WO2003035037A1

WO2003035037A1 - Solid pharmaceutical formulation for a piperazine urea derivative

Info

Publication number: WO2003035037A1
Application number: PCT/EP2002/011229
Authority: WO
Inventors: Heiko Kranz; Christoph Völkel; Ralph Lipp; Johannes Tack; Herbert Wiesinger
Original assignee: Schering Aktiengesellschaft
Priority date: 2001-10-18
Filing date: 2002-10-07
Publication date: 2003-05-01
Also published as: CN1571660A; DE10152351B4; RS32204A; AU2002333896A2; ECSP045108A; NO20042022L; DE10152351A1; RU2004115328A; BR0213340A; KR20040047920A; PE20030472A1; PL367987A1; MXPA04003522A; NZ532287A; JP2005506365A; AR037111A1; RU2311172C2; HRP20040435A2; AU2002333896B2; ZA200403781B

Abstract

The invention relates to a solid pharmaceutical formulation that contains (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbon yl-2-methyl-4-(4-fluorobenzyl)piperazine or a salt thereof.

Description

Solid drug formulation for a piperazine urea derivative

The invention relates to a solid pharmaceutical formulation 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 compounds and especially (2f?) - 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 find use in the treatment of inflammatory diseases and the like. of multiple sclerosis and rheumatoid arthritis. In addition, they are used in psoriasis and atopic dermatitis. They are very poorly soluble at basic pH's. At a pH of 1, (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine hydrogensulfate dissolves about 5 mg / ml, while at a pH of 6.35 or 6.8 only about 0.15 mg / ml or 0.1 mg / ml dissolve. Due to this very poor solubility in the intestinal tract can not be achieved therapeutically required uniform plasma levels, avoiding significant side effects in conventional oral formulation. In addition to increasing the solubility in the intestinal tract, it would also be desirable that the release of the active ingredient be controlled over a longer period of time, so as to substantially extend dosing intervals. At the same time, however, a large-scale production of the drug would have to be possible.

Various ways of increasing the absorption of poorly soluble drugs have been described in the literature (e.g., in "Techniques of Solubilization of Drugs", S.H. Yalkowsky Ed., In Drugs and the Pharmaceutical Sciences). Especially recommended is the use of solubilizers such as e.g. Surface-active substances for very poorly soluble substances (WO01 / 05376). But this way was only badly suited to solve the problem at hand. The addition of the surfactant SDS to (2f?) - 1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine hydrogen sulfate resulted in only a slight increase the release (see Fig. 2).

Other publications address the problem of pH independent release. Streubel et al (2000, J Controlled Release 67, 101-110) describe the addition of acids to a drug. The described drug dissolves but without the addition of acids at pH 6.35 very well (more than 100 mg / ml). Goal of Streubel et al. was it the pH To compensate for value-related fluctuations. This was achieved by adding acids. In the present invention, the problem is not only to compensate for pH-related fluctuations, but also to increase the solubility per se. The properties of the drug 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 , In addition, the formulation is used only for the individual production of tablets, not for large-scale production. Therefore, it was questionable whether this method can be applied to the problem underlying the invention.

The present invention solves the problem of increasing the solubility and the pH-independent release while being industrially producible by a solid pharmaceutical formulation containing (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2 methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, wherein the pharmaceutical formulation additionally comprises a polymer matrix, an organic acid and one or more adjuvants for the targeted control of pH independent drug release (release modification) and for influencing the mechanical strength of the dosage form contains and the particle sizes of the powder mixtures are 90% in the range between 0.1 and 750 microns.

(2) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine is hereinafter called piperazine urea and has the following structure:

The preparation of (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine and its salts is carried out by the method described in WO98 / 56771 in Example 2 is described. Salts of these are, for example, the hydrochloride, dihydrogen phosphate, hydrogen sulfate, sulfate, mesylate, ethylsulfonate, malate, fumarate and tartrate.

Solid drug formulations according to the invention are single-unit systems, such as e.g. Tablets, and multiparticulate systems. Multiparticulate systems can e.g. Granules, pellets or minitablets. These can be filled in hard or soft gelatin capsules, and compressed into tablets. The original formation usually breaks down into many subunits in the stomach. The minidots then gradually pass from the stomach into the intestine. The mini spots can usually pass through the pylorus with the sphincter closed.

