WO2011131347A1

WO2011131347A1 - Pramipexole-containing matrix tablet

Info

Publication number: WO2011131347A1
Application number: PCT/EP2011/001989
Authority: WO
Inventors: Katrin Rimkus; Daniela Stumm
Original assignee: Ratiopharm GmbH
Current assignee: Ratiopharm GmbH
Priority date: 2010-04-22
Filing date: 2011-04-19
Publication date: 2011-10-27
Anticipated expiration: 2012-10-22
Also published as: EP2560622A1; EA201291094A1; EP2380560A1

Abstract

The present invention relates to a matrix tablet for the modified release of pramipexole, and to a process for the preparation of such matrix tablets. The invention furthermore relates to pramipexole-containing matrix tablets for the treatment of Parkinson's disease.

Description

Pramipexole-Containing Matrix Tablet

The present invention relates to a matrix tablet for the modified release of pramipexole, and to a process for the preparation of such matrix tablets. The invention furthermore relates to pramipexole-containing matrix tablets for the treatment of Parkinson's disease. S)-2-Amino-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole is known by the INN name "pramipexole" and has the following structural formula:

Pramipexole is a dopamine agonist which is currently already being employed for the symptomatic treatment of idiopathic Parkinson's disease. Parkinson's disease is a progressive brain disorder with the symptoms shaking, slow movements and muscle stiffness. In patients who suffer from Parkinson's disease, dopamine-producing cells start to die off, so that the amount of dopamine in the brain decreases. Being a messenger substance, dopamine is involved in the regulation of movement and coordination. The consequence of a lack of dopamine is that the patients lose the ability of regulation. Pramipexole, being a dopamine agonist, is a substance which mimics the effect of dopamine and which stimulates the brain just like, or similar to, dopamine, so that the symptoms of Parkinson' s disease are alleviated.

Pramipexole can be employed not only for treating Parkinson's disease, but also for treating what is known as "restless-legs" syndrome. This is a disorder where patients, usually during the night, have an irresistible urge to move their limbs to provide relief of a sensation, in the limbs, which is experienced as unpleasant to painful. Pramipexole-containing tablets are currently already available in Germany under the trade name Sifrol^®. Not only tablets for the immediate release are available under this trade name, but also sustained-release tablets with active substance concentrations of 0.26 mg, 0.52 mg, 1.05 mg, 2.1 mg and 3.15 mg of pramipexole. The sustained-release tablets contain, as pharmaceutical adjuvants, hypromellose (hydroxypropylmethylcellulose HPMC), corn starch, Carbomer 941 (polyacrylic acid), highly-disperse silica and magnesium stearate. The sustained-release action is caused by the use of two polymers: Carbomer 941 as a non-swelling, pH-dependent polymer, and hypromellose as a swelling, pH-independent polymer. Suitable formulations are proposed for example in the international applications WO 2007/090881 and WO 2006/0159942.

These sustained-release tablets have a series of disadvantages. Firstly, the tablets must have a certain minimum size in order to make possible the required swelling of the swelling polymer. This is necessary in order to achieve a desired diffusion which obeys Fick's first law. Furthermore, a pronounced dependency on food and fluid can be observed since a sufficient amount of fluid must be available for a sufficient swelling of the tablet in the body. Furthermore, polymers in large amounts tend to form toxic degradation products and also to resinter, which has a disadvantageous effect on the release behaviour.

It is therefore an object of the present invention to overcome, or at least to lessen, one or more of the above mentioned disadvantages. In particular, it is intended to provide a sustained-release tablet which releases pramipexole essentially, independently of the food and fluid uptake.

This object was achieved by the matrix tablet according to the invention and by a process for its preparation.

The present invention relates to a matrix tablet for the modified release of pramipexole, comprising: a) 0.05 to 5% by weight of pramipexole or a pharmaceutically acceptable salt thereof,

b) 40 to 80% by weight of a matrix former which is selected from the group consisting of waxes, fats, oils, fatty acids having more than 12 carbon atoms, fatty alcohols, monoglycerides, diglycerides, triglycerides and mixtures of these,

c) 10 to 50% by weight of tableting agent,

d) 0 to 25% by weight of matrix modifier,

e) 0 to 5% by weight of flow regulator and

f) 0 to 5% by weight of lubricant,

based on the total weight of the matrix tablet.

In the present application, the total weight of the matrix tablet refers to the matrix tablet per se, that is to say to a matrix tablet which is not covered by a film or lacquer. Unless otherwise specified, the percentages by weight stated herein relate to the total weight of the matrix tablet.

The present invention furthermore relates to a process for the preparation of a matrix tablet according to the invention for the modified release of pramipexole, comprising:

(i) preparing a mixture comprising pramipexole or a pharmaceutically acceptable salt thereof a), matrix former b), tableting agent c), if appropriate matrix modifier d), if appropriate flow regulator e) and if appropriate lubricant f),

(ii) compression of the mixture obtained in step (i).

The invention furthermore relates to a matrix tablet according to the invention for the treatment of Parkinson's disease. The modification of the release, or the sustained-release action, of the matrix tablets according to the invention is based exclusively or at least essentially on the fact that pramipexole is embedded in a matrix of the above mentioned matrix formers, in particular, fats and waxes and substances related with them or similar thereto. These specific matrix formers have the advantage that, in comparison with the polymers used in the prior art, in particular in Sifrol^®, they are capable of better degradation in the body since the degradation takes place enzymatically via lipases and can therefore always take place in a uniform manner, independently of the amount of water present in the gastrointestinal tract. Besides the matrix formers, comparatively small amounts of matrix modifiers may optionally be present in the matrix, with the aid of which modifiers the properties of the matrix, and therefore the kinetics of the release of the active substance from the matrix, can be adjusted.

According to the invention, 0.05 to 5% by weight of pramipexole or a pharmaceutically acceptable salt thereof may be present in the matrix tablet. This may take the form of a salt or a mixture of salts. Salts are preferably understood as meaning acid addition salts such as, for example, hydrochlorides, carbonates, hydrogencarbonates, acetates, lactates, butyrates, propionates, sulphates, methanesulphonates, citrates, tartrates, nitrates, sulphonates, oxalates and/or succinates. Furthermore, the expression pramipexole and its salts is also understood as comprising pharmaceutically acceptable solvates, in particular hydrates. Pramipexole dihydrochloride monohydrate is especially preferably employed. Pramipexole may be present in the matrix tablet in amorphous or crystalline form.

