regulating the flow. 10. A solid formulation of a pharmaceutical reagent according to claims 1 to 9, characterized in that the particle size of the powder mixture is between 20 and 400 μm in 90% of cases. 11. A solid formulation of a pharmaceutical reagent according to claims 1 to 10, characterized in that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4 -(4-fluorobenzyl)piperazine or its salt homogeneously dispersed in the matrix. 12. A solid formulation of a pharmaceutical reagent according to claims 1 to 11, characterized in that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4 -(4-Fluorobenzyl)piperazine or its salt surrounded by a matrix. 13. A process for obtaining a solid formulation of a pharmaceutical reagent in accordance with patent claims 1 to 12, which is characterized in that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl- 4-(4-Fluorobenzyl)piperazine or its salt is mixed with one or more adjuvants, polymer matrix, organic acid and lubricant, and then brought to tablet form, with all substances present in powder form and classified or individually before mixing or together after mixing. 14. A process for obtaining a solid formulation of a pharmaceutical reagent in accordance with patent claims 1 to 12, which is characterized in that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl- 4-(4-Fluorobenzyl)piperazine or a salt thereof is mixed with one or more adjuvants, a polymer matrix, an organic acid and then subjected to a granulation process, followed by the addition of a lubricant, followed by tableting. 15. The method of obtaining a solid multiparticulate formulation of a pharmaceutical reagent in accordance with claims 1 to 12, which is characterized in that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl -4-(4-Fluorobenzyl)piperazine or its salt, polymer matrix, organic acid and adjuvant are processed into balls by extrusion and spheronization will follow immediately. 16. The method of obtaining a solid multiparticulate formulation of a pharmaceutical reagent in accordance with claims 1 to 12, which is characterized in that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl -4-(4-Fluorobenzyl)piperazine or its salt, polymer matrix, organic acid and adjuvant are mixed and processed into beads using a binder solution or dissolved additives. 17. A process for obtaining a solid multiparticulate formulation of a pharmaceutical reagent in accordance with claims 1 to 12, characterized in that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl -4-(4-Fluorobenzyl)piperazine or its salt, polymer matrix, organic acid and adjuvant are processed into balls by means of spray drying and spray solidification. 18. The method of obtaining a solid multiparticulate formulation of a pharmaceutical reagent in accordance with patent claims 1 to 12, which is characterized in that (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl -4-(4-Fluorobenzyl)piperazine or its salt, polymer matrix, organic acid and adjuvant are processed into beads using rotor granulation. 19. The method of obtaining a solid multiparticulate formulation of a pharmaceutical reagent in accordance with patent claims 1 to 12, which is characterized by the fact that the polymer matrix, organic acid and adjuvant are processed into balls in such a way that a layered application is performed on (2R)-1-( (4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine or a salt thereof. 20. The use of a solid multiparticulate formulation of a pharmaceutical reagent in accordance with claims 1 to 12, which is indicated for the purpose of producing drugs for the treatment of inflammatory diseases. 21. Use according to claim 20, which is characterized in that said inflammatory disease is multiple sclerosis. 22. Use according to claim 20, which is characterized in that said inflammatory disease is rheumatoid arthritis. 23. Use according to claim 20, which is characterized in that said inflammatory disease is psoriasis. 24. Use according to claim 20, which is characterized in that said inflammatory disease is atopic dermatitis. 25. Use according to claim 20, which is characterized in that said inflammatory disease is psoriasis.