HK1117755A - Solid, orally applicable pharmaceutical administration forms containing rivaroxaban having modified release - Google Patents

Description

Solid pharmaceutical administration form for oral administration with improved release properties and containing RIVAROXABAN

The invention relates to solid pharmaceutical administration forms which are orally administrable and contain 5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl ] -1, 3-oxazolidin-5-yl) -methyl) -2-thiophenecarboxamide and have improved release properties, and also to methods for the production thereof, to the use thereof as medicaments, for the prophylaxis, auxiliary prophylaxis and/or treatment of diseases and for the production thereof for the prophylaxis, auxiliary prophylaxis and/or treatment of diseases.

By modified-release dosage forms, in the context of the present invention, are understood those preparations whose active ingredient release can be adjusted after administration as a function of time, distribution and/or location in the gastrointestinal tract, as is not possible with conventional pharmaceutical preparations (e.g. oral solutions or solid dosage forms with rapid release of active ingredient). In addition to the term "modified release", alternative terms such as "sustained release", "delayed" or "controlled release" are often used. These are also included in the scope of the present invention.

For the preparation of modified-Release dosage forms, various methods are known, see for example "Oral Controlled Release Products" by b.lippold: therapeutic and biopharmaceutical Association "Hrsg.U.Gundert-Remy und H.M ö ller, Stuttgart, Wiss.Verl. -ges., 1989, 39-57.

5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl ] -1, 3-oxazolidin-5-yl) -methyl) -2-thiophenecarboxamide (I) is an orally administrable low molecular weight inhibitor of coagulation factor Xa, which can be used for the prophylaxis, co-prophylaxis and/or treatment of various thromboembolic disorders (see, for example, WO-A01/47919, the disclosure of which is incorporated by reference). When active substance (I) is mentioned below, all crystal modifications and amorphous forms of 5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl ] -1, 3-oxazolidin-5-yl } -methyl) -2-thiophenecarboxamide (I) and also their hydrates, solvates and cocrystals are also included.

For diseases that must be treated over a longer period of time or for long-term disease prevention, it is desirable to keep the frequency of drug administration as low as possible. This not only provides comfort to the patient, but also improves treatment reliability (compliance) by reducing the drawbacks of irregular dosing. This desirable reduction in dosing frequency, for example from twice daily to once daily, can be achieved by prolonging the therapeutically effective plasma concentration by improving the release of the active ingredient from the dosage form being administered.

The occurrence of undesirable, concentration-peak-related side effects can also be reduced after administration of an administration form with improved active ingredient release, by smoothing the plasma level curve (minimizing the so-called peak-to-trough ratio), i.e. by avoiding high plasma active ingredient concentrations, which are usually observed after administration of a fast-releasing medicament.

Especially for the continuous treatment or prevention and adjuvant prophylaxis of arterial and/or venous thromboembolic diseases, such as deep vein thrombosis, stroke, myocardial infarction and pulmonary embolism, preference is given to using an active ingredient (I) in such a form that, via an improved release of the active ingredient, leads to a reduction in the peak-to-trough ratio and enables a once-a-day administration.

The physico-chemical and biological properties of the active ingredient (I), such as a relatively low water solubility (about 7 mg/L; 25 ℃), a higher melting point of about 230 ℃ of the active ingredient (I) in the crystal modification, in which the active ingredient (I) is prepared according to the route described in example 44 of WO01/47919, and a plasma half-life of about 7 hours, are also taken into account when developing the medicament. For ideal once-a-day administration, it is therefore necessary to use specific galenic agents which are capable of releasing the active ingredient (I) with an improved release in a general formula which has a compromise between physicochemical and biological properties.

DEl0355461 describes an administration form containing the active ingredient (I) in hydrophilic form. Preferably a fast-release tablet, and which has a Q value of 75% (30 minutes) as measured by the USP-release method using apparatus 2 (paddle).

It has now surprisingly been found that administration forms which release the active ingredient (I) at a specific, specifically modified rate enable once-a-day administration under conditions of relatively constant plasma concentration.

The invention relates to solid pharmaceutical administration forms for oral administration with modified release, containing 5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl ] -1, 3-oxazolidin-5-yl } -methyl) -2-thiophenecarboxamide (I), characterized in that 80% of the active ingredient (I) (based on the specified total amount of active ingredient) is released over a period of at least 2 and at most 24 hours, measured according to the USP-release method using apparatus 2 (paddle).

In a preferred embodiment of the invention, 80% of the active ingredient (I) is released over a period of 4 to 20 hours, as measured by the USP-release method using apparatus 2 (paddle).

In the pharmaceutical administration form according to the invention, the active ingredient (I) may be present in crystalline form and in amorphous form or in the form of a mixture of crystalline and amorphous active ingredients.

If the administration form according to the invention contains the active ingredient (I) in crystalline form, a preferred embodiment of the invention provides for the active ingredient (I) to be used in the form of a crystal-modified micronised form. Of these, the active ingredient (I) preferably has an average particle diameter X of less than 10 μm, in particular less than 8 μm₅₀And X of less than 20 μm, in particular less than 15 μm₉₀Value (90% content).

In another preferred embodiment of the present invention, if crystalline active ingredient (I) is used, the micronized active ingredient (I) is present in a hydrophilic form, thereby increasing its dissolution rate. The preparation of hydrophilized active ingredients (I) is described in detail in DE10355461, the disclosure of which is also incorporated herein by reference.

Preferably, the active ingredient (I) is not present in crystalline form in the pharmaceutical composition of the invention but in completely or predominantly amorphous form. An advantage of amorphization of the active ingredient (I) is that it increases the solubility of the active ingredient and thus may increase the absorption rate of the active ingredient (I), especially by lower intestinal segments.

Different pharmaceutically suitable preparation methods can be considered for amorphizing the active ingredient (I).

Here, the dissolution method in which the active ingredient and optionally the auxiliaries are dissolved and then further processed is not very suitable, since the crystalline active ingredient (I) has only a limited solubility in pharmaceutically suitable organic solvents, such as acetone or ethanol, and therefore disproportionately large amounts of solvent have to be used.

The preferred process according to the invention for amorphizing the active ingredient (I) is a melt process, in which the active ingredient is melted together with or in one or more suitable auxiliaries.