A polymer matrix may be selected from the group consisting of cellulose derivatives [e.g. Methylcellulose, hydroxypropylmethylcellulose (eg hydroxypropylmethylcellulose K 4 M, hydroxypropylmethylcellulose K 15 M), hydroxypropylcellulose, hydroxyethylcellulose, sodium-carboxymethylcellulose, ethylcellulose (eg ethylcellulose 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, hydroxypropylmethyl cellulose phthalate,

Hydroxypropyl methylcellulose acetate succinate], acrylic derivatives [e.g. Polyacrylates, cross-linked polyacrylates (e.g., polymethacrylates, polyethyl acrylates, polymethyl acid ethyl acrylates, polymethyl methyl methacrylates, polymethyl methyl methacrylates, polymethyl acrylate trimethyl ammonium ethyl methacrylate chlorides, polyethyl acrylate trimethyl ammonium ethyl methacrylate gallate,

Dimethylaminoethylmethacrylatmethacrylatcopolymere, Carbopol ^® 971 P, Carbopol ^® 974 P, Carbopol ^® 71 G)], vinyl polymers (eg, polyvinyl pyrrolidones, polyvinyl acetates, Polyvinylacetatphthalate), polyethylene glycols, polyanhydrides, polyester polyorthoesters, polyurethanes, polycarbonates, polyphosphazenes, polyacetals, polysaccharides (eg, xanthans, xanthan Gum), Zuckerester (for example sucrose stearate, Saccharosepaimitat, sucrose laurate, sucrose behenate, saccharose oleate, Saccharoseerucat and Saccharoseester with mixed fatty acids), diethylene glycol monoethyl ether (for example Transcutol ^® P), diethylene glycol monopalmitostearat (eg Hydrines ^®), ethylene glycol monopalmitostearat (eg Monthyle ^® ) Gycerol-behenate and Gycerol-Dibehenate (eg Compritol ^® 888 ATO, Compritol ^® HD 5 ATO and Compritol ^® e), glycerol distearates, Glyceroldipalmitostearate and Glycerolpalmitostearate (eg, Precirol ^® ATO 5 and Precirol ^® WL 2155), glycerol mono-oleate 40, (for example Peceol ^®), glycerol monostearate 40-55 (eg Geleo l ^®), macrogolglycerol Iaurate (for example, Gelucire ^® 44/14 and Labrafil ^® M 2130 CS), macrogolglycerol-stearate (for example Gelucire ^® 50/13), propylene glycol-monopalmitostearat (eg Monosteol ^®), chitosan, galactomannan, pectin, shellac and alginates are selected. Particularly suitable is a physical mixture consisting of water-insoluble polyvinyl acetate and water-soluble polyvinylpyrrolidone as polymer matrix. This mixture, which in addition contains sodium lauryl sulfate and silicon dioxide, for example, is sold under the trade name Kollidon SR ^® sold (Kollidon SR, Technical Information, ME 397e, BASF, July 2000: 80% polyvinyl acetate, 19% polyvinyl pyrrolidone, 0.8% sodium lauryl sulfate and 0, 2% silica)

The organic acid can be 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. Preference is given to fumaric acid.

For targeted control of the pH-independent drug release (release modification) and for influencing the mechanical strength of the dosage form, water-soluble or water-insoluble adjuncts such as. Lactose, calcium diphosphates, mannitol, sorbitol, sucrose, fructose, glucose, starch or a starch derivative. It is also possible to use mixtures of one or more auxiliaries. Lactose is preferred. Particularly advantageous is coarse-grained lactose.

As an additional aid for the targeted control of the pH-independent drug release (release modification) and for influencing the mechanical strength of the pharmaceutical form, cellulose or cellulose derivatives can be used. Particularly advantageous is microcrystalline cellulose. This swells in an aqueous environment and leads to an improved pH-independent release of Piperzinhamstoffs and its salts.

The single-unit drug forms such as tablets, in addition, lubricants to reduce the inter-particle friction and to reduce the sliding friction between Gut- and Matrizenwandung can be added. As a lubricant, substances are used, which have layers due to their lamellar structure, which can be easily shifted against each other. Pharmaceutically usable organic substances are, for example, the divalent metal soaps, the higher fatty alcohols and the polyethylene glycols with higher Molecular weights. Particularly advantageous are the magnesium and calcium salts of higher fatty acids.

In the case of single-unit dosage forms, a flow control agent can be added to improve the flow properties of the material to be tabletted. This causes the material to be tableted to regularly fill the die of the machine with sufficient packing density. The addition of a flow control agent may be necessary especially in direct tableting. Substances with a purely flow regulating action are mainly the fumed silicas, i. the micronized silica gels and the pyrolytic silicas. Starches and talc are substances that can be used as Fließregulierungsmittel- as well as Zerfallhilfs- or as a lubricant.