In the description which follows, "pramipexole" will, for the sake of simplicity, be used not only for the free base, but also for salts and solvates thereof. Preferably, pramipexole is present in the matrix tablet in an amount of less than 1 % by weight, preferably up to a maximum of including 0.94% by weight or a maximum of including 0.92% by weight.

Furthermore preferred are matrix tablets with an amount of pramipexole, based on the free base, of 0.26 mg, 0.52 mg, 1.05 mg, 2.1 mg or 3.15 mg. In this context, the amount of 3.15 mg of pramipexole free base corresponds to an amount of 4.5 mg of pramipexole dihydrochloride monohydrate, to mention only one example. For example, pramipexole can be employed in a form in which 90% by volume of the pramipexole particles have a particle size of smaller than 190 μιη (Ο9ο = 190 μπι) and/or 50% by volume of the pramipexole particles have a smaller particle size than 80 μιη (D₅₀ = 80 μπι) and/or 10% by volume of the pramipexole particles have a smaller particle size than 21 μηι (D io = 2 1 μιη). In this context, "particle size" refers to the diameter of an equivalent particle of which it is assumed that it is spherical and that it has the same light-scattering pattern as the particle to be determined. In this context, the particle size is determined using laser diffractometry, for example with the aid of a Mastersizer 2000 from Malvern Instruments. Preferred is wet measurement on a dispersion of particles (2000 rpm, ultrasound 60 seconds, obscuration 4 to 15%). The evaluation is carried out in general for particles with a D₅₀ value of less than 5.0 μπι with the aid of the Mie method and for particles with a D₅₀ value of at least 5.0 μπι with the aid of the Fraunhofer method.

In a further example of an embodiment, pramipexole can be present in micronized form, where for example 90% by volume of the pramipexole particles have a particle size of smaller than 30 μπι (Dgo) or for example smaller than 20 μηι (Dgo).

According to the present invention, matrix formers are wax, fat, oil, fatty acid, fatty alcohol, monoglyceride, diglyceride, triglyceride and mixtures thereof. The matrix former may contain one or more of these substances. The definitions of the above mentioned matrix formers overlap to a certain extent and are specified hereinbelow:

Triglycerides are esters of the trihydric alcohol glycerol (glycerine, propane- 1 ,2,3-triol) with three carboxylic acid radicals (triester, also referred to as acyl glycerine). The carboxylic acid radicals can be identical or different. Diglycerides are esters of glycerol with two carboxylic acid radicals, i.e. only two of the three hydroxyl groups of the glycerol are esterified (diester). Depending on the position of the carboxylic acid radicals, one distinguishes between 1 ,2- and 1 ,3 -diglycerides. Here too, the carboxylic acid radicals may be identical or different. Monoglycerides are esters of glycerol with only one carboxylic acid radical, i.e. only one of the three hydroxyl groups of the glycerol is esterified (monoester). Examples of monoglycerides which can be employed in accordance with the invention are: glycerol (mono)behenate(2,3-dihydroxypropyl docosanate), glycerol monostearate, glycerol monocaprate, glycerol monococoate, glycerol monoerucate, glycerol monohydroxystearate, glycerol monoisostearate, glycerol monolanolate, glycerol monolaurate, glycerol monolinoleate, glycerol monomyristate, glycerol monooleate, glycerol monopalmitate, glycerol monoricinoleate, glycerol (mono)myristate, glycerol (mono)montanate and mixtures of these, such as, for example, glycerol palmitate stearate, the monoester of glycerol with a mixture of palmitic and stearic acid. Examples of diglycerides which can be employed according to the invention are diesters with identical carboxylic acid radicals as those which have been mentioned for the monoglycerides, for example glycerol dilaurate, glycerol dimyristate, glycerol dioleate, glycerol dipalmitate, glycerol distearate, glycerol diisostearate, and mixtures of these, and diesters with different carboxylic acid radicals (mixed diesters) such as, for example, glycerol palmitostearate (Precirol^®) and mixtures of these.

Triglycerides which can be employed in accordance with the invention comprise for example glycerol tricaprylate, glycerol trilaurate, glycerol trioleate, glycerol triricinoleate, glycerol tristearate and mixtures of these.

Mixtures of mono- and diglycerides, such as, for example, glycerol monooleate and glycerol dioleate, or glycerol monostearate and glycerol distearate, may also be used in accordance with the invention. Furthermore, it is possible to employ mixtures of mono- and triglycerides, mixtures of di- and triglycerides or mixtures of mono-, di- and triglycerides. However, it is also possible to employ mono-, di- and triglycerides in each case by themselves, that is to say triglycerides in the absence of mono- and/or diglycerides, diglycerides in the absence of mono- and/or triglycerides and monoglycerides in the absence of di- and/or triglycerides.

Preferred examples of glycerides or glyceride mixtures are glycerol monobehenate (Compritol^®), glycerol palmitostearate (Precirol^®), glycerol monostearate (Cutina GMS^®), neutral oil (mixture of short- and medium-chain triglycerides, preferably with the fatty acids caprylic acid and capric acid; Miglyol^®) and mixtures of these. "Fats" are understood as meaning esters of glycerol (glycerin) with three fatty acids, that is to say a certain group of carboxylic acids. They are, therefore, a subgroup of the triglycerides. The fatty acids in the ester of a fat may be different (mixed glycerides) or, alternatively, identical. The fatty acids can be saturated or unsaturated and even-numbered or odd-numbered. The physical properties of a fat are determined by the chain lengths and in particular by the frequency of double bonds, i.e. the degree of saturation, in the fatty acids. Fats can be solid or liquid at room temperature and atmospheric pressure (25°C, 1013 hPa). Fats which are liquid at room temperature and atmospheric pressure (25°C, 1013 hPa) are also referred to as fatty oils. The animal fats contain predominantly mixed glycerides of three acids, which are palmitic acid, stearic acid and oleic acid. Apart from glycerides of palmitic acid, stearic acid and oleic acid, the vegetable oils predominantly contain glycerol esters of the polyunsaturated acids. Examples of vegetable oils are sesame seed oil, olive oil, almond oil, corn oil, palm oil, peanut oil, coconut oil, rapeseed oil, wheatgerm oil, hemp seed oil, poppy seed oil, linseed oil, castor oil, sunflower oil, cotton seed oil and soybean oil. Presently, hydrogenated, or hardened, fats and oils are also comprised, for example hardened, or hydrogenated, castor oil (for example Cutina HR^®), which is a preferred embodiment of the present matrix formers. Derivatized fats such as, for example, polyoxyethylated fats are less preferably present, or advantageously not present at all.