Particularly preferred are Melt extrusion methods [ Breitenbach, j.,, Melt extrusion: from process to drug delivery technology ", European Journal of pharmaceuticals and biopharmaceuticals 54(2002), 107-; breitenbach, J.,, Feste L ö sungen durch Schmelzextrusion-ein integratters Herstellkonzept ", Pharmazie in nonserver Zeit 29(2000), 4649 ].

By selecting suitable receptors and suitable production parameters, it is ensured in this process that the decomposition of the active ingredient does not exceed pharmaceutically acceptable limits. If the melting point of active ingredient (I) is about 230 ℃, this is a difficult task in the crystallization modification process I, since significant decomposition of the active ingredient and/or auxiliaries is generally to be expected in this high temperature range.

The melt extrusion process for preparing the amorphous active ingredient (I) is carried out according to the invention in the presence of polymers such as polyvinylpyrrolidone, polyethylene glycol (PEG), polymethacrylates, polymethyl methacrylate, polyethylene oxide (in particular water-soluble polyethylene oxide resins, such as P)OLYOX^TMWater Soluble Resins, Dow), polyoxyethylene-polyoxypropylene block copolymers, vinylpyrrolidone-vinyl acetate copolymers or cellulose ethers, such as hydroxypropyl cellulose (HPC) or mixtures of different polymers, such as mixtures of two or more of the abovementioned polymers. Preferred polymers are hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP) or a mixture of HPC and PVP. Particularly preferred polymers are hydroxypropyl cellulose (HPC) or polyvinylpyrrolidone (PVP).

The polymer content in the melt extrudate is preferably at least 50% of the total mass of the melt extrudate according to the invention.

The active ingredient (I) is preferably present in the melt extrudate according to the invention in a concentration of from 1 to 20% based on the total mass of the melt extrudate.

In the melt extrusion process for preparing amorphous active ingredient (I), it is preferable to add one or more pharmaceutically suitable substances to lower the melting point of active ingredient (I) or to act as softeners, thereby reducing the consequent decomposition of active ingredient during extrusion and simplifying the processing.

These pharmaceutically suitable substances are preferably added according to the invention in a concentration of 2 to 40% relative to the total mass of the melt extrudate.

Suitable for this are, for example, urea, polymers such as polyvinylpyrrolidone, polyethylene glycol, polymethacrylates, polymethyl methacrylate, polyoxyethylene-polyoxypropylene-block polymers, vinylpyrrolidone-vinyl acetate copolymers or sugar alcohols such as erythritol, maltitol, mannitol, sorbitol and xylitol. Sugar alcohols are preferably used. By selecting suitable preparation parameters, it is ensured that the active ingredient (I) is converted into the amorphous state as completely as possible, thereby increasing the solubility of the active ingredient.

The extrudates obtained by melt extrusion and containing active ingredient (I) are cut, optionally rounded and/or coated and can, for example, be further processed into sachets or filled into capsules (multiple unit formulations). Another possibility is that the extrudate obtained after melt extrusion is mixed with conventional tableting aids after cutting and grinding, compressed into tablets and then optionally coated again (single-component formulation).

According to the invention, various orally administrable pharmaceutical dosage forms with modified release of the active ingredient (I) can be used. For this purpose, the following solutions may be mentioned, for example and preferably, without limiting the invention:

1. tablets based on eroding matrix-systems ("single unit")

2. Multiparticulate dosage forms having erosion and/or diffusion controlled release kinetics, such as granules, pellets, minitablets and dosage forms made therefrom, such as capsules, capsules or tablets

3. Administration form based on osmotic delivery system

1. Tablets based on eroding matrix systems

Here, an improved active ingredient release is obtained by formulating the active ingredient in an erodable matrix consisting of one or more dissolved polymers, wherein the active ingredient release depends on the swelling and dissolution or erosion rate of the matrix and the dissolution, solubility and diffusion rates of the active ingredient. The principle of this modified release of active ingredient is also known under the term "corrosive matrix or hydrocolloid matrix-system". The principle of erosion/hydrocolloid-matrix to improve the release of active ingredients from pharmaceutical administration forms is described, for example, in:

·Alderman，D.A.，，，A review of cellulose ethers in hydrophilic matrixes for oral controlled-release dosage forms“，Int.J.Pharm.Tech.Prod.Mfr.5(1984)，1-9.

·Melia，CD.，，，Hydrophilic matrix sustained release systems based on polysaccharidecarriers“，Critical Reviews in Therapeutic Drug Carrier Systems 8(1991)，395-421.

vazques, M.J. et al,, influx of technical variables on release of drugs from hydrophilic matrices, Drug Dev.Ind.pharm.18(1992)，1355-1375

The desired release kinetics can be controlled, for example, via the type of polymer, the viscosity of the polymer, the particle size of the polymer and/or of the active ingredient, the ratio of active ingredient to polymer and the addition of other pharmaceutical customary auxiliaries, such as dissolved and/or undissolved fillers.

Suitable as matrix formers within the scope of the present invention are a large number of polymers, for example polysaccharides and cellulose ethers, such as methylcellulose, carboxymethylcellulose, hydroxyethylmethylcellulose, ethylhydroxyethylcellulose, hydroxyethylcellulose, and among these preferably Hydroxypropylcellulose (HPC) or Hydroxypropylmethylcellulose (HPMC) or mixtures of hydroxypropylcellulose and hydroxypropylmethylcellulose are used.

In the tablets according to the invention based on a corrosive matrix system, the matrix former is preferably contained in a concentration of 10 to 95% relative to the total weight of the tablet.

In the tablets according to the invention based on a corrosive matrix system, the active ingredient (I) is preferably contained in a concentration of 1 to 50% relative to the total weight of the tablet.

In addition to the polymer and active ingredient used to form the erosion- (hydrocolloid) matrix, other tablet adjuvants well known to those skilled in the art (e.g., binders, fillers, lubricating/slip/flow agents) may be added to the tablet. The tablets may also be coated.

Suitable materials for the light-aging protection layer and/or the pigment coating are, for example, polymers, such as polyvinyl alcohol, hydroxypropyl cellulose and/or hydroxypropylmethyl cellulose, and optionally also in combination with suitable softeners, such as polyethylene glycol or polypropylene glycol and pigments, such as titanium dioxide and iron oxide.