In the case of the single-unit dosage form, it is important for their large-scale production that the material to be tabletted have granule-like properties such as good flowability, high bulk density and defined particle size distribution. The grain size of the Guts to be tabletted depends on the size of the tablets to be produced and generally varies between 0.1 and 750 μm. Within the material to be tabletted, a particle size distribution which is as uniform as possible is important in order to prevent segregation (for example when shaking the tablet machine) and thus accumulation of larger particles in the upper part of the product, since otherwise larger variations in the dosage may occur. A defined particle size and particle size distribution is achieved by classification (e.g., wet or dry screening) or by granulation of the starting materials. The particle size can be measured by the method described in Example 5. The particle sizes should be 90% in the range between 0.1 - 750 microns. Preferred is a range of 20-400 microns.

The piperazine urea or its salts may be homogeneously distributed in the matrix or surrounded by the matrix. In the latter case, the drug forms a nucleus surrounded by the matrix shell.

Further, the solid drug formulation according to this invention may be coated with a lake for optical and flavor purposes. This usually consists of a binder (for example hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol), lubricants (for example talc) and color pigment (for example iron oxide pigment, titanium dioxide). A preferred solid pharmaceutical agent formulation contains (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, lactose, Kollidon SR ^® , Silica and magnesium stearate, with 90% of the particles ranging from 0.1-750 microns. Particularly preferred is the use of the hydrogen sulfate as a salt. A tablet with this formulation shows a 60% release of the piperazine urea after 6 hours. Another preferred pharmaceutical formulation 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 ^®, silicon dioxide and magnesium stearate, whereby 90% of the particles in the range 0.1 to 750 microns are. Particularly preferred is the use of the hydrogen sulfate as a salt. A tablet with this formulation shows an 80-90% release of the piperazine urea after 4 hours.

Another preferred solid drug formulation contains (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, lactose, Kollidon SR ^®, silicon dioxide and magnesium stearate, whereby 90% of the particles in the range 0.1 to 750 microns are, and the tablet is subsequently coated with a color coat consisting of hydroxypropylmethylcellulose, talc, titanium dioxide and iron oxide pigment. A tablet with this formulation shows a 60% release of the piperazine urea after 6 hours.

The pharmaceutical formulation according to the invention considerably increases the solubility and the release of the piperazine urea and its salts. While in a conventional formulation consisting of (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) -piperazine or a salt thereof, lactose, Corn starch, polyvinylpyrrolidone, croscarmellose sodium and magnesium stearate, only about 10% is released after 8-10 hours at pH 6.8, the release increases by the inventive formulation to about 60-90%. The advantage of the pharmaceutical formulation according to the invention is also evident in clinical studies. Compared with a conventional oral formulation, the plasma levels of (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine of the treated subjects when given the formulation of the invention over a longer period increased (see Figure 11).

The formulation of the invention has all the properties that are necessary for large-scale production, such as good flow properties, high bulk density, good Dosing accuracy, high plastic deformability and thus easy compressibility and high mechanical strength of the tablets produced.

The invention further provides a process for the preparation of a solid pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof is mixed with the polymer matrix, the organic acid, the lubricant and the auxiliary and tableted (direct tabletting). The direct production of tablets is basically carried out by mixing the powder constituents, metering via the filling device of the tablet machine and subsequent compression of the powder mixture. In direct tableting, the particle size and particle size distribution of the piperazine urea used and its salts, polymer matrix, organic acid and auxiliaries have a considerable influence on the large-scale production of the tablets. These are therefore to be classified individually (for example by sieving) before mixing the powder constituents. Alternatively, the entire powder mixture or individual components of the powder mixture may be classified together (e.g., sieved). The powder ingredients are weighed as described in the examples and mixed for a sufficient period of time in a free fall (e.g., Turbulam mixer, V mixer) or compulsory mixer (e.g., ploughshare mixer, planetary mixer). In particular, the addition of the flow control agent and lubricant (both together are also referred to as FST complex) takes place shortly before the loading of the tableting machine. The FST complex must be finely sieved onto the pre-mixed tabletting material and mixed in as described above, whereby the mixing time must not be too short (inhomogeneous distribution) or too long (dead mixing of the material).

Furthermore, the invention relates to a process for the preparation of a solid pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a Salt thereof, the polymer matrix, the organic acid and the adjuvants prior to mixing and tableting are subjected to an operation called granulating. After granulation and addition of the lubricant, tabletting is carried out as described above. The granulation can be carried out by stepwise enlargement or agglomeration of primary particles of the powder mixture to the desired secondary size (building granulation) or by dividing a dandy powder mass to the desired Granulatkomgröße (degradation end granulation). For example, plate granulation and fluidized-bed granulation are among the constituent granulations. The degrading granulation can For example, by compaction of the starting materials and subsequent mechanical fragmentation and screening of the compressed done. Degrading or nascent granulation may be moist (eg, adhesive or crust granules) or dry (eg, briquette or melt solidification granules).

A further subject of the invention is a process for the preparation of a solid multiparticulate pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, the polymer matrix, the organic acid and the auxiliaries (preferably cellulose, cellulose derivatives and lactose) are processed into pellets by extrusion and subsequent spheronization.