Fatty acids are saturated or unsaturated carboxylic acids. The fatty acids containing more than 12 carbon atoms which can be employed in accordance with the invention are referred to as higher fatty acids. As a rule, and preferred within the present context, fatty acids are unbranched, i.e. straight-chain. Examples of fatty acids which can be used in accordance with the invention are: tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachinic acid, behenic acid, lignoceric acid, cerotic acid, melissic acid, palmitoleic acid, oleic acid, erucic acid, linoleic acid, linolenic acid, elaeostearic acid, arachidonic acid and clupanodonic acid. A preferred fatty acid is stearic acid. Within the context of the present invention, oils comprise the fatty oils which have already been mentioned hereinabove, liquid paraffin and liquid propylene glycol diesters of fatty acids such as, for example, Miglyol^® 840.

Fatty alcohols are linear, saturated or unsaturated primary alcohols (1 -alkanols) having at least six carbon atoms, preferably 6 to 22 carbon atoms. In most cases, they are obtained from fatty acids by means of reduction. In the present context, the fatty alcohols are also intended to include those which have more than 22 carbon atoms and which are sometimes referred to as "wax alcohols". Examples of fatty alcohols are: capronic alcohol (1 -hexanol), oenanthic alcohol (1 -heptanol), caprylic alcohol (1 -octanol), pelargonic alcohol (1 -nonanol), capric alcohol (1 -decanol), 1 -undecanol, 10-undecen-l -ol, lauryl alcohol (1 - dodecanol), 1 -tridecanol, myristyl alcohol (1 -tetradecanol), 1 -pentadecanol, cetyl alcohol (1 -hexadecanol), 1 -heptadecanol, stearyl alcohol (1 -octadecanol), oleyl alcohol (9-cz.s-octadecen- l -ol), erucyl alcohol (9-tra«i-octadecen- l -ol), ricinol alcohol (9-czs-octadecen- l , 12-diol), linoleyl alcohol (all-cis-9, \2- octadecadien- l -ol), linolenyl alcohol (a/7-c/s-9, 12, 15-octadecatrien-l -ol), 1 - nonadecanol, arachidyl alcohol (1 -eicosanol), gadoleyl alcohol (9-c/s-eicosen- l -ol), 5,8, 1 , 14-eicosentetraen- l -ol, 1 -heneicosanol, behenyl alcohol (1 - docosanol), erucyl alcohol ( l -S-c/s-docosen- l -ol), brassidyl alcohol ( \ - -trans- docosen-l -ol), lignoceryl alcohol, ceryl alcohol, myricyl alcohol. A preferred example is stearyl alcohol. Waxes are typically understood as meaning, phenomenologically, those substances which at 20°C (and 1013 hPa) are malleable, solid to brittle hard, have a coarsely- to finely-crystalline structure, are translucent to opaque, but not glossy, melt at above 40°C (and 1013 hPa) without decomposition and have low viscosity even immediately above their melting point. Their consistency and solubility is highly temperature-dependent, and they can be polished with light pressure. In the present context, waxes are preferably furthermore selected from the group consisting of, or comprising, esters of fatty acids, preferably higher fatty acids (C>12), with alcohols with the exception of glycerol, preferably long-chain aliphatic alcohols, in particular the abovementioned wax alcohols (C>22), or mixtures of such esters. Waxes can be solid or liquid at room temperature and atmospheric pressure (25°C, 1013 hPa). Examples of waxes are natural waxes such as plant waxes, animal waxes or petrochemical waxes. Examples of these are carnauba wax, myrtle wax, japan wax, sugarcane wax (of vegetable origin), beeswax (of animal origin), paraffin wax or microcrystalline wax (petrochemical waxes). Preferably not comprised by the expression wax are, in the present context, so-called synthetic waxes.

According to the invention, it is also possible to use solutions of waxes in organic oils, or highly viscous wax.

Matrix formers b) which are preferably employed are those which are solid at room temperature and atmospheric pressure (25°C, 1013 hPa). In preferred embodiments, the matrix former b) is selected from the group consisting of carnauba wax, stearic acid, glycerol behenate, glycerol monostearate, hydrogenated castor oil and mixtures of these. An example which is preferably employed is glycerol behenate in combination with stearic acid, or carnauba wax in combination with stearic acid, or a combination of glycerol behenate, hydrogenated castor oil and glycerol monostearate. Stearic acid may also be employed as the only matrix former in advantageous embodiments. In general, a combination of a plurality of matrix formers permits a finely tuneable control of the release properties of the matrix, while the use of a single matrix former has the advantage of a simplified preparation process.

At least 40% by weight of the abovementioned matrix formers b) is employed, based on the total weight of the matrix tablet, preferably more than 40% by weight, for example at least 40.5% by weight, such as at least 41 % by weight and preferably more than 45% by weight, for example at least 45.5% by weight. In advantageous embodiments, the content of matrix former b) can be more than 50% by weight, for example at least 50.5% by weight, preferably more than 55% by weight and especially preferably more than 60% by weight. Here, a maximum of 80% by weight of matrix former b) is employed, preferably up to and including 75, 74, 70 or 69% by weight.

In embodiments in which stearic acid is used as matrix former b) or part of the matrix former b), the matrix former preferably amounts to between 45 and 65%) by weight of the total weight of the matrix tablet. If stearic acid is employed as matrix former b) for example together with another matrix former, such as, for example, glycerol behenate or carnauba wax, the amount of stearic acid used is preferably 25 to 35% by weight and the total amount of matrix former b) 50 to 70% by weight, especially preferably 55 to 65% by weight, in each case based on the total weight of the matrix tablet.

Glycerol behenate is preferably employed in combination with at least one further matrix former b). A combination of glycerol behenate and a single further matrix former preferably amounts to at least 55% by weight of the total weight of the matrix tablet, with glycerol behenate preferably amounting to at least 20 to 40% by weight of the total weight of the matrix tablet, i.e. approximately half of the weight of the matrix former, or more. A combination of glycerol behenate and two further matrix formers preferably amounts to at least 55% by weight of the total weight of the matrix tablet, with glycerol behenate preferably amounting to 15 to 35% by weight, preferably 17.5 to 25.0% by weight, of the total weight of the matrix tablet. If a combination of two matrix formers b) is employed, this is done for example in a ratio of the weight proportions of the first and second matrix former of from 10: 1 to 1 : 10, for example 2: 1 to 1 :2, preferably 1.5 : 1 to 1 : 1.5, and even more preferably 1.25 : 1 to 1 : 1.25. This preferably applies in particular to combinations of a matrix former b) and glycerol behenate, carnauba wax or stearic acid, for example the combinations of glycerol behenate and carnauba wax or the combination of glycerol behenate and stearic acid.