Furthermore, suitable materials for the preparation of the coating are, for example, aqueous dispersions, such as ethylcellulose dispersions (e.g.Aquacoat, FMC) or poly (ethyl acrylate, methyl methacrylate) -dispersions (Eudragit NE 30D, R ö hm/Degussa). In addition, softeners and wetting agents (e.g., triethyl citrate or polysorbate), anti-tacking agents, such as talc or magnesium stearate, and hydrophilic pore formers, such as hydroxypropyl methylcellulose, polyvinylpyrrolidone or sugars, may also be added to the coating. The effect of the coating is essentially to delay the release of the active ingredient within one to at most two hours from the start after application.

Also suitable as materials for the preparation of the coating are those used to obtain gastric juice resistance, for example methacrylic acid-based anionic polymers (Eudragit L + S, R ö hm/Degussa) or cellulose acetate phthalate.

For the preparation of the tablets according to the invention containing the active ingredient (I) in crystalline or predominantly crystalline form, the customary processes known to those skilled in the art, such as direct compression, dry granulation followed by compression, melt granulation, extrusion or wet granulation, such as fluidized bed granulation, are suitable.

For tablets based on a corrosive matrix-system according to the invention, preference is given to using the active ingredient (I) in an amorphous or predominantly amorphous state, in particular as a melt-extrudate, so that the active ingredient (I) is present in the final formulation in the amorphous state.

The invention also relates to a method for producing tablets according to the invention based on an erosion matrix system, whereby extrudates containing the active ingredient (I) are produced, preferably by melt extrusion, then ground, mixed with other tabletting aids (matrix formers, binders, fillers, lubricants/sliding/flow agents) known to the skilled worker and then compressed, preferably by direct compression, into tablets, which can finally be coated.

2. Multiparticulate dosage forms, e.g. granules, pellets, minitablets and capsules made therefrom, Capsule and tablet

In addition to the so-called "single-unit" (individual (Einzelk ö rper)) -administration forms described in 1, multiparticulate administration forms are also suitable for the active ingredient (I), and the modified release of the active ingredient is effected in an erosion/diffusion-controlled manner. By the term "multiparticulate dosage form" according to the invention is understood those preparations which, in contrast to "single units" (tablets), are composed of a multiplicity of small particles, such as microgranules, spherical particles (pellets) or minitablets. The diameter of the particles is generally between 0.5 and 3.0mm, preferably 1.0 to 2.5 mm.

The advantage of such a multiparticulate system over a single unit is that the gastrointestinal variability within and from individual to individual is small and thus also results in a small variability of the plasma distribution and often also in a reduction of food dependence (food impact), i.e. a reduction of the difference between fed and fasted administration. Granules (pellets) and small tablets (mini-tablets with a diameter of up to 3mm) can be filled into capsules or prepared as sachets. Another possibility is further processing into larger tablets which after contact with water/gastric juice release primary particles/pellets due to rapid disintegration.

Substantially all of the adjuvants and processes described in 1 are suitable for the preparation of multiparticulate pharmaceutical administration forms containing the active ingredient (I).

Among them, a polymer selected from cellulose ethers is preferably used as a matrix construct, particularly hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC) or a mixture of hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

In the pharmaceutical compositions of the invention based on multiparticulate dosage forms, the polymer is present in an amount of from 10 to 99%, particularly preferably between 25 and 95%, by weight of the total composition.

In the pharmaceutical administration form of the present invention based on the multiparticulate dosage form, the content of the active ingredient (I) is 1 to 30% by weight based on the total weight of the composition.

The Extrusion/spheronization method is particularly suitable for the preparation of pellets containing the active ingredient (I) in crystalline or predominantly crystalline form and is described, for example, in Gandhi, R., Kaul, C.L., Panchagnaula, R., "Extrusion and dispersion in the purification of organic controlled-release granules for use", Pharmaceutical Science & Technology today. 2, No.4(1999), 160. 170.

In a preferred embodiment of the invention, multiparticulate dosage forms contain the active ingredient (I) in amorphous form and are preferably prepared by melt extrusion.

The particles/pellets/chips may optionally be coated, for example with an aqueous dispersion such as an ethylcellulose dispersion (e.g. Aquacoat, FMC) or poly (ethyl acrylate, methyl methacrylate) dispersion (Eudragit NE 30D, R ö hm/Degussa). Additionally, softeners and wetting agents (e.g., triethyl citrate or polysorbate), anti-tacking agents such as talc or magnesium stearate and hydrophilic pore formers such as hydroxypropyl methylcellulose, polyvinylpyrrolidone or sugars may also be added to the coating. The coating essentially acts to prolong the release of the active ingredient within one to at most two hours after application.

Also suitable as materials for preparing the coating are substances to obtain gastric juice resistance, such as methacrylic acid-based anionic polymers (Eudragit L + S, R ö hm/Degussa) or cellulose acetate phthalate.

The invention also relates to a pharmaceutical administration form, preferably a capsule, capsule or tablet, comprising the multiparticulate administration form described above.

The invention also relates to a method for producing multiparticulate pharmaceutical administration forms according to the invention, wherein extrudates containing amorphous active ingredient (I) are obtained, preferably by melt extrusion. In a preferred embodiment of the invention, a spherical multiparticulate dosage form is directly prepared by cutting the extrudate strip and optionally followed by rounding. The pellets thus obtained may then be coated and filled into capsules or as capsules.

3. Osmotic delivery system

Other suitable forms of administration for the modified release of the active ingredient (I) are based on osmotic release systems. Wherein a core, such as a capsule or tablet, and preferably a tablet, is surrounded by a semi-permeable membrane having at least one opening. The water permeable membrane is impermeable to the components of the core but allows water to enter the system from the outside by osmosis. The permeated water then releases the dissolved or dispersed active ingredient from the open pores within the membrane via the resulting osmotic pressure. The overall active ingredient release and rate of release can be substantially controlled via the thickness and porosity of the semi-permeable membrane, the composition of the core and the number and size of the pores. Relevant advantages, formulations, forms of use and preparation information are for example described in the following publications:

·Santus，G.，Baker，R.W.，，，Osmotic drug delivery：a review of the patent literature”，Journal of Controlled Release 35(1995)，1-21

·Verma，R.K.，Mishra，B.，Garg，S.，，，Osmotically controlled oral drug delivery“，DrugDevelopment and Industrial Pharmacy 26(7)，695-708(2000)

·Verma，R.K.，Krishna，D.M.，Garg，S.，，，Formulation aspects in the development ofosmotically controlled oral drug delivery systems“，Journal of Controlled Release 79(2002)，7-27

·US 4,327,725，US 4,765,989，US 20030161882，EP 1024793.

both single compartment systems (primary osmotic pumps) and two compartment systems (pull-push systems) are suitable for active ingredient (I). The active ingredient (I) may be present in the osmotic system in crystalline, preferably micronized, as well as amorphous form or mixed with crystalline and amorphous ingredients.