The invention further provides a process for the preparation of a solid multiparticulate pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, the organic acid and the auxiliaries (preferably cellulose, cellulose derivatives and lactose) are processed into pellets by means of extrusion and subsequent spheronization. The pellets containing the active ingredient are then coated with the polymer matrix (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac). Under certain circumstances, the active substance-containing pellets can be coated with a subcoat (preferably cellulose derivatives and vinyl polymers) before application of the polymer matrix. Function of the subcoat is the prevention of incompatibilities between (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof and the Polymer matrix or a premature diffusion of (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof in the Polymer matrix during pellet storage.

The invention further provides a process for the preparation of a solid multiparticulate pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof and the auxiliaries (preferably cellulose, cellulose derivatives and lactose) are processed into pellets by means of extrusion and subsequent spheronization. The pellets containing the active ingredient are then coated with the organic acid and the polymer matrix (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac). Under certain circumstances, the active substance-containing pellets can be coated with a subcoat (preferably cellulose derivatives and vinyl polymers) before application of the polymer matrix. The invention further provides a process for the preparation of a solid multiparticulate pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, the polymer matrix, the organic acid and the adjuvants are processed into pellets by direct pelletization. The starting materials are mixed and processed into pellets by means of a binder solution (wet granulation) or melted additives (eg fats).

The invention further provides a process for the preparation of a solid multiparticulate pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, the polymer matrix, the organic acid and the adjuvants are processed into pellets by spray-drying or spray-drying.

The invention further provides a process for the preparation of a solid multiparticulate pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, the polymer matrix, the organic acid and the auxiliaries are processed into pellets by means of rotor granulation.

Furthermore, the invention relates to a process for the preparation of a solid pharmaceutical formulation according to the invention wherein the polymer matrix, the organic acid and the auxiliaries by applying in layers on (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl ) Carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof are processed into pellets (layering).

Furthermore, the invention relates to a process for the preparation of a solid pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a Salt thereof, the polymer matrix, the organic acid and the aids are processed by applying in layers to a drug-free core (so-called non-pareils) to pellets. In this process, generally (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof is converted to an active substance applied free core (so-called non-pareils). Subsequently, the organic acid is applied. To complete the process, the pellets are coated with a polymer matrix (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac). In certain circumstances For example, the pellets may be coated with a subcoat (preferably cellulose derivatives and vinyl polymers) prior to application of the polymer matrix.

Furthermore, the invention relates to a method for filling the pellets produced in pharmaceutically used capsules (preferably gelatin capsules, starch capsules or cellulose derivative capsules) or the compression of the pellets produced into tablets. The filling of the pellets into capsules or processing of the pellets into tablets may optionally be carried out with the addition of further auxiliaries (preferably cellulose, cellulose derivatives, lactose, lubricants and flow regulators).

The invention further provides a process for the preparation of a solid pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof are mixed with the polymer matrix, the organic acid, the lubricant and the adjuvants, and then processed by direct tableting into minitablets (more preferably tablet diameter 1-5 mm).

Furthermore, the invention relates to a process for the preparation of a solid pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a Salt thereof, the polymer matrix, the organic acid and the adjuvants prior to mixing and tableting are subjected to an operation called granulating. After granulation and addition of the lubricant, the starting materials are processed into mini-tablets (preferably tablet diameter 1-5 mm).

Furthermore, the invention relates to a method for filling the minitablets produced in pharmaceutically used capsules (preferably gelatin capsules, starch capsules or cellulose derivative capsules). The filling of the minitablets into capsules may, if appropriate, be carried out with the addition of further auxiliaries (preferably cellulose, cellulose derivatives, lactose).

The invention also provides the use of the solid pharmaceutical formulation of the invention for the manufacture of a medicament for the treatment of inflammatory diseases. The inflammatory disease can be, for example, multiple sclerosis, rheumatoid arthritis, psoriasis or atopic dermatitis. Preferably, the treatment of a patient suffering from an inflammatory disease is by administering one tablet a day. Description of the pictures

Fig. 1 describes the solubility of piperazine urea bisulfate as a function of pH.

Fig. 2 shows the effect of the addition of SDS (sodium dodecyl sulfate) on the release of piperazineurea-hydrogen sulfate in phosphate buffer solution pH 6.8 (33% Piperazinhamstoff- hydrogen sulfate and 25% Kollidon SR ^®, based on the total weight of the tablet).

Fig. 3 shows the effect of fumaric acid (%, relative to the total weight of the tablet) on the release of piperazineurea-hydrogen sulfate in phosphate buffer solution pH 6.8 (33% Piperazinhamstoff-hydrogen sulfate and 25% Kollidon SR ^®, based on the total weight of the tablet ).