If a combination of three matrix formers b) is employed, this is done for example in a ratio of the proportions by weight, or ranges of proportions by weight, of the first to the second to the third matrix former of 1 :(0.1 to 10) :(0.1 to 10), preferably 1 :(0.5 to 2):(0.5 to 2), and more preferably 1 :(0.75 to 1.25):(0.75 to 1.25). Optionally, it is possible to employ, in addition to the matrix former b), a matrix modifier d), and this up to including 25% by weight of the total weight of the matrix tablet. In examples of embodiments, the matrix modifier d) is present in amounts of from 1 to 22% by weight, preferably 3 to including 20% by weight, of the total weight of the matrix tablet.

If a matrix modifier d) is employed, the matrix modifier d) comprises, or is, preferably, a pH-dependent adjuvant, preferably a pH-dependent polymer, or a mixture of pH-dependent adjuvants or, preferably, pH-dependent polymers. The matrix modifier d) preferably consists of a single pH-dependent polymer.

A pH-dependent adjuvant such as, for example, a polymer is understood as meaning, within the scope of the present invention, those adjuvants whose retarding activity differs at different pH values, i.e. adjuvants which release the active substance at different rates at different pH values (for example pH 1 .2 and pH 6.8). The pH-dependent adjuvant is preferably selected in such a way that the release of pramipexole from the matrix tablet in the first 4 hours at pH 1 to pH 6.8, using the USP testing apparatus I (basket) and a speed of rotation of 100 revolutions per minute in 750- 1000 ml of medium at a temperature of 37°C, is reduced to not more than 50%.

For example, the matrix modifier d) can be selected from the following group of pH-dependent adjuvants:

- polymers of acrylic acid (polyacrylic acid) and their derivatives, polyacrylates and their derivatives, copolymers of methacrylic acid and methyl methacrylate,

- hydrophilic cellulose-based polymers, for example cellulose esters and cellulose ethers, and their salts and derivatives, for example carboxymefhylcellulose sodium, carboxymethylcellulose calcium, carboxymethylethylcellulose sodium, carboxymethylethylcellulose calcium, cellulose acetate phthalate, cellulose diacetate phthalate, cellulose triacetate phthalate, hydroxypropylmethylcellulose phthalate, sodium cellulose acetate phthalate, cellulose ester phthalate, cellulose ether phthalate, cellulose ester ether phthalate, hydroxypropylcellulose phthalate, methylcellulose phthalate,

- polysaccharides such as, for example, alginates, gum Arabic, xanthan gum, chitin derivatives such as chitosan, and carrageenan,

- keratin,

- and mixtures of these.

Preferred matrix modifiers d) are polysaccharides and polymers of acrylic acid (polyacrylic acid), with carrageenan being especially preferred. Carrageenan is a polysaccharide extract from carrageen (dried red algae from the North Atlantic). Carrageenan is an anionic polyelectrolyte with a high electrical charge. Preferred polymers of acrylic acid are known by the trade name Carbopol^® or Carbomer. Examples which are suitable are polyacrylic acids with a viscosity of a 0.5% (w/v) solution in water of 4000-40 000 mPa*s.

A combination of polyacrylic acid (Carbopol^®), stearic acid and glycerol behenate (Compritol^®) and a combination of polyacrylic acid (Carbopol^®), carnauba wax and stearic acid have proved to be especially advantageous. If hydrophilic polymers from the group of polyacrylic acid or its derivatives, polyacrylates or their derivatives, or copolymers of methacrylic acid and methacrylate, preferably in each case alone or in combination, are employed as matrix modifier d), then these polymers amount preferably to from 1.0 to 10.0% by weight, more preferably to from 2.0 to 7.5% by weight and most preferably to from 2.5 to 5.0% by weight of the total weight of the matrix tablet. If these hydrophilic polymers are employed as the only matrix modifiers d), they are advantageously employed in a weight ratio of matrix modifier d) to matrix former b) which is in the range of from, for example, 1 : 10 to 1 :30, preferably 1 : 12 to 1 :25 and especially preferably between 1 : 15 to 1 : 18.

If a polysaccharide or polysaccharide mixture such as, for example, carrageenan, preferably on its own, is employed as the matrix modifier d), it preferably amounts to from 5.0 to 25.0% by weight, more preferably to from 7.5 to 22.5% by weight and most preferably to from 9.0 to 21.0% by weight of the total weight of the matrix tablet.

A combination of carrageenan and stearic acid has proved to be particularly advantageous. In such combinations, the carrageenan amounts to preferably from 2.0 to 5.0% by weight of the total weight of the matrix tablet, and the stearic acid to preferably from 45.0 to 65.0% by weight.

In preferred embodiments, the matrix modifier d) acts as a wicking agent. In general, a wicking agent is understood as meaning an agent with the ability of drawing a biological fluid (preferably water) into a solid, for example by means of physisorption. Physisorption is defined as a form of adsorption in which the molecules of the fluid can adhere to the surface of the wicking agent, preferably by means of van-der-Waals bonds between the surface of the wicking agent and the adsorbed liquid molecule (preferably water). A wicking agent can bring this about with or without swelling. A wicking agent in the matrix tablets according to the invention can bring about, or promote, the development of channels or pores in the matrix or the matrix tablet. This can facilitate the penetration of the water molecules, in particular by physisorption. The function of the wicking agent is therefore that of transporting water towards the inside of the matrix tablet and thereby to create channels in, or a network on, an enlarged surface. By using a matrix modifier and in particular a wicking agent, the disintegration properties of the matrix in total, and thereby the release behaviour of the matrix, or the matrix tablet, can be controlled in an advantageous manner.

The matrix tablet according to the invention furthermore contains a tableting agent c) in an amount of from 10 to 50% by weight, preferably 15 to 45% by weight and, for example, 17.5 to 42.5% by weight.