In either the single or dual compartment systems, the outer shell of the agent osmotic delivery system is formed of a material that is permeable to water but impermeable to the core components. Such casing materials are known in principle and are described, for example, in EP-B1-1024793, pages 3-4, and the disclosure thereof is hereby incorporated into the present invention. Cellulose acetate or a mixture of cellulose acetate and polyethylene glycol is preferably used as the shell material in the present invention.

If desired, a coating, such as a light-aging protection layer and/or a pigment layer, can also be applied to the housing. Suitable materials for this are, for example, polymers such as polyvinyl alcohol, hydroxypropyl cellulose and/or hydroxypropylmethyl cellulose, optionally in combination with suitable softeners such as polyethylene glycol or polypropylene glycol and pigments, such as titanium dioxide or iron oxide.

In a permeable single compartment system, the core preferably comprises:

2 to 30% of active ingredient (I),

from 20 to 50% of xanthan gum,

10 to 30% of vinylpyrrolidone-vinyl acetate copolymer,

wherein 100% is satisfied optionally by one or more additional ingredients selected from the group consisting of other hydrophilic swellable polymers, osmotically active additives and conventional pharmaceutical adjuvants. The sum of the core constituents is 100% and% refers to the total weight of the core.

The permeable single compartment system contains as a key component of a core the hydrophilic water swellable polymer xanthan gum. This refers to an anionic heteropolysaccharide and may be available, for example, under the trade name Rhodigel ® (manufactured by Rhodia). It is present in an amount of 20 to 50%, preferably 25 to 40%, relative to the total weight of the core component.

Another key component of the core is a vinylpyrrolidone-vinyl acetate copolymer. Such copolymers are known per se and can be prepared in any desired monomer mixing ratio. The preferred commercially available Kollidon ® VA64 (from BASF) is for example a 60: 40-copolymer. Typically, it has a weight average molecular weight of about 45000 to about 70000, as determined by light diffraction. The amount of vinylpyrrolidone-vinyl acetate copolymer in the core is from 10 to 30%, preferably from 15 to 25%, relative to the total weight of the core components.

Hydrophilic swellable polymers which may optionally also be present in the core are, for example, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch, polyacrylic acid or salts thereof.

Osmotically active additives which optionally can also be present in the nucleus are, for example, all water-soluble substances whose use is not at risk pharmaceutically, such as those water-soluble auxiliaries mentioned in the pharmacopoeias or in "Hager" and "Remington Pharmaceutical Science". In particular, salts of inorganic or organic acids or nonionic organic substances with a very high water solubility, such as carbohydrates, in particular sugars, sugar alcohols or amino acids, can also be used. For example, the osmotically active additive may be selected from inorganic salts, such as chlorides, sulfates, carbonates and bicarbonates of alkali or alkaline earth metals, such as lithium, sodium, potassium, magnesium, calcium, and their phosphates, hydrogen or dihydrogen phosphates, acetates, succinates, benzoates, citrates or ascorbates. Furthermore, it is also possible to use pentosans, such as arabinose, ribose or xylose, hexoses, such as glucose, fructose, galactose or mannose, disaccharides such as sucrose, maltose or lactose or trisaccharides such as raffinose. Among the water-soluble amino acids are glycine, leucine, alanine or methionine. According to the invention, the use of sodium chloride is particularly preferred. The osmotically active additive is preferably contained in an amount of 10 to 30% relative to the total weight of the core component.

Usual pharmaceutical auxiliaries which may optionally also be present in the core are, for example, buffering agents, such as sodium bicarbonate, binding agents, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and/or polyvinylpyrrolidone, lubricating agents, such as magnesium stearate, wetting agents, such as sodium lauryl sulfate, and/or flow-regulating agents, such as highly disperse silicon dioxide.

A further subject matter of the invention is a process for preparing the osmotic monocompartment system according to the invention, in which the individual constituents of the core are mixed with one another and optionally wet-or dry-granulated, then sheeted and coated with an outer shell on the core thus formed, and the outer shell is optionally further coated with a light-aging-resistant layer and/or a pigment layer and provided with one or more openings.

In a preferred embodiment of the invention, the osmotic one-compartment system is produced by coating the ingredient with moist granules, since this procedure serves to improve the wettability of the core ingredient of the tablet, thereby allowing the entering gastrointestinal fluids to better penetrate the core and, more so, allowing a faster and more complete release of the active ingredient.

The inner core in the osmotic dual-compartment system consists of two layers, an active ingredient layer and an osmotic layer. Such a permeable two-compartment system is described, for example, in DE3417113C2, the detailed disclosure of which is also incorporated into the present invention.

The active ingredients preferably contain:

1 to 40% of active ingredient (I),

from 50 to 95% of one or more osmotically active polymers, preferably of medium-viscosity polyethylene oxide (40 to 100 mPas; 5% aqueous solution, 25 ℃; preferably measured with a suitable Brookfield viscometer and a suitable spindle at a suitable rotational speed, in particular with a Brookfield viscometer model RVT type and spindle number 1 with a rotation number of 50U/min or with a comparable model under corresponding conditions (spindle, number of revolutions)).

The permeation layer preferably comprises:

from 40 to 90% of one or more osmotically active polymers, preferably polyethylene oxide of high viscosity (5000 to 8000 mPas; 1% aqueous solution, 25 ℃; preferably measured with a suitable Brookfield viscometer and a suitable spindle at a suitable rotational speed, in particular with a Brookfield viscometer model RVT type and spindle number 2U/min or with a comparable model under corresponding conditions (spindle, number of revolutions)),

10 to 40% of an osmotically active additive,

and make up 100% independently of one another in the individual layers by means of additional ingredients in the form of one or more pharmaceutically customary auxiliaries. % refers to the total weight of each core layer.