Fig. 4 shows the effect of the addition of different concentrations of fumaric acid (%, relative to the total weight of the tablet) on the release of Piperazinhamstoff-hydrogen sulfate in phosphate buffer solution pH 6.8 (33% Piperazinharnstoff- hydrogen sulfate and 25% Kollidon SR ^®, based on the total weight of the tablet).

Figure 5 shows the effect of pH on the release of the piperazine urea hydrogen sulfate (33% piperazine urea hydrogen sulfate, 25% Kollidon SR and 16% fumaric acid, based on the total weight of the tablet).

Fig. 6 shows the effect of pH on the release of Piperazinhamstoff- hydrogen sulfate (33% piperazineurea-hydrogen sulfate, Kollidon SR ^® 12.5% and 16% fumaric acid, relative to the total weight of the tablet).

Fig. 7 shows the effect of pH on the release of Piperazinharnstoff- hydrogen sulfate (33% piperazineurea-hydrogen sulfate, 25% Kollidon SR ^®, 16% fumaric acid and 10% microcrystalline cellulose, based on the total weight of the tablet).

Fig. 8 shows the particle size distribution determined by laser diffractometry of a typical Pulverpreßmasse for direct tableting.

Figure 9 shows the effect of adding different polymer matrices (Examples 3-9) to the release of piperazine urea bisulfate in phosphate buffer solution pH 6.8. Figure 10 shows the effect of adding different organic acids (Examples 10-13) to the release of piperazine urea bisulfate in phosphate buffer solution pH 6.8.

FIG. 11 shows, in semilogarithmic representation, the effect of the drug formulation on in vivo plasma levels in humans after administration of 100 mg piperazineurea hydrogensulfate in the form of a conventional oral formulation and after administration of the formulations mentioned in Example 1 (matrix tablet C) and 2 (matrix tablet E) formulations.

Examples

Example 1 Preparation of a matrix tablet by means of direct tabletting

Composition per basic unit:

100 mg piperazinurea hydrogen sulfate

69 mg of lactose

75 mg of Kollidon SR ^®

50 mg of fumaric acid

3 mg of fumed silica

3 mg magnesium stearate

Lactose, piperazineurea-hydrogen sulfate and Kollidon SR ^® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.

Example 2 Preparation of a matrix tablet by direct tabletting

Composition per basic unit:

100 mg piperazine urea hydrogen sulfate

39 mg lactose

75 mg of Kollidon SR ^®

50 mg of fumaric acid

30 mg microcrystalline cellulose

3 mg of fumed silica

3 mg magnesium stearate

Lactose, piperazineurea-hydrogen sulfate, Kollidon SR ^® and microcrystalline cellulose are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all Components mixed for another 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.

Example 3 Preparation of a matrix tablet by means of direct tabletting

Composition per basic unit:

100 mg piperazine urea hydrogen sulfate

104 mg lactose

40 mg Precirol ^® ATO 5

50 mg of fumaric acid

3 mg of fumed silica

3 mg magnesium stearate

Lactose, piperazineurea-hydrogen sulfate and Precirol ^® ATO 5 (Glyceroldipalmitostearat) are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.

Example 4 Preparation of a matrix tablet by means of direct tabletting

Composition per basic unit:

100 mg piperazine urea hydrogen sulfate

104 mg lactose

40 mg Compritol ^® 888 ATO

50 mg of fumaric acid

3 mg of fumed silica

3 mg magnesium stearate

Lactose, piperazineurea-hydrogen sulfate and Compritol ^® 888 ATO (glycerol dibehenate) are individually sieved and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients for mixed for another 5 min in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.

Example 5 Preparation of a matrix tablet by direct tabletting

Composition per basic unit:

100 mg piperazine urea hydrogen sulfate

69 mg of lactose

Carbopol ^® 75 G 71 mg

50 mg of fumaric acid

3 mg of fumed silica

3 mg magnesium stearate

Lactose, Piperazinhamstoff-hydrogen sulfate and Carbopol 71 G ^® (quervemetztes polyacrylate) are individually sieved and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.

Example 6 Preparation of a matrix tablet by means of direct tabletting

Composition per basic unit:

100 mg piperazine urea hydrogen sulfate

69 mg of lactose

75 mg of Xantural ^® 75

50 mg of fumaric acid

3 mg of fumed silica

3 mg magnesium stearate

Lactose, Piperazinhamstoff-hydrogen sulfate and Xantural ^® 75 (xanthan gum) are individually sieved and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.

Example 7 Preparation of a matrix tablet by direct tabletting

Composition per basic unit:

100 mg piperazinurea hydrogen sulfate

84 mg lactose

60 mg of ethylcellulose 100

50 mg of fumaric acid

3 mg of fumed silica

3 mg magnesium stearate

Lactose, piperazine urea hydrogensulfate and ethylcellulose 100 are individually screened and mixed in order in the turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.