The tableting agent c) is preferably selected from among the pharmaceutical fillers which are conventional in the art. These are typically substances which are required for building the body of the oral dosage form in dosage forms with small amounts of active substance, in order to obtain a sufficient amount of dosage composition for a suitable dosage size.

Tableting agents c) which can be employed are, for example, alkali or alkaline earth metal salts such as calcium phosphates, for example calcium hydrogenphosphate (CaHP0₄, for example in the form of the dihydrate or, preferably, of the anhydrate), calcium carbonate, magnesium carbonate, magnesium oxide, calcium sulphate, sodium chloride, potassium chloride, lactose, lactose derivatives, starch, starch derivatives, treated starch, chitin, cellulose and derivatives thereof, for example microcrystalline cellulose (for example Avicel^®), sucrose, dextrates, dextrin, dextrose, maltodextrin, kaolin and mixtures of these. It is also possible to use Si0₂-modified microcrystalline cellulose (for example Prosolv^®, Rettenmaier & Sonne, Germany). Sugar alcohols and/or sugars (in particular mono- and disaccharides) such as mannitol, sorbitol, xylitol, Isomalt, glucose, fructose, maltose and mixtures of these are also used. In principle, it is also possible to use mixtures of the abovementioned tableting agents. The tableting agent employed, preferably the only tableting agent employed, is, preferably, calcium hydrogenphosphate (CaHP0₄, for example in the form of the anhydrate). The matrix tablet according to the invention can optionally also contain a flow regulator e), preferably up to an amount of 5% by weight of the total weight of the matrix tablet.

The purpose of flow regulators in a tableting mixture is, generally, to reduce the interparticulate friction (cohesion) between the individual particles and the adhesion of the latter on the wall areas of the mould. An example of a flow regulator, that is to say an additive for improving the flowability of the powder, is disperse silica (for example Aerosil^®). It is preferred to use silica with a specific surface area of 50 to 400 m²/g, as determined by gas adsorption as specified in Ph. Eur., 6^th edition, 2.9.26. The flow regulator e) may consist of one substance or else of a substance mixture.

A flow regulator e) can be used for example in an amount of from 0.1 to 5% by weight, preferably from 0.3 to 3% by weight, more preferably from 0.5 to 2.5% by weight, based on the total weight of the matrix tablet.

The matrix tablet can furthermore comprise a lubricant f), preferably in an amount up to 5% by weight, based on the total weight of the matrix tablet. In preferred embodiments, the matrix tablet contains lubricants f). The purpose of lubricants is, generally, to reduce the sliding friction. In particular, it is intended to reduce the sliding friction which exists firstly between the pistons which reciprocate within the die chamber and the die wall and, secondly, between the tablet band and the die wall, during tableting. Examples of suitable lubricants f) are sodium stearyl fumarate (Pruv^®), magnesium stearate and/or calcium stearate. Magnesium stearate is preferred in this context.

The lubricant f) can be used for example in an amount of from 0.1 to 4% by weight, preferably from 0.3 to 3% by weight, more preferably from 0.5 to 2% by weight, based on the total weight of the matrix tablet. Further adjuvants may optionally be present in the matrix tablet according to the invention. In preferred embodiments, the matrix tablets will, however, be composed of components a) to f) in the percentages stated, without further adjuvants being present. The components a) to f) are preferably different from each other, that is to say no constituent fulfils more than one function. If, for example, stearic acid is employed as matrix former, stearic acid is preferably not additionally also used as lubricant. Preferably, in each case only one substance, preferably in each case only one compound, is employed for each of components c) to f) of the matrix tablet.

The matrix tablets are intended to release the active substance in a modified manner. In preferred embodiments, the release profile of the matrix tablets according to the invention shows, during measurement using the USP apparatus I (basket) in phosphate buffer at pH 6.8 (900 ml, 100 revolutions per minute, 37°C), after 1 hour, a released content of at least approximately 10% of the active substance and/or after 4 hours at least approximately 25% of the active substance and/or after 8 hours at least approximately 40% of the active substance and/or after 16 hours at least approximately 60% of the active substance and/or after 24 hours at least approximately 80% of the active substance. Furthermore, the release profile (in accordance with the above USP method) is, after the individual times, preferably within the ranges specified hereinbelow, and it is preferred that the release specifications are met for all the times indicated:

Furthermore, the matrix tablets according to the invention are especially preferably monolithic, in other words, they are composed of a single discrete functional unit. This is in contrast to the so-called multiparticulate systems, where a tablet disintegrates into many subunits, each of which releasing the active substance independently of the other. What is not provided in particular are so-called agglomeration pellets, where the active substance is applied to inert starter nuclei. This means further that the matrix tablet has an essentially homogeneous active-substance distribution and adjuvant distribution over its entire cross-section. In this respect, moreover, only one release profile exists for the active substance; preferably, no delay principles or delay structures which differ from each other and which would provide different release profiles for different parts of the active substance are provided.

Embodiments of the matrix tablets according to the invention preferably have a mass of 150 to 600 mg, preferably 200 to 550 mg, or especially preferably 240 to 500 mg.

For the purposes of the invention, the resulting tablets may be in coated or uncoated form (with or without a film). Film formers used for the coating can be for example cellulose derivatives such as methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), methacrylic acid/acrylate copolymers such as, for example, methacrylic acid/ethacrylate copolymer or methacrylic acid/methyl methacrylate copolymer, vinyl polymers, such as, for example, polyvinylpyrrolidone or polyvinyl acetate phthalate, or natural film formers, such as, for example, shellac. By special preference, the coating does not contain any pramipexole. The thickness of the layer, if present, is usually from 0.1 to 100 μηι, preferably from 1 to 80 μπι.

It is greatly preferred that the layer which is optionally applied has essentially no effects on the release. It therefore preferably takes the form of layers or films without any, or with a negligible degree of, influence on the release of the active substance. For the purposes of the present invention, it is preferred to use neither gastric-resistant film coatings nor release-delaying coatings. The resulting tablets preferably have a hardness of from 20 to 150 N, especially preferably from 20 to 100 N, in particular from 25 to 50 N. The hardness is determined as specified in Ph. Eur. 6.0, section 2.9.8. Furthermore, the resulting tablets preferably have low friability, in other words for example a friability of from 0.1 to 0.8%, preferably from 0.2 to 0.6% and especially preferably from 0.3 to 0.5%. The friability is determined as specified in Ph. Eur. 6.0, section 2.9.7. As already mentioned, the process according to the invention for the preparation of a matrix tablet according to the invention for the modified release of pramipexole comprises the following steps:

(ii) compression of the mixture obtained in step (i) to give a matrix tablet.