Within the core of an osmotic dual-compartment system, the same osmotically active additives as in the case of the single-compartment system described above may be used. Sodium chloride is preferred here.

Within the core of the osmotic dual-compartment system, the same pharmaceutically conventional adjuvants as in the case of the single-compartment system described above can be used. Binders such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose and/or polyvinylpyrrolidone, lubricants such as magnesium stearate, wetting agents such as sodium lauryl sulfate and/or flow control agents such as highly disperse silicon dioxide and pigments such as iron oxide in one of the two layers to distinguish the active ingredient layer from the osmotic layer are preferred here.

A further subject of the invention is a process for preparing the osmotic dual compartment system of the invention, in which the ingredients of the active ingredient layer are mixed and granulated, the ingredients of the osmotic layer are mixed and granulated and then the two granules are compressed on a bi-layer tablet press to form a bi-layer tablet. The core thus formed is then coated with a shell which is provided with one or more openings on the active ingredient side and is then optionally further coated with a coating.

In a preferred embodiment of the invention, the active ingredient and the osmotic layer are dry granulated, in particular by roller granulation, when preparing an osmotic two-compartment system.

Depending on the physicochemical properties of the active ingredient (I), the present invention prefers a two-compartment osmotic system (pull-push system) and in which the active ingredient and the osmotic layer are separated, for example and preferably formulated in the form of a 2-layer tablet. The advantage over osmotic single compartment systems is that there is a uniform release rate over a longer period of time and the necessity for overdosing of the active ingredient by the system can be reduced.

A further subject of the invention is a medicament comprising an orally administrable solid pharmaceutical administration form according to the invention and containing the active ingredient (I) and having a modified release.

A further subject of the invention is the use of solid pharmaceutical administration forms which contain the inventive oral administration and contain the active ingredient (I) and have a modified release for the prophylaxis, auxiliary prophylaxis and/or therapy of diseases, in particular of arterial and/or venous thromboembolic diseases, such as myocardial infarction, angina pectoris (including unstable angina pectoris), reocclusion and restenosis after angioplasty or coronary bypass surgery, stroke, transient ischemic attacks, peripheral arterial infarct diseases, pulmonary embolism or deep vein thrombosis.

A further subject of the invention is the use of solid pharmaceutical administration forms containing the inventive orally administrable active ingredient (I) and having modified release properties for the preparation of a medicament for the prophylaxis, auxiliary prophylaxis and/or treatment of diseases, in particular arterial and/or venous thromboembolic diseases such as myocardial infarction, angina pectoris (including unstable angina pectoris), reocclusion and restenosis after angioplasty or coronary artery bypass surgery, stroke, transient ischemic attacks, peripheral arterial infarction diseases, pulmonary embolism or deep vein thrombosis.

A further subject matter of the present invention is the use of 5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl ] -1, 3-oxazolidin-5-yl } -methyl) -2-thiophenecarboxamide (I) for the preparation of an orally administrable, solid pharmaceutical administration form of the invention with modified release.

A further subject of the invention is a method for the prophylaxis, auxiliary prophylaxis and/or treatment of arterial and/or venous thromboembolic diseases by administration of an orally administrable solid pharmaceutical administration form according to the invention, which contains the active ingredient (I) and has modified release properties.

The invention is illustrated by the following preferred examples, but is not limited thereto. All dosage descriptions refer to weight percentages unless otherwise indicated.

Experimental part

Unless otherwise stated, the in vitro release tests described below were carried out according to the USP-release method using apparatus 2 (paddle). The stirrer was rotated at a rate of 75UpM (revolutions per minute) and was kept in 900ml of a pH6.8 buffer solution prepared from 1.25ml of orthophosphoric acid, 4.75g of citric acid monohydrate and 27.46g of disodium hydrogen phosphate in 10l of water. Optionally, a surfactant, preferably sodium lauryl sulfate, is also added to the solution at 1% or less. The tablet is preferably obtained from sinker described in japanese pharmacopoeia.

1. Tablets based on a corrosive matrix system

1.1 Corrosion substrate sheets containing crystalline active ingredient (I)

Formulation example 1.1.1

Tablet composition, mg/tablet

Active ingredient (I), micronized 25.0mg

Microcrystalline cellulose 10.0mg

Lactose monohydrate 26.9mg

Hydroxypropyl cellulose, HPC-L form (Nisso) 52.0mg

Hydroxypropyl cellulose, HPC-M type (Nisso) 10.0mg

Sodium lauryl sulfate 0.5mg

Magnesium stearate 0.6mg

Hydroxypropyl methylcellulose, 15cp 1.8mg

Polyethylene glycol 3.3500.6 mg

Titanium dioxide0.6mg

128.0mg

Preparation:

a portion of the amount of hydroxypropyl cellulose form L and sodium lauryl sulfate was dissolved in water. The micronized active ingredient (I) is dispersed in suspension in this solution. The suspension thus obtained is sprayed as granulation liquid onto a mass of microcrystalline fibres, HPC-L and HPC-M and lactose monohydrate in a fluid bed granulation process. After drying and sieving (0.8mm screen width) the formed granules, magnesium stearate was added and mixed. The compacted mixture thus obtained is compressed into tablets having a diameter of 7mm and a breaking strength of 50 to 100N. The tablets were then coated with titanium dioxide suspended in an aqueous solution of hydroxypropyl methylcellulose (15cp) and polyethylene glycol.