Example 8 Preparation of a matrix tablet by direct tabletting

Composition per basic unit:

100 mg piperazinurea hydrogen sulfate

10 mg lactose

134 mg of cellulose acetate butyrate 171-15 PG

50 mg of fumaric acid

3 mg of fumed silica

3 mg magnesium stearate

Lactose, piperazine urea bisulfate and cellulose acetate butyrate 171-15 PG (cellulose acetate butyrate) are sieved individually and mixed in order in the turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients for further Mixed for 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.

Example 9 Preparation of a matrix tablet by direct tabletting

Composition per basic unit:

100 mg piperazinurea hydrogen sulfate

94 mg lactose

50 mg hydroxypropyl methylcellulose K 15 M

50 mg of fumaric acid

3 mg of fumed silica

3 mg magnesium stearate

Lactose, piperazineurea-bisulfate and hydroxypropylmethylcellulose K 15 M are sieved individually and mixed in the order mentioned in the turbula for 10 min. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.

Example 10 Preparation of a matrix tablet by direct tabletting

Composition per basic unit:

100 mg piperazinurea hydrogen sulfate

69 mg of lactose

75 mg of Kollidon SR ^®

50 mg glutaric acid

3 mg of fumed silica

3 mg magnesium stearate

Lactose, piperazineurea-hydrogen sulfate and Kollidon SR ^® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Glutaric acid, sieved, becomes Add and mix all ingredients for another 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.

Example 11 Preparation of a matrix tablet by direct tabletting

Composition per basic unit:

100 mg piperazine urea hydrogen sulfate

69 mg of lactose

75 mg of Kollidon SR ^®

50 mg of tartaric acid

3 mg of fumed silica

3 mg magnesium stearate

Lactose, Piperazinhamstoff-hydrogen sulfate and Kollidon SR ^® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Tartaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.

Example 12 Preparation of a matrix tablet by direct tableting

Composition per basic unit:

100 mg piperazinurea hydrogen sulfate

69 mg of lactose

75 mg of Kollidon SR ^®

50 mg adipic acid

3 mg of fumed silica

3 mg magnesium stearate

Lactose, Piperazinhamstoff-hydrogen sulfate and Kollidon SR ^® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Adipic acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. colloidal anhydrous Silica, sieved, is added and all ingredients mixed for an additional 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.

Example 13 Preparation of a matrix tablet by direct tableting

Composition per basic unit:

100 mg piperazine urea hydrogen sulfate

69 mg of lactose

75 mg of Kollidon SR ^®

50 mg ascorbic acid

3 mg of fumed silica

3 mg magnesium stearate

Lactose, piperazineurea-hydrogen sulfate and Kollidon SR ^® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Ascorbic acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.

Example 14 Production of a matrix tablet by means of direct tabletting with subsequent film coating

Composition per basic unit:

100 mg piperazine urea hydrogen sulfate

82.5 mg lactose

60 mg of Kollidon SR ^®

50 mg of fumaric acid

3 mg of fumed silica

4.5 mg magnesium stearate

7.6 mg of hydroxypropylmethylcellulose, Visk. 5 1, 5 mg talcum

5.9 mg of titanium dioxide, E 171

0.02 mg iron oxide pigment yellow, E 172 (EOP yellow) Lactose, Piperazinhamstoff-Hydrogensuifat and Kollidon SR ^® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound by means of an eccentric or rotary tablet press (tablet cores). Talcum, iron oxide pigment yellow and titanium dioxide are suspended with stirring (eg Ultra-Turrax mixer or colloid mill) in water (dye suspension). Hydroxypropylmethylcellulose is dissolved with stirring (eg Ultra-Turrax mixer or colloid mill) in water (binder solution). Dye suspension and binder solution are combined with stirring (eg Ultra-Turrax mixer or colloid mill) (film paint). The produced film paint is sprayed onto the tablet cores with the introduction of heat in a drum coater, the water used evaporating.

Example 15 Production of a matrix tablet by means of direct tabletting with subsequent film coating

Composition per basic unit:

300 mg piperazine urea hydrogen sulfate

247.5 mg lactose

180 mg of Kollidon SR ^®

150 mg of fumaric acid

9 mg of fumed silica

13.5 mg magnesium stearate

10.1 mg of hydroxypropylmethylcellulose, Visk. 5

2 mg talc

7.8 mg of titanium dioxide, E 171

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

Lactose, piperazineurea-hydrogen sulfate and Kollidon SR ^® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting of Pulverpreßmasse done by means of an eccentric or rotary tablet press (tablet cores). Talcum, iron oxide pigment yellow and titanium dioxide are suspended with stirring (eg Ultra-Turrax mixer or colloid mill) in water (dye suspension). Hydroxypropylmethylcellulose is dissolved with stirring (eg Ultra-Turrax mixer or colloid mill) in water (binder solution). Dye suspension and binder solution are combined with stirring (eg Ultra-Turrax mixer or colloid mill) (film paint). The produced film paint is sprayed onto the tablet cores with the introduction of heat in a drum coater, the water used evaporating.