In step (i), further pharmaceutically acceptable adjuvants may optionally be added, but analogously to what has been said above regarding the matrix tablet it is preferred that no further adjuvants are employed besides the components a) to f). Otherwise, what has been said for the matrix tablets according to the invention also applies analogously to the process according to the invention. In a preferred embodiment, pramipexole and adjuvants b) to f) are employed in powder form; the resulting mixture is therefore a powder mixture. In what follows, reference is made, for the sake of simplicity, in each case to the adjuvants b) to f), with the adjuvants d) to f) being optional in accordance with the process according to the invention. The reference to all adjuvants, therefore, does not mean that all these adjuvants must necessarily be present.

Direct tableting is one of the especially preferred embodiments of the process according to the invention. In this process, a solids mixture or powder mixture of active substance and adjuvants b) to f) is compressed to give a matrix tablet. Accordingly, the process according to the invention comprises the following steps:

(i) preparation of a mixture comprising pramipexole or a pharmaceutically acceptable salt there of a), matrix former b), tableting agent c), if appropriate matrix modifier d), if appropriate flow regulator e) and if appropriate lubricant f) by mixing pramipexole or a pharmaceutically acceptable salt there of a), matrix former b), tableting agent c), if appropriate matrix modifier d), if appropriate flow regulator e) and if appropriate lubricant f), in each case preferably in solid form and more preferably in powder form, and immediately thereafter, i.e. without further working-up of the mixture,

(ii) compressing the mixture obtained in step (i) to give a matrix tablet. In the present context, "mixing" is understood as meaning a method for combining substances with the aim of essentially homogeneously distributing various substances by the action of mechanical forces. Mixing can be performed in customary mixing apparatuses, such as, for example, roller mixers, shaker mixers, gravity mixer, shear mixer, ploughshare mixer, planetary mixer- kneader, Z- or sigma kneader or fluid mixer or intensive mixers. It is preferred to use a gravity mixer.

The time for the mixing step (i) can be, for example, from 0.5 minutes to 1 hour, preferably from 2 minutes to 50 minutes, more preferably from 3 minutes to 30 minutes. The mixing step can comprise, for example, the joint grinding of pramipexole a) and matrix former b) and/or tableting agent c) and/or, if appropriate, matrix modifier d) and/or, if appropriate, one or more further adjuvants.

The tableting machines conventionally used for the preparation of tablets may be used for compressing. It is preferred to use rotary presses or eccentric presses. In the case of rotary presses, a compressive force of 2 to 40 kN, preferably from 2.5 to 35 kN, is usually employed. In the case of eccentric presses, a compressive force of 1 to 20 kN, preferably from 2.5 to 10 kN, is usually employed. For example, the iva Piccola machine is used.

In a preferred embodiment of the process according to the invention, step (i) comprises the following substeps:

(i- 1) mixing of pramipexole or of a pharmaceutically acceptable salt thereof a) with matrix former b) and, if appropriate, matrix modifier d),

(i-2) if appropriate, granulation of the mixture obtained in step (i- 1),

(i-3) addition of tableting agent c), if appropriate flow regulator e) and/or lubricant f) and/or one or more further adjuvants to the mixture obtained in step (i- 1 ) or, if appropriate, to the granules obtained in step (i-2).

It is, therefore, preferred to mix the constituents a) to f) (and, if appropriate, further adjuvants) of the tablet stepwise with each other. In a first step of this embodiment, pramipexole and matrix former b) and, if appropriate, matrix modifier d) are mixed with each other. If a matrix modifier d) is used, it is preferably mixed with matrix former b) and pramipexole a) in this first step, i.e. before the addition of other adjuvants. It is preferred not to add further adjuvant in this step.

Step (i- 1) can also be subdivided further into substeps, for example by initially mixing pramipexole and matrix former b) with each other, before admixing matrix modifier d), and/or portions of the matrix former b) can be admixed stepwise.

A granulation may optionally be carried out as step (i-2). This granulation may take the form of a dry granulation, a wet granulation or else a melt granulation, with wet and dry granulation being preferred. The two last-mentioned granulation types have the advantage of being more gentle for active substance and adjuvants. In addition, dry granulation, in particular, is an economical process. By "granulating" there is generally understood the formation of coarser or more granular clusters than powders by agglomerating and/or aggregating finer powder particles (agglomeration granulation) and/or the formation of finer granules by dividing coarser aggregates (disintegrating granulation). Dry granulation is generally performed by applying pressure or temperature. Wet granulation is generally performed using dispersants and, optionally, surface stabilizers. Granulation is generally performed in customary granulation devices, such as, for example, extruder granulators, punch-disc granulators, perforated-roller granulators or fluidized-bed granulators. It is also possible to use mechanical mixers or spray dryers.

The granulation time will, in particular in the case of wet granulation, usually amount to from 1 minute to 1 hour, preferably 2 minutes to 30 minutes. Dry granulation is usually carried out as a continuous process.

In one embodiment of the process according to the invention, in which step (i-2) provides a dry granulation, the mixture of step (i- 1 ) is compacted to give a slug. The compacting conditions here are preferably chosen such that the slug

3 3 has a density of from 1.03 to 1.8 g/cm , in particular from 1.05 to 1.7 g/cm . Compacting is preferably carried out in a roller granulator. Here, the rolling force per roller width preferably amounts to from 2 to 50 kN/cm, more preferably to from 4 to 30 kN/cm, in particular to from 10 to 25 kN/cm. The gap width of the roller granulator is, for example, from 0.8 to 5 mm, preferably from 1 to 4 mm, more preferably from 1.5 to 3 mm, in particular from 1.8 to 2.8 mm. The slug is subsequently preferably granulated. Granulating can generally be performed using processes known in the prior art. In a preferred embodiment, the granulation of the slug is effected in a sieve mill. In this case, the mesh size of the sieve insert usually amounts to from 0.063 to 2 mm, preferably to from 0.5 to 1.5 mm, in particular preferably to from 0.71 to 1.25 mm. It is preferred only to use the mixture of step (i- 1) for the dry granulation method. If appropriate, but not by preference, it is also possible to add small amounts of other pharmaceutical adjuvants.