Formulation examples 1.1.2

Tablet composition, mg/tablet

Active ingredient (I), micronized 25.0mg

Microcrystalline cellulose 10.0mg

Lactose monohydrate 26.9mg

Hydroxypropyl cellulose, HPC-L form (Nisso) 12.0mg

Hydroxypropyl cellulose, HPC-M form (Nisso) 50.0mg

Sodium lauryl sulfate 0.5mg

Magnesium stearate 0.6mg

Hydroxypropyl methylcellulose, 15cp 1.8mg

Polyethylene glycol 3.3500.6 mg

Titanium dioxide0.6mg

128.0mg

Preparation is carried out analogously to formulation example 1.1.1

Formulation examples 1.1.1 and 1.1.2 in vitro release:

time [ min ]]	120	240	480	720	960
						Release [% ]]1.1.1	38	74	94	96	97
1.1.2	14	32	66	89	98

The method comprises the following steps: USP-slurry, 75UpM, 900ml of phosphate buffer pH6.8+ 0.5% sodium lauryl sulfate, JP-sinker

1.2 Corrosion-matrix tablets containing amorphous active ingredient (I)

Formulation example 1.2

Tablet composition, mg/tablet

Melt extrusion:

active ingredient (I), 30.0mg micronised

Hydroxypropyl cellulose, HPC-M form (Nisso) 210.0mg

Xylitol, its preparation method and use60.0mg

300.0mg

And (3) tablet preparation: AB C

Melt extrudate, 300.0mg 300.0mg

Mannitol (Pearlitol, Roquette) 195.0mg 100.0 mg-

Hydroxypropyl cellulose (HPC-L form, Nisso) -95.0 mg

Hydroxypropyl methylcellulose (15cp) - - -95.0 mg- -

Microcrystalline cellulose 50.0 mg-

Highly dispersed silica 2.5mg 2.5mg 2.5mg

(Aerosil200，Degussa)

Magnesium stearate2.5mg 2.5mg 2.5mg

550.0mg 500.0mg 400.0mg

Preparation:

the micronized active ingredient (I), hydroxypropylcellulose and xylitol were mixed and processed in a twin screw extruder (Leistritz Micro 18PH) with an outflow nozzle of 2mm diameter. The mixture was extruded at a temperature of 195 ℃ (measured at the nozzle outlet). The resulting extruded strands are cut into pieces of 1 to 2mm size and then ground in a impact mill.

After sieving (0.63mm), the milled extrudate was mixed with further auxiliaries (see above table) and the mixture was compressed into oval tablets of 15X 7mm (A + B) or 14X 7mm (C).

Formulations 1.2 in vitro release of a to C:

time [ min ]]	240	480	720	1440
					Rate of release [% ]]A	30	63	83	95
B	27	56	77	99
					C	23	45	64	98

The method comprises the following steps: USP-Paddle, 75Upm, 900ml phosphate buffer pH6.8, JP-sinker

Under the same conditions, conventional fast release tablets, in which the same amount of active ingredient in micronized crystalline state is present, 30mg of active ingredient (I) per tablet, only give incomplete active ingredient release rates: only about 33% release of the active ingredient can be achieved after 4 to 6 hours. In contrast, the nearly complete active ingredient release rates of the extruded formulations a-C show a clear increase in the solubility of the active ingredient (I) in the surfactant-free release medium. This is achieved by converting the active ingredient (I) into an amorphous state by melt extrusion.

2.Multiparticulate formulations

2.1 minitablets containing crystalline active ingredient (I)

Formulation example 2.1

Tablet composition, mg/mini-tablet

Active ingredient (I), micronised 0.50mg

Hydroxypropyl cellulose (Klucel HXF, Hercules) 5.91mg

Hydroxypropyl cellulose (HPC-L, Nisso) 0.04mg

Sodium lauryl sulfate 0.01mg

Magnesium stearate0.04mg

6.50mg

Preparation:

the hydroxypropylcellulose Klucel HXF is granulated together with the active ingredient (I) and an aqueous suspension of hydroxypropylcellulose HPC-L form and lauryl sulfate. After drying and sieving the formed granules, magnesium stearate is added and mixed. The compression mixture thus obtained was compressed into 2mm 6.5mg minitablets. The release of an equivalent amount of 25mg of active ingredient (I) from a minitablet (50 pieces) is illustrated below:

in vitro release of formulation 2.1:

time [ min ]]	240	480	720	1200
					Rate of release [% ]]	14	31	52	89

The method comprises the following steps: USP-Paddle, 75UpM, 900ml of phosphate buffer pH6.8+ 0.5% sodium lauryl sulfate

2.2 pellets containing amorphous active ingredient (I)

Formulation example 2.2.1

Composition of active ingredient (I) in a single dose of 30mg per dose, mg

Melt extrudate

Active ingredient (I), 30.0mg micronised

Hydroxypropyl cellulose, Klucel HXF type (Hercules) 510.0mg

Xylitol, its preparation method and use60.0mg

600.0mg

Coating shell

Hydroxypropyl methylcellulose, 3cp 15.0mg

Magnesium stearate 6.9mg

Poly (ethyl acrylate, methyl methacrylate) -Dispersion 30% 126.0mg^*

(Eudragit NE 30 D，Röhm/Degussa)

Polysorbate 200.3mg

60.0mg^**

^*Corresponds to 37.8mg of coated dry substance

^**Coating of dry substances

Preparation:

mixing the micronized active ingredient (I), hydroxypropyl cellulose and xylitol. 1.5kg of this mixture are processed in a twin-screw extruder (Leistritz Micro 18PH) with a 2mm diameter nozzle. The mixture was extruded at a temperature of 200 ℃ (measured at the nozzle). The resulting extruded strands were cut into 1.5mm sized pieces. After sieving to remove fine components, the granules were coated in a fluidized bed. For this purpose, an aqueous coating dispersion consisting of the above-mentioned components and 20% solids is sprayed onto the granules. After drying and sieving the pellets can be filled into containers such as glass bottles, bags or rigid gel capsules.

Formulation example 2.2.2

Composition of active ingredient (I) in a single dose of 30mg per dose, mg

Melt extrudate

Active ingredient (I), 30.0mg micronised

Hydroxypropyl cellulose, Klucel HXF type (Hercules)570.0mg

600.0mg

Coating shell

Hydroxypropyl methylcellulose, 3cp 15.0mg

Magnesium stearate 6.9mg

Poly (ethyl acrylate, methyl methacrylate) -Dispersion 30% 126.0mg^*

(Eudragit NE 30 D，Röhm/Degussa)

Polysorbate 200.3mg

60.0mg^**

^*Corresponds to 37.8mg of coated dry substance

^**Coating of dry substances

Preparation: similar to 2.2.1

Although a similar process/method for the preparation of multiparticulate sustained release formulations is described in EP1113787, the difference is also that the active ingredient (I) in examples 2.2.1 and 2.2.2 described herein is converted to amorphous form due to suitable operating parameters. This makes it possible in particular to achieve an increase in the solubility of the active ingredient:

formulations 2.2.1 in vitro Release of 2.2.2

Time [ min ]]	240	480	720	1440
					Rate of release [% ]]3.2.1	34	69	91	95
3.2.2	30	57	80	94

The method comprises the following steps: USP-Paddle, 75UpM, 900ml phosphate buffer pH6.8

Dosage forms containing the active ingredient (I) in crystalline form can only achieve a release rate of about 33% under the same conditions (see discussion of the release results of formulation example 1.2).