Example 16 Preparation of Minitablets by Direct Tableting

10 mg piperazineurea-hydrogensulfate 6.9 mg lactose. 7.5 mg of Kollidon SR ^®

5 mg fumaric acid

0.3 mg of fumed silica 0.3 mg of magnesium stearate

Lactose, Piperazinhamstoff-hydrogen sulfate and Kollidon SR ^® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting of the powder molding compound to minitablets by means of an eccentric or rotary tablet press. The minitablets produced are filled into hard gelatine capsules.

Example 17 Preparation of Minitablets with Subsequent Film Painting

Composition per basic unit: 10 mg piperazinurea hydrogen sulfate 8.25 mg lactose

6 mg Kollidon SR ^® 5 mg fumaric acid

0.3 mg of fumed silica

0.45 mg magnesium stearate

0.76 mg of hydroxypropylmethylcellulose, Visk. 5 0.15 mg talc

0.59 mg of titanium dioxide, E 171

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

Lactose, piperazineurea-hydrogen sulfate and Kollidon SR ^® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound to minitablets is then carried out by means of an eccentric or rotary tablet press (tablet cores). Talcum, iron oxide pigment yellow and titanium dioxide are suspended with stirring (eg Ultra-Turrax mixer or colloid mill) in water (dye suspension). Hydroxypropylmethylcellulose is dissolved with stirring (eg Ultra-Turrax mixer or colloid mill) in water (binder solution). Dye suspension and binder solution are combined with stirring (eg Ultra-Turrax mixer or colloid mill) (film paint). The produced film paint is sprayed onto the tablet cores with the introduction of heat in a drum coater, the water used evaporating. The minitablets produced are filled into hard gelatine capsules.

Example 18 Preparation of a matrix tablet after granulation

Composition per basic unit:

100 mg piperazinurea hydrogen sulfate

72 mg lactose

75 mg of Kollidon SR ^®

50 mg of fumaric acid

3 mg magnesium stearate

Lactose, piperazineurea-hydrogen sulfate, Kollidon SR ^® and fumaric acid are introduced into a fluid bed granulator and granulated by spraying water. On the dried granules magnesium stearate is scattered and mixed for 30 seconds in the Turbula. The tabletting of the granules is then carried out by means of an eccentric or rotary tablet press.

Example 19 Preparation of minitablets after granulation Composition per basic unit:

10 mg piperazinurea hydrogen sulfate

7.2 mg lactose

7.5 mg of Kollidon SR ^®

5 mg fumaric acid

0.3 mg of magnesium stearate

Lactose, Piperazinhamstoff-hydrogen sulfate, Kollidon SR ^® and fumaric acid are introduced into a fluid bed granulator and granulated by spraying water. On the dried granules magnesium stearate is scattered and mixed for 30 seconds in the Turbula. The pellets are then tableted into minitablets by means of an eccentric or rotary tablet press. The minitablets produced are filled into hard gelatine capsules.

Example 20 Preparation of Pellets by Extrusion and Spharonization

Composition per capsule:

60 mg piperazineurea-hydrogensulfate

30 mg microcrystalline cellulose

10 mg of fumaric acid

25.5 Eudragit ^® NE 30 D mg

4.25 mg talc

0.18 mg of anhydrous fumed silica

Piperazine urea bisulfate, microcrystalline cellulose and fumaric acid are pelletized using a Nica pelleting system. In this process, piperazine urea hydrogensulfate, microcrystalline cellulose and fumaric acid are first dry blended. The powder mixture is then extruded with the addition of water. The processing of the extrudate into pellets is done using a spheronizer. An aqueous suspension consisting of Eudragit ^® NE 30 D and talc is sprayed under heat supply by means of a fluid bed granulator with a Wurster insert onto the pellets. The film-coated pellets are filled into hard gelatine capsules with the addition of silicon dioxide.

Example 21 Measurement of Release of Piperazine Urea Hvdroxide Sulfate Measurement of the release of active ingredient is carried out according to a one-compartment method (paddle stirrer apparatus) as described in USP XXIV. The release of the piperazineurea bisulfate was achieved at pH 1 (0.1 N hydrochloric acid) and in phosphate buffer. pH 4.5 and 6.8 (composition see USP XXIV). To establish sink conditions that ensure that the release of piperazineurea-hydrogensulfate is primarily controlled by the formulation, if necessary, an addition of surfactant (SDS) or hydroxypropyl-β-cyclodextrin to the release medium occurs.