Wet granulation, too, can be performed using customary methods. To carry out the wet granulation method, it is likewise preferred only to use the mixture of step (i-1 ). If appropriate, but not by preference, it is possible to add relatively small amounts of other pharmaceutical adjuvants. The wet granulation can be performed for example using a class 3 dispersant or solvent, for example isopropanol, ethanol, a mixture of ethanol and water, aqueous solutions or pure water. The use of pure water is preferred in this context. It can be carried out for example in a fluidized-bed granulator or in a mixer, such as, for example, a mechanical mixer. For wet granulation, again, a sieve with a mesh size of from 0.063 to 2 mm, preferably from 0.5 to 1 .5 mm, in particular preferably from 0.71 to 1.25 mm, through which the wet substance is passed, is preferably employed.

If a wet granulation is carried out in step (i-2), a "drying" step is usually employed. The drying step is presently considered to be part of the wet granulation step (i-2).

For the purposes of the present invention, "drying" is understood as meaning the removal of liquids which adhere to solids. In general, drying is carried out in customary drying devices, for example drying cabinets, hurdle dryers, vacuum dryers, fluidized-bed dryers, spray dryers or freeze-dryers. The drying and granulation process is preferably carried out in one apparatus. The drying conditions are preferably chosen in such a way that the water content of the resulting granules amounts to from 0.1 to 5% by weight, preferably to from 1 to 3% by weight. When using organic solvents and/or dispersants, the content of solvents and/or dispersants of the resulting granules is in each case preferably 1 to 5000 ppm, preferably 5 to 100 ppm. The optional granulation in step (i-2) can also be a melt granulation. In this context, the melt granulation can be carried out for example in such a way that a melt of, for example, the matrix former b) and, optionally, of the matrix modifier d) and, optionally, of one or more further adjuvants of the matrix tablet according to the invention is added to an active substance and, optionally, a powder containing one or more further adjuvants of the matrix tablet according to the invention, for example by pouring in or spraying in of the melt.

In the embodiment of the process according to the invention which comprises a granulation step, therefore, the adjuvants tableting agent c), if appropriate flow regulator e) and/or lubricant f) and/or one or more further adjuvants, added after the granulation step, are present in the resulting matrix tablet in intergranular form, i.e. they are present between the granule particles.

In the present text, the indication of various steps in the processes according to the invention is preferably to be understood as meaning that the steps follow each other in the order stated, preferably without the insertion of further steps.

The invention is illustrated in greater detail by examples hereinbelow, with reference to the figures. The figures show:

Figure 1 release profiles of the matrix tablet prepared in accordance with

Example 1 ,

Figure 2 release profiles of the matrix tablet prepared in accordance with

Example 2, and

Figure 3 a release profile of the matrix tablet prepared in accordance with

Example 6.

EXAMPLES

Example 1: Direct tableting Pramipexole dihydrochloride monohydrate 4.5 mg

Carbopor 71 G 17.15 mg

Compritor 888 ATO 146.75 mg

Stearic acid 146.75 mg

Calcium hydrogenphosphate 171.35 mg

Magnesium stearate 3.5 mg

Pramipexole dihydrochloride monohydrate together with Carbopol , Compritol^® and stearic acid was mixed for 10 min in a gravity mixer (Turbula^® TB 10). After the addition of calcium hydrogenphosphate, the mixture was mixed for a further 10 min (if appropriate screened), and magnesium stearate was added (if appropriate through a 0.5 mm sieve). The mixture obtained was mixed for a further 3 min. The resulting mixture was subsequently compressed in a rotary press (Riva). Release profiles of the matrix tablet thus prepared are shown in Figure 1 . The release profiles were measured using the following measuring conditions:

1 ) USP test apparatus I (basket) using 900 ml of 0.1 N HC1 at pH 1.2, using a speed of 100 revolutions per minute and at a temperature of 37°C (abbreviated to "pH 1.2");

2) USP test apparatus I (basket) using 750 ml of 0.1 N HC1 at pH 1.2 for the first two hours and then change of the pH to pH 6.8 by adding 250 ml of phosphate buffer, using a speed of 100 revolutions per minute and at a temperature of 37°C (abbreviated to "0.1 N HC1 + phosphate buffer");

3) USP test apparatus I (basket) using 900 ml of phosphate buffer at pH 6.8, using a speed of 100 revolutions per minute and at a temperature of 37°C (abbreviated to "pH 6.8"). Example 2: Direct tableting

Pramipexole dihydrochloride monohydrate 4.5 mg

Carrageenan 49.0 mg

Stearic acid 235.45 mg

Calcium hydrogenphosphate 196.15 mg

Magnesium stearate 4.9 mg

Pramipexole dihydrochloride monohydrate together with carrageenan and stearic acid was mixed for 10 min in a gravity mixer (Turbula^® TB 10). After the addition of calcium hydrogenphosphate, the mixture was mixed for a further 10 min (if appropriate screened), and magnesium stearate was added (if appropriate through a 0.5 mm sieve). The mixture obtained was mixed for a further 3 min. The resulting mixture was subsequently compressed in a rotary press (Riva).

Release profiles of the matrix tablet thus prepared are shown in Figure 2. The release profiles were measured as specified in Example 1. Example 3: Direct tableting

Pramipexole dihydrochloride monohydrate 4.5 mg

Carrageenan 98.0 mg

Stearic acid 294.0 mg

Calcium hydrogenphosphate 88.6 mg

Magnesium stearate 4.9 mg

Example 4: Wet granulation

Pramipexole dihydrochloride monohydrate 4.5 mg

Carrageenan 45.0 mg

Stearic acid 294.0 mg

Calcium hydrogenphosphate 141.6 mg

Magnesium stearate 4.9 mg

Water 100.0 mg

Pramipexole dihydrochloride monohydrate together with carrageenan and stearic acid was mixed for 10 min in a gravity mixer (Turbula^® TB 10). Thereafter, water was granulated in and the mixture was dried. After the addition of calcium hydrogenphosphate, the resulting granules were mixed for a further 10 min (if appropriate screened), and magnesium stearate was added (if appropriate through a 0.5 mm sieve). The mixture obtained was mixed for a further 3 min. The resulting mixture was subsequently compressed in a rotary press (Riva).