3.Osmotic system

3.1 Single-compartment System containing crystalline active ingredient (I)

Formulation example 3.1

Tablet composition, mg/tablet (set content ═ 30 mg/tablet)

Core

Active ingredient (I), micronized 36.0mg

Xanthan gum (Rhodigel TSC, Rhodia) 100.0mg

Copolyvidon(Kollidon VA 64，BASF) 55.0mg

Sodium chloride 55.0mg

Sodium bicarbonate 17.5mg

Sodium carboxymethyl starch 23.0mg

Hydroxypropyl methylcellulose (5cp) 10.0mg

Sodium lauryl sulfate 0.5mg

Highly dispersed silica (Aerosil 200, Degussa) 1.5mg

Magnesium stearate1.5mg

300.0mg

Casing (osmotic membrane)

Cellulose acetate 19.95mg

Polyethylene glycol 4001.05mg

21.00mg

Preparation:

xanthan gum, copovidon, sodium chloride, sodium bicarbonate and sodium carboxymethylcellulose are mixed and then wet granulated with an aqueous dispersion of active ingredient (I) and hydroxypropylmethylcellulose. After drying and sieving, Aerosil and magnesium stearate are mixed and the compression mixture thus obtained is compressed into tablets having a diameter of 8 mm. The tablet cores were coated with an acetone solution of cellulose acetate and polyethylene glycol and dried. Two openings, each 1mm in diameter, were then provided for each tablet using a hand drill.

Formulation example 3.1 in vitro Release

Time [ min ]]	240	480	720	1440
					Rate of release [% ]]	21	54	72	90

The method comprises the following steps: USP-Paddle, 100UpM, 900ml of phosphate buffer pH6.8+ 1.0% sodium lauryl sulfate, JP-sinker

3.2 two-compartment System containing crystalline active ingredient (I)

Formulation example 3.2

Tablet composition, mg/tablet (set content ═ 30 mg/tablet)

Core

Active ingredient layer

Active ingredient (I), micronised 33.0mg

Hydroxypropyl methylcellulose (5cp) 8.2mg

Polyethylene oxide^* 122.2mg

Highly disperse silica (Aerosil 200, Degussa) 1.3mg

Magnesium stearate0.8mg

165.5mg

Permeable layer

Hydroxypropyl methylcellulose (5cp) 4.1mg

Sodium chloride 23.9mg

Polyethylene oxide^** 52.9mg

Iron oxide Red 0.8mg

Magnesium stearate0.2mg

81.9mg

Casing (osmotic membrane)

Cellulose acetate 29.07mg

Polyethylene glycol 4001.53mg

30.60mg

^*5% aqueous solution viscosity (25 ℃, Brookfield viscometer model RVT, Spindelnr.1, speed: 50 rpm): 40-100 mPas (e.g., POLYOX)^TMWater-soluble resin NF WSR N-80; DOW)

^**1% aqueous solution viscosity (25 ℃, Brookfield viscometer model RVT, Spindelnr.2, speed: 2 rev/min): 5000-^TMWater-soluble resin NF WSR coagulunt; DOW)

Preparation of

The ingredients of the active ingredient layer are mixed and dried for granulation (roller granulation). The ingredients of the permeate layer were also mixed and dried for granulation (roller granulation). The two pellets were compressed on a bi-layer tablet press into bi-layer tablets (8.7 mm diameter). The tablets were coated with an acetone solution of cellulose acetate and polyethylene glycol and dried. Two 0.9mm diameter openings were then provided on the active ingredient side of each tablet using a hand drill.

Formulation example 3.2 in vitro Release

Time [ min ]]	240	480	720	1200
					Releasing[％]	21	54	81	99

The method comprises the following steps: USP-Paddle, 100UpM, 900ml of phosphate buffer pH6.8+ 1.0% sodium lauryl sulfate, JP-sinker

Claims (44)

1. Solid pharmaceutical dosage form for oral administration comprising 5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl ] -1, 3-oxazolidin-5-yl } -methyl) -2-thiophenecarboxamide with improved release, characterized in that 80% of the active ingredient (I) is released over a period of 2 to 24 hours, measured according to the USP-release method using device 2 (paddle).

2. The pharmaceutical dosage form according to claim 1, wherein 80% of the active ingredient (I) is released over a period of 4 to 20 hours, as measured by the USP-release method using apparatus 2 (paddle).

3. Pharmaceutical administration form according to claim 1 or 2, characterized in that the active ingredient (I) is present in crystalline form.

4. Pharmaceutical administration form according to claim 3, characterized in that it contains the active ingredient (I) in micronized form.

5. Pharmaceutical administration form according to claim 4, containing the active ingredient (I) in hydrophilized form.

6. Pharmaceutical administration form according to claim 1 or 2, characterized in that the active ingredient (I) is present in amorphous form.

7. Pharmaceutical administration form according to claim 6, characterized in that the active ingredient (I) is amorphized by melt extrusion.

8. Pharmaceutical administration form according to claim 7, characterized in that Hydroxypropylcellulose (HPC) or polyvinylpyrrolidone (PVP) is used as polymer in melt extrusion and the polymer content in the melt extrusion is at least 50% and the active ingredient (I) is present in the melt extrusion in a concentration of 1 to 20%.

9. Pharmaceutical administration form according to one of claims 7 or 8, characterized in that at least one pharmaceutically suitable substance is added as an emollient in a concentration of 2 to 40% and/or to lower the melting temperature of the active ingredient (I).

10. Pharmaceutical administration form according to claim 9, characterized in that the pharmaceutically suitable additive is a sugar alcohol.