Example 22 Measurement of particle size

The particle size of Piperazinhamstoff-hydrogen sulfate, lactose, Kollidon SR ^®, fumaric acid, microcrystalline cellulose or referred to in Example 1 to 9 the powder mixtures was measured by laser diffractometry (Muller, RH, Schuhmann, R., particle size measurement in the laboratory practice, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1996). The volume distribution of the particle sizes was used as measurement parameter.

Claims

claims

A solid pharmaceutical formulation comprising (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, characterized in that it additionally contains a polymer matrix, an organic acid, a lubricant and one or more auxiliaries and that the particle sizes of the powder mixtures are 90% in the range between 0.1 and 750 microns.

2. The solid pharmaceutical formulation according to claim 1, wherein 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 behenates and glycerol dibehenates, glycerol distearates and glycerol palmitostearates, glycerol monooleate 40, glycerol monostearate 40-55, macrogolglycerol laurates, macrogolglycerol stearates, propylene glycol monopalmitostearate, chitosan, galactomannan, pectin, shellac and alginates is.

3. A solid pharmaceutical formulation according to claim 1 or 2 wherein the polymer matrix consists of a mixture of water-soluble polyvinylpyrrolidone and water-insoluble polyvinyl acetate.

4. The solid pharmaceutical formulation according to any one of claims 1-3 wherein the polymer matrix has the following composition: 80% polyvinyl acetate, 19% polyvinylpyrrolidone, 0.8% sodium lauryl sulfate and 0.2% silica.

5. The solid pharmaceutical formulation according to claim 1, wherein the organic acid is selected from the group consisting of fumaric acid, citric acid, trisodium citrate, 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 is selected.

6. Solid drug formulation according to any one of claims 1-5 wherein additionally a lubricant is added.

7. A solid pharmaceutical formulation according to any one of claims 1-6 wherein the aid is lactose, calcium diphosphate, mannitol or a starch.

8. Solid drug formulation according to any one of claims 1-7 wherein it contains as an additional aid microcrystalline cellulose.

A solid drug formulation according to any one of claims 1-8, wherein it additionally contains a flow control agent.

10. Solid drug formulation according to any one of claims 1-9 wherein the particle sizes of the powder mixtures are 90% in the range between 20 and 400 microns.

11. A solid pharmaceutical formulation according to any one of claims 1-10 wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof is homogeneously distributed in the matrix.

12. A solid pharmaceutical formulation according to any one of claims 1-11 wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt of which is surrounded by the matrix.

A process for preparing a solid pharmaceutical formulation according to any one of claims 1-12 wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof with one or more adjuvants, the polymer matrix, the organic acid, and the lubricant is mixed and tabletted, all of which are in powder form and are classified together either before mixing individually or after mixing.

14. A process for the preparation of a solid pharmaceutical formulation according to any one of claims 1-12 wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof with one or more adjuvants, the polymer matrix and the organic acid are mixed and then granulated, then the lubricant is added and then tabletted.

A process for preparing a solid multiparticulate drug formulation according to any one of claims 1-12 wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl ) piperazine or a salt thereof, the polymer matrix, the Organic acid and the aids by extrusion and subsequent Spharonisation be processed into pellets.

A process for preparing a solid multiparticulate drug formulation according to any one of claims 1-12, wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4- fluorobenzyl) piperazine or a salt thereof, the polymer matrix, the organic acid and the adjuvants are mixed and made into pellets by means of a binder solution or molten additives.

A process for preparing a solid multiparticulate drug formulation according to any one of claims 1-12, wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4- fluorobenzyl) piperazine or a salt thereof, the polymer matrix, the organic acid and the adjuvants are processed into pellets by spray-drying or spray-hardening.

A process for preparing a solid multiparticulate drug formulation according to any one of claims 1-12, wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4- fluorobenzyl) piperazine or a salt thereof, the polymer matrix, the organic acid and the auxiliaries are processed into pellets by means of rotor granulation.

A process for the preparation of a solid pharmaceutical formulation according to any one of claims 1 to 12, wherein the polymer matrix, the organic acid and the excipients are applied by coating in layers on (2R) -1 - ((4-chloro-2-)

(ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof are processed into pellets.

Use of a solid drug formulation according to any one of claims 1-12 for the manufacture of a medicament for the treatment of inflammatory diseases.

21. Use according to claim 20 wherein the inflammatory disease is multiple sclerosis.

Use according to claim 20 wherein the inflammatory disease is rheumatoid arthritis.

Use according to claim 20 wherein the disease is psoriasis.

Use according to claim 20 wherein the disease is atopic dermatitis.