Example 5: Wet granulation

Pramipexole dihydrochloride monohydrate 4.5 mg

Carbopol^® 71 G 17.15 mg

Compritol^® 888 ATO 146.75 mg

Stearic acid 146.75 mg

Calcium hydrogenphosphate 169.95 mg

Magnesium stearate 4.9 mg

Water 100.0 mg

Pramipexole dihydrochloride monohydrate together with Carbopol , Compritol^® and stearic acid was mixed for 10 min in a gravity mixer (Turbula^® TB 10). Thereafter, water was granulated in and the mixture was dried. After the addition of calcium hydrogenphosphate, the granules were mixed for a further 10 min (if appropriate screened), and magnesium stearate was added (if appropriate through a 0.5 mm sieve). The mixture obtained was mixed for a further 3 min. The resulting mixture was subsequently compressed in a rotary press (Riva).

Example 6: Direct tableting

Pramipexole dihydrochloride monohydrate 4.5 mg

Compritol^® 888 ATO 100.0 mg

Cutina HR^® 100.0 mg

Cutina GMS^® 100.0 mg

Calcium hydrogenphosphate 180.6 mg

Magnesium stearate 4.9 mg Pramipexole dihydrochloride monohydrate together with Compritol was mixed for 10 min in a gravity mixer (Turbula^® TB 10). After the addition of Cutina HR^® and Cutina GMS^®, the mixture was mixed for a further 10 min (if appropriate screened). Thereafter, calcium hydrogenphosphate and magnesium stearate were added (if appropriate through a 0.5 mm sieve). The resulting mixture was mixed for a further 3 min. The resulting mixture was subsequently compressed in a rotary press (Riva).

A release profile of the thus-prepared matrix tablet in an aqueous solution with a pH of 6.8 is shown in Figure 3. The release profile was measured as specified in Example 1 (measuring conditions 3).

Example 7: Direct tableting

Pramipexole dihydrochloride monohydrate 4.5 mg

Carbopol^® 71 G 17.15 mg

Carnauba wax 140.0 mg

Stearic acid 150.5 mg

Calcium hydrogenphosphate 170.35 mg

Aerosil^® 200 3.0 mg

Magnesium stearate 4.5 mg

Pramipexole dihydrochloride monohydrate together with Carbopol , carnauba wax and stearic acid was mixed for l O min in a gravity mixer (Turbula^® TB 10). After the addition of calcium hydrogenphosphate and Aerosil^®, the mixture was mixed for a further l O min (if appropriate screened), and magnesium stearate was added (if appropriate through a 0.5 mm sieved). The resulting mixture was mixed for a further 3 min. The resulting mixture was subsequently compressed in a rotary press (Riva).

Claims

Matrix tablet for the modified release of pramipexole, comprising:

a) 0.05 to 5% by weight of pramipexole or a pharmaceutically acceptable salt thereof,

b) 40 to 80% by weight of a matrix former which is selected from the group consisting of waxes, fats, oils, fatty acids having at least carbon atoms, fatty alcohols, monoglycerides, diglycerides, triglycerides and mixtures of these,

c) 10 to 50% by weight of tableting agent,

d) 0 to 25% by weight of matrix modifier,

e) 0 to 5% by weight of flow regulator and

f) 0 to 5% by weight of lubricant,

based on the total weight of the matrix tablet.

Matrix tablet according to Claim 1 , where the matrix modifier d) comprises a pH-dependent polymer.

Matrix tablet according to Claim 1 or 2, where the matrix modifier d) is selected from the group consisting of polysaccharides, alginates, polymers of acrylic acid and their derivatives, polyacrylates and their derivatives, copolymers of methacrylic acid and methyl methacrylate, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylethylcellulose sodium, carboxymethylethylcellulose calcium, cellulose acetate phthalate, cellulose diacetate phthalate, cellulose triacetate phthalate, gum arabic, xanthan gum, chitin derivatives such as chitosan, hydroxypropylme hylcellulose phthalate, sodium cellulose acetate phthalate, cellulose ester phthalate, cellulose ether phthalate, cellulose ester ether phthalate, hydroxypropylcellulose phthalate, methylcellulose phthalate, keratin, carrageenan and mixtures of these.

4. Matrix tablet according to one of Claims 1 to 3, where the matrix modifier d) is selected from the group consisting of polysaccharides and polymers of acrylic acid, and is preferably carrageenan.

5. Matrix tablet according to one of Claims 1 to 4, where the tableting agent c) comprises calcium hydrogenphosphate.

6. Matrix tablet according to one of Claims 1 to 5, where the matrix former b) is selected from the group consisting of carnauba wax, stearic acid, glycerol behenate, glycerol monostearate, hydrogenated castor oil and mixtures of these.

7. Matrix tablet according to Claim 6, where the matrix former b) comprises a combination of glycerol behenate, hydrogenated castor oil and glycerol monostearate.

8. Matrix tablet according to one of Claims 1 to 6, where the matrix former b) is stearic acid and the matrix modifier d) is carrageenan.

9. Matrix tablet according to one of Claims 1 to 6, where the matrix former b) is a combination of stearic acid and glycerol behenate or a combination of stearic acid and carnauba wax and the matrix modifier d) is a polyacrylic acid.

10. Matrix tablet according to one of Claims 1 to 7, where the matrix modifier d) amounts to 0% by weight.

1 1. Matrix tablet according to one of Claims 1 to 10, comprising less than 1 % by weight of pramipexole or a pharmaceutically acceptable salt thereof.

12. Process for the preparation of a matrix tablet for the modified release of pramipexole according to one of Claims 1 to 1 1 , comprising: (i) preparing a mixture comprising pramipexole or a pharmaceutically acceptable salt thereof a), matrix former b), tableting agent c), if appropriate matrix modifier d), if appropriate flow regulator e) and if appropriate lubricant f),

(ii) compression of the mixture obtained in step (i).

13. Process according to Claim 12, where step (i) comprises the following substeps:

(i- 1 ) mixing of pramipexole or of a pharmaceutically acceptable salt thereof a) with matrix former b) and, if appropriate, matrix modifier d),

(i-2) if appropriate, granulation of the mixture obtained in step (i- 1 ), (i-3) addition of tableting agent c), if appropriate flow regulator e) and/or lubricant f) and/or one or more further adjuvants to the mixture obtained in step (i- 1 ) or, if appropriate, to the granules obtained in step (i-2).

14. Process according to Claim 13, where, in step (i-2), a granulation takes place which is selected from among dry granulation, wet granulation and melt granulation.

15. Process according to Claim 12, where the process is a direct-tableting process in which, in step (i), a powder mixture is prepared which is compressed directly in step (ii).