11. Pharmaceutical administration form according to one of claims 1 or 2, which is based on a corrosive matrix system.

12. Pharmaceutical administration form according to claim 11, characterized in that the active ingredient (I) is present in amorphous form.

13. Pharmaceutical administration form according to one of claims 11 or 12, containing hydroxypropyl cellulose or hydroxypropylmethyl cellulose or a mixture of hydroxypropyl cellulose and hydroxypropylmethyl cellulose as hydrophilic matrix former.

14. Pharmaceutical administration form according to one of claims 11 to 13, characterized in that the active ingredient (I) is contained in a concentration of 1 to 50%.

15. Process for the preparation of a pharmaceutical administration form according to one of claims 11 to 14, characterized in that an extrudate containing the active ingredient (I) is prepared by melt extrusion, ground and mixed with further tablet auxiliaries and then compressed into tablets by a direct tableting process.

16. A multiparticulate pharmaceutical dosage form according to any one of claims 1 or 2.

17. The multiparticulate pharmaceutical dosage form according to claim 16, wherein the active ingredient (I) is present in an amorphous state.

18. A multiparticulate pharmaceutical dosage form according to any one of claims 16 or 17, comprising hydroxypropyl cellulose as the hydrophilic matrix former.

19. The multiparticulate pharmaceutical dosage form according to claim 18, wherein the hydroxypropyl cellulose as the hydrophilic matrix former is contained at a concentration of 10 to 99%.

20. Multiparticulate pharmaceutical dosage form according to any one of claims 16 to 19, characterised in that the active ingredient (I) is contained in a concentration of 1 to 30%.

21. A multiparticulate pharmaceutical dosage form according to any one of claims 16 to 20, wherein the particles have a diameter of between 0.5 and 3.0 mm.

22. The multiparticulate pharmaceutical dosage form according to claim 21, wherein the particles have a diameter of between 1.0 and 2.5 mm.

23. Pharmaceutical administration form comprising a multiparticulate pharmaceutical administration form according to any one of claims 16 to 22.

24. A pharmaceutical administration form according to claim 23 in the form of a capsule, sachet or tablet.

25. Process for the preparation of a multiparticulate pharmaceutical dosage form according to any one of claims 16 to 22, characterized in that extrudate strands containing the active ingredient (I) are prepared by melt extrusion and cut.

26. The method of claim 25, wherein the resulting shaped body is rounded after cutting the extruded strip.

27. The method of any of claims 25 or 26, wherein the resulting shaped body is coated.

28. Pharmaceutical administration form according to one of claims 1 or 2, which is based on an osmotic delivery system.

29. Pharmaceutical administration form according to claim 28, characterized in that the active ingredient (I) is present in amorphous form.

30. Pharmaceutical administration form according to one of claims 28 or 29, consisting of an osmotic single-compartment system comprising a core containing,

2 to 30% of active ingredient (I),

from 20 to 50% of xanthan gum,

10 to 30% of vinylpyrrolidone-vinyl acetate copolymer,

and a shell constructed of a water permeable, core component impermeable material and having at least one aperture.

31. The pharmaceutical dosage form of claim 30, further comprising sodium chloride as an osmotically active additive in the core.

32. Pharmaceutical dosage form according to one of claims 30 or 31, in which the shell consists of cellulose acetate or a mixture of cellulose acetate and polyethylene glycol.

33. A method of preparing an osmotic single compartment system according to any of claims 30 to 32, wherein the ingredients of the core are mixed with each other, granulated and tabletted, the core thus formed is coated with a shell and finally the shell is provided with one or more holes.

34. Pharmaceutical administration form according to one of claims 28 or 29, consisting of an osmotic dual-compartment system and comprising a core with an active ingredient layer containing the following ingredients,

1 to 40% of active ingredient (I),

50 to 95% of one or more osmotically active polymers, and an osmotic layer comprising

From 40 to 90% of one or more osmotically active polymers

10 to 40% of an osmotically active additive,

and a shell constructed of a material that is permeable to water and impermeable to the core component and having at least one aperture.

35. Pharmaceutical administration form according to claim 34, containing as osmotically active polymer polyethylene oxide with a viscosity of 40 to 100 mPa-s (5% in water, 25 ℃) in the core in the active ingredient layer and polyethylene oxide with a viscosity of 5000 to 8000 mPa-s (1% in water, 25 ℃) in the core in the osmotic layer.

36. Pharmaceutical dosage form according to one of claims 34 or 35, in which the shell consists of cellulose acetate or a mixture of cellulose acetate and polyethylene glycol.

37. A process for the preparation of an osmotic dual chamber system according to any of claims 34 to 36,

mixing the active ingredient layers and granulating, and

mixing the ingredients of the permeable layer and granulating,

the two granules are then compressed in a double tablet press into a double tablet,

coating the core thus formed with a shell and

providing one or more openings in the active ingredient layer of the shell.

38. A medicament comprising a pharmaceutical administration form which is administrable orally and has a modified release of active ingredient (I) as defined in claim 1.

39. Use of an orally administrable solid pharmaceutical administration form containing an active ingredient (I) and having a modified release as defined in claim 1 for the prophylaxis, auxiliary prophylaxis and/or treatment of diseases.

40. Use of an orally administrable solid pharmaceutical administration form containing an active ingredient (I) and having a modified release as defined in claim 1 for the preparation of a medicament for the prophylaxis, auxiliary prophylaxis and/or treatment of diseases.

41. The use according to claim 39 or 40 for the prophylaxis, co-prophylaxis and/or treatment of thrombotic disorders.

42. The use according to claim 41 for the prevention, co-prevention and/or treatment of myocardial infarction, angina pectoris, re-infarction and restenosis following angioplasty or coronary artery bypass surgery, stroke, transient ischemic attack, peripheral arterial infarction disease, pulmonary embolism or deep vein thrombosis.

Use of 5-chloro-N- ({ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl ] -1, 3-oxazolidin-5-yl } -methyl) -2-thiophenecarboxamide (I) for the preparation of a pharmaceutical administration form as defined in claim 1.

44. A method for the prophylaxis, auxiliary prophylaxis and/or treatment of thrombotic disorders by administering orally administrable solid pharmaceutical administration forms which contain active ingredient (I) and have a modified release as defined in claim 1.